abnormal hepatic expression: Topics by Science.gov

Sample records for abnormal hepatic expression

Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome.

PubMed

Parvaiz, Fahed; Manzoor, Sobia; Iqbal, Jawed; McRae, Steven; Javed, Farrakh; Ahmed, Qazi Laeeque; Waris, Gulam

2014-05-01

Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.
Downregulation of SIRT1 signaling underlies hepatic autophagy impairment in glycogen storage disease type Ia

PubMed Central

Cho, Jun-Ho; Pan, Chi-Jiunn; Anduaga, Javier

2017-01-01

A deficiency in glucose-6-phosphatase-α (G6Pase-α) in glycogen storage disease type Ia (GSD-Ia) leads to impaired glucose homeostasis and metabolic manifestations including hepatomegaly caused by increased glycogen and neutral fat accumulation. A recent report showed that G6Pase-α deficiency causes impairment in autophagy, a recycling process important for cellular metabolism. However, the molecular mechanism underlying defective autophagy is unclear. Here we show that in mice, liver-specific knockout of G6Pase-α (L-G6pc-/-) leads to downregulation of sirtuin 1 (SIRT1) signaling that activates autophagy via deacetylation of autophagy-related (ATG) proteins and forkhead box O (FoxO) family of transcriptional factors which transactivate autophagy genes. Consistently, defective autophagy in G6Pase-α-deficient liver is characterized by attenuated expressions of autophagy components, increased acetylation of ATG5 and ATG7, decreased conjugation of ATG5 and ATG12, and reduced autophagic flux. We further show that hepatic G6Pase-α deficiency results in activation of carbohydrate response element-binding protein, a lipogenic transcription factor, increased expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a lipid regulator, and suppressed expression of PPAR-α, a master regulator of fatty acid β-oxidation, all contributing to hepatic steatosis and downregulation of SIRT1 expression. An adenovirus vector-mediated increase in hepatic SIRT1 expression corrects autophagy defects but does not rectify metabolic abnormalities associated with G6Pase-α deficiency. Importantly, a recombinant adeno-associated virus (rAAV) vector-mediated restoration of hepatic G6Pase-α expression corrects metabolic abnormalities, restores SIRT1-FoxO signaling, and normalizes defective autophagy. Taken together, these data show that hepatic G6Pase-α deficiency-mediated down-regulation of SIRT1 signaling underlies defective hepatic autophagy in GSD-Ia. PMID:28558013
Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance

PubMed Central

Al-Share, Qusai Y.; DeAngelis, Anthony M.; Lester, Sumona Ghosh; Bowman, Thomas A.; Ramakrishnan, Sadeesh K.; Abdallah, Simon L.; Russo, Lucia; Patel, Payal R.; Kaw, Meenakshi K.; Raphael, Christian K.; Kim, Andrea Jung; Heinrich, Garrett; Lee, Abraham D.; Kim, Jason K.; Kulkarni, Rohit N.; Philbrick, William M.

2015-01-01

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic β-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance. PMID:25972571
Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by (1)H-NMR-based metabonomics.

PubMed

Dan Yue; Zhang, Yuwei; Cheng, Liuliu; Ma, Jinhu; Xi, Yufeng; Yang, Liping; Su, Chao; Shao, Bin; Huang, Anliang; Xiang, Rong; Cheng, Ping

2016-04-14

Hepatitis B virus X protein (HBx) plays an important role in HBV-related hepatocarcinogenesis; however, mechanisms underlying HBx-mediated carcinogenesis remain unclear. In this study, an NMR-based metabolomics approach was applied to systematically investigate the effects of HBx on cell metabolism. EdU incorporation assay was conducted to examine the effects of HBx on DNA synthesis, an important feature of nucleic acid metabolism. The results revealed that HBx disrupted metabolism of glucose, lipids, and amino acids, especially nucleic acids. To understand the potential mechanism of HBx-induced abnormalities of nucleic acid metabolism, gene expression profiles of HepG2 cells expressing HBx were investigated. The results showed that 29 genes involved in DNA damage and DNA repair were differentially expressed in HBx-expressing HepG2 cells. HBx-induced DNA damage was further demonstrated by karyotyping, comet assay, Western blotting, immunofluorescence and immunohistochemistry analyses. Many studies have previously reported that DNA damage can induce abnormalities of nucleic acid metabolism. Thus, our results implied that HBx initially induces DNA damage, and then disrupts nucleic acid metabolism, which in turn blocks DNA repair and induces the occurrence of hepatocellular carcinoma (HCC). These findings further contribute to our understanding of the occurrence of HCC.
PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity

PubMed Central

Matsumoto, Michihiro; Ogawa, Wataru; Akimoto, Kazunori; Inoue, Hiroshi; Miyake, Kazuaki; Furukawa, Kensuke; Hayashi, Yoshitake; Iguchi, Haruhisa; Matsuki, Yasushi; Hiramatsu, Ryuji; Shimano, Hitoshi; Yamada, Nobuhiro; Ohno, Shigeo; Kasuga, Masato; Noda, Tetsuo

2003-01-01

PKCλ is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKCλ specifically in the liver (L-λKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element–binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-λKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKCλ and was mimicked by overexpression of WT PKCλ. Restoration of PKCλ expression in the liver of L-λKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKCλ is thus a determinant of hepatic lipid content and whole-body insulin sensitivity. PMID:12975478
Nonselective inhibition of prostaglandin-endoperoxide synthase by naproxen ameliorates hepatic injury in animals with acute or chronic liver injury

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Gupta, Sanjeev

2014-01-01

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury. PMID:24220607
Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Ying

Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined bymore » molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and inhibiting HSC growth.« less
Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor.

PubMed

Yoshino, Satoshi; Satoh, Tetsurou; Yamada, Masanobu; Hashimoto, Koshi; Tomaru, Takuya; Katano-Toki, Akiko; Kakizaki, Satoru; Okada, Shuichi; Shimizu, Hiroyuki; Ozawa, Atsushi; Tuchiya, Takafumi; Ikota, Hayato; Nakazato, Yoichi; Mori, Munemasa; Matozaki, Takashi; Sasaki, Tsutomu; Kitamura, Tadahiro; Mori, Masatomo

2014-09-01

Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.
Decreased C-reactive protein induces abnormal vascular structure in a rat model of liver dysfunction induced by bile duct ligation.

PubMed

Jun, Ji Hye; Choi, Jong Ho; Bae, Si Hyun; Oh, Seh Hoon; Kim, Gi Jin

2016-09-01

Chronic liver disease leads to liver fibrosis, and although the liver does have a certain regenerative capacity, this disease is associated with dysfunction of the liver vessels. C-reactive protein (CRP) is produced in the liver and circulated from there for metabolism. CRP was recently shown to inhibit angiogenesis by inducing endothelial cell dysfunction. The objective of this study was to determine the effect of CRP levels on angiogenesis in a rat model of liver dysfunction induced by bile duct ligation (BDL). The diameter of the hepatic vein was analyzed in rat liver tissues using hematoxylin and eosin (H&E) staining. The expression levels of angiogenic factors, albumin, and CRP were analyzed by real-time PCR and Western blotting. A tube formation assay was performed to confirm the effect of CRP on angiogenesis in human umbilical vein endothelial cells (HUVECs) treated with lithocholic acid (LCA) and siRNA-CRP. The diameter of the hepatic portal vein increased significantly with the progression of cirrhosis. The expression levels of angiogenic factors were increased in the cirrhotic liver. In contrast, the expression levels of albumin and CRP were significantly lower in the liver tissue obtained from the BDL rat model than in the normal liver. The CRP level was correlated with the expression of albumin in hepatocytes treated with LCA and siRNA-CRP. Tube formation was significantly decreased in HUVECs when they were treated with LCA or a combination of LCA and siRNA-CRP. CRP seems to be involved in the abnormal formation of vessels in hepatic disease, and so it could be a useful diagnostic marker for hepatic disease.
Fish oil improves lipid profile in juvenile rats with intrauterine growth retardation by altering the transcriptional expression of lipid-related hepatic genes.

PubMed

Chen, Lian-Hui; Liang, Li; Fang, Yan-Lan; Wang, Ying-Min; Zhu, Wei-Fen

2016-10-01

To determine whether maternal intrauterine undernutrition and post-weaning fish oil intake influence lipid profile in juvenile offspring, and explore the possible mechanisms at transcriptional levels. After weaning, 32 control offspring and 24 intrauterine growth retardation (IUGR) offspring were randomly allocated to standard chow or fish oil diet. At 10 weeks, fasting plasma glucose, triglycerides, total cholesterol and expressions of related hepatic genes were examined. IUGR offspring without catch-up growth tended to develop hyperglycemia, dyslipidemia and hepatic steatosis. Down-regulation of CPT-1 and LDLR at transcriptional levels were found in IUGR offspring. Early short-term fish oil intervention reversed these unfavorable changes in juvenile rats with IUGR. The mechanisms might be mediated by decreased expression of ACC-1, increased expression of CPT-1, LDLR and ABCG5. These data suggest that IUGR offspring already present lipid abnormality in juvenile stage, and early short-term fish oil consumption is beneficial to prevent these unfavorable changes.
Attenuation of oxidative stress and cardioprotective effects of zinc supplementation in experimental diabetic rats.

PubMed

Barman, Susmita; Srinivasan, Krishnapura

2017-02-01

Oxidative stress plays a major role in the pathogenesis of diabetes mellitus, which further exacerbates damage of cardiac, hepatic and other tissues. We have recently reported that Zn supplementation beneficially modulates hyperglycaemia and hypoinsulinaemia, with attendant reduction of associated metabolic abnormalities in diabetic rats. The present study assessed the potential of Zn supplementation in modulating oxidative stress and cardioprotective effects in diabetic rats. Diabetes was induced in Wistar rats with streptozotocin, and groups of diabetic rats were treated with 5- and 10-fold dietary Zn interventions (0·19 and 0·38 g Zn/kg diet) for 6 weeks. The markers of oxidative stress, antioxidant enzyme activities and concentrations of antioxidant molecules, lipid profile, and expressions of fibrosis and pro-apoptotic factors in the cardiac tissue were particularly assessed. Supplemental Zn showed significant attenuation of diabetes-induced oxidative stress in terms of altered antioxidant enzyme activities and increased the concentrations of antioxidant molecules. Hypercholesterolaemia and hyperlipidaemia were also significantly countered by Zn supplementation. Along with attenuated oxidative stress, Zn supplementation also showed significant cardioprotective effects by altering the mRNA expressions of fibrosis and pro-apoptotic factors (by >50 %). The expression of lipid oxidative marker 4-hydroxy-2-nonenal (4-HNE) protein in cardiac tissue of diabetic animals was rectified (68 %) by Zn supplementation. Elevated cardiac and hepatic markers in circulation and pathological abnormalities in cardiac and hepatic tissue architecture of diabetic animals were ameliorated by dietary Zn intervention. The present study indicates that Zn supplementation can attenuate diabetes-induced oxidative stress in circulation as well as in cardiac and hepatic tissues.
Gallic acid ameliorates hyperglycemia and improves hepatic carbohydrate metabolism in rats fed a high-fructose diet.

PubMed

Huang, Da-Wei; Chang, Wen-Chang; Wu, James Swi-Bea; Shih, Rui-Wen; Shen, Szu-Chuan

2016-02-01

Herein, we investigated the hypoglycemic effect of plant gallic acid (GA) on glucose uptake in an insulin-resistant cell culture model and on hepatic carbohydrate metabolism in rats with a high-fructose diet (HFD)-induced diabetes. Our hypothesis is that GA ameliorates hyperglycemia via alleviating hepatic insulin resistance by suppressing hepatic inflammation and improves abnormal hepatic carbohydrate metabolism by suppressing hepatic gluconeogenesis and enhancing the hepatic glycogenesis and glycolysis pathways in HFD-induced diabetic rats. Gallic acid increased glucose uptake activity by 19.2% at a concentration of 6.25 μg/mL in insulin-resistant FL83B mouse hepatocytes. In HFD-induced diabetic rats, GA significantly alleviated hyperglycemia, reduced the values of the area under the curve for glucose in an oral glucose tolerance test, and reduced the scores of the homeostasis model assessment of insulin resistance index. The levels of serum C-peptide and fructosamine and cardiovascular risk index scores were also significantly decreased in HFD rats treated with GA. Moreover, GA up-regulated the expression of hepatic insulin signal transduction-related proteins, including insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3 kinase, Akt/protein kinase B, and glucose transporter 2, in HFD rats. Gallic acid also down-regulated the expression of hepatic gluconeogenesis-related proteins, such as fructose-1,6-bisphosphatase, and up-regulated expression of hepatic glycogen synthase and glycolysis-related proteins, including hexokinase, phosphofructokinase, and aldolase, in HFD rats. Our findings indicate that GA has potential as a health food ingredient to prevent diabetes mellitus. Copyright © 2016 Elsevier Inc. All rights reserved.
Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-ι.

PubMed

Sajan, Mini P; Nimal, Sonali; Mastorides, Stephen; Acevedo-Duncan, Mildred; Kahn, C Ronald; Fields, Alan P; Braun, Ursula; Leitges, Michael; Farese, Robert V

2012-04-01

Excessive activity of hepatic atypical protein kinase (aPKC) is proposed to play a critical role in mediating lipid and carbohydrate abnormalities in obesity, the metabolic syndrome, and type 2 diabetes mellitus. In previous studies of rodent models of obesity and type 2 diabetes mellitus, adenoviral-mediated expression of kinase-inactive aPKC rapidly reversed or markedly improved most if not all metabolic abnormalities. Here, we examined effects of 2 newly developed small-molecule PKC-ι/λ inhibitors. We used the mouse model of heterozygous muscle-specific knockout of PKC-λ, in which partial deficiency of muscle PKC-λ impairs glucose transport in muscle and thereby causes glucose intolerance and hyperinsulinemia, which, via hepatic aPKC activation, leads to abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. One inhibitor, 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)], binds to the substrate-binding site of PKC-λ/ι, but not other PKCs. The other inhibitor, aurothiomalate, binds to cysteine residues in the PB1-binding domains of aPKC-λ/ι/ζ and inhibits scaffolding. Treatment with either inhibitor for 7 days inhibited aPKC, but not Akt, in liver and concomitantly improved insulin signaling to Akt and aPKC in muscle and adipocytes. Moreover, both inhibitors diminished excessive expression of hepatic, aPKC-dependent lipogenic, proinflammatory, and gluconeogenic factors; and this was accompanied by reversal or marked improvements in hyperglycemia, hyperinsulinemia, abdominal obesity, hepatosteatosis, hypertriglyceridemia, and hypercholesterolemia. Our findings highlight the pathogenetic importance of insulin signaling to hepatic PKC-ι in obesity, the metabolic syndrome, and type 2 diabetes mellitus and suggest that 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl-[1R-(1a,2b,3b,4a)] and aurothiomalate or similar agents that selectively inhibit hepatic aPKC may be useful treatments. Published by Elsevier Inc.
Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-04-15

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis. The enhanced hepatic glycolysis is reflected by increased lactate accumulation, increased expression of many glycolytic enzymes, and elevated expression of c-Myc that stimulates glycolysis. The increased HMS is reflected by increased glucose-6-phosphate dehydrogenase activity and elevated production of NADPH and the reduced glutathione. We have previously shown that restoration of hepatic G6Pase-α expression in G6Pase-α-deficient liver corrects metabolic abnormalities, normalizes autophagy, and prevents HCA/HCC development in GSD-Ia. We now show that restoration of hepatic G6Pase-α expression normalizes both glycolysis and HMS in GSD-Ia. Moreover, the HCA/HCC lesions in L-G6pc-/- mice exhibit elevated levels of hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) which play an important role in aerobic glycolysis and cancer cell proliferation. Taken together, hepatic G6Pase-α deficiency causes metabolic reprogramming, leading to enhanced glycolysis and elevated HMS that along with impaired autophagy can contribute to HCA/HCC development in GSD-Ia. Published by Elsevier Inc.
Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease.

PubMed

Fukuo, Yuka; Yamashina, Shunhei; Sonoue, Hiroshi; Arakawa, Atsushi; Nakadera, Eisuke; Aoyama, Tomonori; Uchiyama, Akira; Kon, Kazuyoshi; Ikejima, Kenichi; Watanabe, Sumio

2014-09-01

Recent evidences indicate that hepatic steatosis suppresses autophagic proteolysis. The present study evaluated the correlation between autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease (NAFLD). Liver biopsy specimens were obtained from patients with chronic liver diseases (chronic hepatitis C [CHC; n = 20], chronic hepatitis B [CHB; n = 16], primary biliary cirrhosis [PBC; n = 23], NAFLD [n = 22] and control [n = 14]). The number of autophagic vesicles in hepatocytes was counted by using transmission electron microscopy. Expression of cathepsin B, D, L and p62 in the liver section was analyzed by immunohistochemical staining. The histological severity of NAFLD is assessed by NAFLD activity score (NAS). The number of autophagic vesicles in hepatocytes was significantly increased in both CHC and NAFLD groups, but not CHB and PBC, more than control. Although hepatocytes with aggregation of p62 were observed in less than 15% of CHC, p62 aggregation was detected in approximately 65% of NAFLD. Cathepsin B, D and L expression was significantly suppressed in the liver from NAFLD patients. Suppression of cathepsin B, D and L expression was not observed in CHB, CHC and PBC. In NAFLD patients, p62 aggregation was correlated with serum alanine aminotransferase value and inflammatory activity by NAS. These results indicate that a decrease in hepatic cathepsin expression in NAFLD is associated with autophagic dysfunction. Hepatic inflammation correlates with autophagic dysfunction in NAFLD. These findings indicate that the suppression of autophagic proteolysis by hepatic steatosis is involved in the pathogenesis of NAFLD. © 2013 The Japan Society of Hepatology.
Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter

PubMed Central

2013-01-01

Background Betaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation. Methods Male wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE−/− mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target genes expression levels and the methylation status of the PPAR alpha gene were determined. Results ApoE−/− mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE−/− mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE−/− mice. In parallel, PPAR alpha promoter methylation level were slightly increased in ApoE−/− mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE−/− mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration. Conclusions Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression. PMID:23497035
Underlying pathways for interferon risk to type II diabetes mellitus.

PubMed

Abdel-Hamid, Nabil; Jubori, Taghreed Al; Farhan, Amaal; Mahrous, Mariam; Gouri, Adel; Awad, Ezzat; Breuss, Johannes

2013-11-01

It has been known that chronic liver treatments interfere with blood glucose metabolism. It was recognized that diabetes mellitus among chronic hepatitis C was greater in other types of chronic liver diseases. Hepatitis C directly promotes insulin resistance through the proteosomal degradation of insulin resistance substrate. It suppressed hepatocyte glucose uptake through down-regulation of surface expression of glucose transporter. Long-term exposure to cytokine over expression seems to be cytotoxic to both beta cells of the pancreas and to hepatocytes. Elevated tumor necrosis factor-a, or its neutralization, increased insulin sensitivity. Interferon-a may also elevate the serum level of interleukin-1 which is cytotoxic to pancreatic islet cells. Both diabetes mellitus and resistance to interferon-a therapy are abnormally mediated by over-expression of suppressor of cytokine signaling-1 in hepatocytes of chronic hepatitis C patients. These data suggest that interferon-a therapy should be administered with caution in patients showing any predisposition to Diabetes mellitus. Anti inflammatory therapy is critically recommended as a protector against disease development due to cytokine mediated Diabetes mellitus during hepatitis C therapy, since inflammation seems to be a main candidate to interferon suspected diabetogenesis.
Effects of 4-nonylphenol on oxidant/antioxidant balance system inducing hepatic steatosis in male rat.

PubMed

Kourouma, Ansoumane; Keita, Hady; Duan, Peng; Quan, Chao; Bilivogui, Koikoi Kebe; Qi, Suqin; Christiane, Ndjiembi Adjonga; Osamuyimen, Aidogie; Yang, Kedi

2015-01-01

An emerging literature suggests that early life exposure to 4-nonylphenol (4-NP), a widespread endocrine disrupting chemical, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that intraperitoneal administration of 4-NP induces hepatic steatosis in rat. 24 male Sprague-Dawley rats were administered with 4-NP (0, 2, 10 and 50 mg/kg b.wt) in corn oil for 30 days. Liver histology, biochemical analysis and gene expression profiling were examined. After treatment, abnormal liver morphology and function were observed in the 4-NP-treated rat, and significant changes in gene expression an indicator of hepatic steatosis and apoptosis were observed compared with controls. Up-regulated genes involved in apoptosis, hepatotoxity and oxidative stress, increased ROS and decrease of antioxidant enzyme were observed in the 4-NP exposed rat. Extensive fatty accumulation in liver section and elevated serum GOT, GPT, LDH and γ-GT were also observed. Incidence and severity of liver steatosis was scored and taken into consideration (steatosis, ballooning and lobular inflammation). Hepatocytes apoptosis could promote NAFLD progression; Fas/FasL, TNF-α and Caspase-9 mRNA activation were important contributing factors to hepatic steatosis. These findings provide the first evidence that 4-NP affects the gene expression related to liver hepatotoxicity, which is correlated with hepatic steatosis.
Computer-aided assessment of hepatic contour abnormalities as an imaging biomarker for the prediction of hepatocellular carcinoma development in patients with chronic hepatitis C.

PubMed

Goshima, Satoshi; Kanematsu, Masayuki; Kondo, Hiroshi; Watanabe, Haruo; Noda, Yoshifumi; Fujita, Hiroshi; Bae, Kyongtae T

2015-05-01

To evaluate whether a hepatic fibrosis index (HFI), quantified on the basis of hepatic contour abnormality, is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. Our institutional review board approved this retrospective study and written informed consent was waved. During a 14-month period, consecutive 98 patients with chronic hepatitis C who had no medical history of HCC treatment (56 men and 42 women; mean age, 70.7 years; range, 48-91 years) were included in this study. Gadoxetic acid-enhanced hepatocyte specific phase was used to detect and analyze hepatic contour abnormality. Hepatic contour abnormality was quantified and converted to HFI using in-house proto-type software. We compared HFI between patients with (n=54) and without HCC (n=44). Serum levels of albumin, total bilirubin, aspartate transferase, alanine transferase, percent prothrombin time, platelet count, alpha-fetoprotein, protein induced by vitamin K absence-II, and HFI were tested as possible risk factors for the development of HCC by determining the odds ratio with logistic regression analysis. HFIs were significantly higher in patients with HCC (0.58±0.86) than those without (0.36±0.11) (P<0.001). Logistic analysis revealed that only HFI was a significant risk factor for HCC development with an odds ratio (95% confidence interval) of 26.4 (9.0-77.8) using a cutoff value of 0.395. The hepatic fibrosis index, generated using a computer-aided assessment of hepatic contour abnormality, may be a useful imaging biomarker for the prediction of HCC development in patients with chronic hepatitis C. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Lack of cilia and differentiation defects in the liver of human foetuses with the Meckel syndrome.

PubMed

Clotman, Frédéric; Libbrecht, Louis; Killingsworth, Murray C; Loo, Christine C K; Roskams, Tania; Lemaigre, Frédéric P

2008-03-01

Meckel syndrome is an autosomal-recessive disease characterized by a combination of renal cysts, anomalies of the central nervous system, polydactyly and ductal plate malformations (DPM), which are hepatic anomalies consisting of excessive and abnormal foetal biliary structures. Among the genomic loci associated with Meckel syndrome, mutations in four genes were recently identified. These genes code for proteins associated with primary cilia and are possibly involved in cell differentiation. The aim of the present work was to investigate the formation of the primary cilia and the differentiation of the hepatic cells in foetuses with Meckel syndrome. Sections of livers from human foetuses with Meckel syndrome were analysed by immunofluorescence, immunohistochemistry and electron microscopy. The primary cilia of the biliary cells were absent in some Meckel foetuses, but were present in others. In addition, defects in hepatic differentiation were observed in Meckel livers, as evidenced by the presence of hybrid cells co-expressing hepatocytic and biliary markers. Defects in cilia formation occur in some Meckel livers, and most cases show DPM associated with abnormal hepatic cell differentiation. Because differentiation precedes the formation of the cilia during liver development, we propose that defective differentiation may constitute the initial defect in the liver of Meckel syndrome foetuses.

Different cytokeratin and neuronal cell adhesion molecule staining patterns in focal nodular hyperplasia and hepatic adenoma and their significance

PubMed Central

Iyer, Anita; Robert, Marie E.; Bifulco, Carlo B.; Salem, Ronald R.; Jain, Dhanpat

2013-01-01

Summary Differentiating focal nodular hyperplasia from hepatic adenoma can be challenging. Cytokeratin 7, neuronal cell adhesion molecule, and cytokeratin 19 are differentially expressed in hepatocytes, biliary epithelium, and possibly hepatic progenitor/stem cells. CD34 is known to have altered expression patterns in the hepatic endothelium in conditions associated with abnormal perfusion and in hepatocellular carcinoma. The purpose of this study was to examine the expression pattern of these markers in focal nodular hyperplasia and hepatic adenoma and assess their diagnostic use. Ten resection specimens each of hepatic adenoma and focal nodular hyperplasia (including a case of telangiectatic focal nodular hyperplasia) were selected for the study. Immunohistochemical analysis was performed using antibodies against cytokeratin 7, cytokeratin 19, neuronal cell adhesion molecule, and CD34 on formalin-fixed, paraffin-embedded sections from each case. The staining patterns and intensity for each marker were analyzed. In hepatic adenoma, the cytokeratin 7 stain revealed strong positivity in hepatocytes in patches, with a gradual decrease in the staining intensity as the cells differentiated towards mature hepatocytes. Although bile ducts were typically absent in hepatic adenoma, occasional ductules could be identified with cytokeratin 7 stain. In focal nodular hyperplasia, cytokeratin 7 showed strong staining of the biliary epithelium within the fibrous septa and staining of the peripheral hepatocytes of most lobules that was focal and weaker than hepatic adenoma. Cytokeratin 19 and neuronal cell adhesion molecule showed patchy and moderate staining in the biliary epithelium of the ductules in focal nodular hyperplasia. While in the hepatic adenoma, cytokeratin 19 showed only rare positivity in occasional cells within ductules, and neuronal cell adhesion molecule marked occasional isolated cells in the lesion. CD34 showed staining of sinusoids in the inflow areas (periportal areas) in both focal nodular hyperplasia and hepatic adenoma. One case of telangiectatic focal nodular hyperplasia revealed both hepatic adenoma–like and focal nodular hyperplasia–like staining patterns. Distinct cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule staining patterns are seen in hepatic adenoma and focal nodular hyperplasia possibly suggest activation of different subsets of hepatic progenitor/stem cell and can be diagnostically useful. PMID:18602664
Molecular Diagnostics in the Neoplasms of the Pancreas, Liver, Gallbladder, and Extrahepatic Biliary Tract: 2018 Update.

PubMed

Zhang, Lei; Bluth, Martin H; Bhalla, Amarpreet

2018-06-01

Pancreatic neoplasms, including ductal adenocarcinoma, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and pancreatoblastoma, are associated with different genetic abnormalities. Hepatic adenomas with beta-catenin exon 3 mutation are associated with a high risk of malignancy. Hepatic adenoma with arginosuccinate synthetase 1 expression or sonic hedgehog mutations are associated with a risk of bleeding. Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations. Copyright © 2018 Elsevier Inc. All rights reserved.
Interferon-alpha receptor 1 mRNA expression in peripheral blood mononuclear cells is associated with response to interferon-alpha therapy of patients with chronic hepatitis C.

PubMed

Massirer, K B; Hirata, M H; Silva, A E B; Ferraz, M L G; Nguyen, N Y; Hirata, R D C

2004-05-01

Interferon (IFN)-alpha receptor mRNA expression in liver of patients with chronic hepatitis C has been shown to be a response to IFN-alpha therapy. The objective of the present study was to determine whether the expression of mRNA for subunit 1 of the IFN-alpha receptor (IFNAR1) in peripheral blood mononuclear cells (PBMC) is associated with the response to IFN-alpha in patients with chronic hepatitis C. Thirty patients with positive anti-HCV and HCV-RNA, and abnormal levels of alanine aminotransferase in serum were selected and treated with IFN-alpha 2b for one year. Those with HBV or HIV infection, or using alcohol were not included. Thirteen discontinued the treatment and were not evaluated. The IFN-alpha response was monitored on the basis of alanine aminotransferase level and positivity for HCV-RNA in serum. IFNAR1-mRNA expression in PBMC was measured by reverse transcription-polymerase chain reaction before and during the first three months of therapy. The results are reported as IFNAR1-mRNA/beta-actin-mRNA ratio (mean +/- SD). Before treatment, responder patients had significantly higher IFNAR1-mRNA expression in PBMC (0.67 +/- 0.15; N = 5; P < 0.05) compared to non-responders (0.35 +/- 0.17; N = 12) and controls (0.30 +/- 0.16; N = 9). Moreover, IFNAR1-mRNA levels were significantly reduced after 3 months of treatment in responders, whereas there were no differences in IFNAR1 expression in non-responders during IFN-alpha therapy. Basal IFNAR1-mRNA expression was not correlated with the serum level of alanine and aspartate aminotransferases or the presence of cirrhosis. The present results suggest that IFNAR1-mRNA expression in PBMC is associated with IFN-alpha response to hepatitis C and may be useful for monitoring therapy in patients with chronic hepatitis C.
Immunization with a Recombinant Vaccinia Virus That Encodes Nonstructural Proteins of the Hepatitis C Virus Suppresses Viral Protein Levels in Mouse Liver

PubMed Central

Sekiguchi, Satoshi; Kimura, Kiminori; Chiyo, Tomoko; Ohtsuki, Takahiro; Tobita, Yoshimi; Tokunaga, Yuko; Yasui, Fumihiko; Tsukiyama-Kohara, Kyoko; Wakita, Takaji; Tanaka, Toshiyuki; Miyasaka, Masayuki; Mizuno, Kyosuke; Hayashi, Yukiko; Hishima, Tsunekazu; Matsushima, Kouji; Kohara, Michinori

2012-01-01

Chronic hepatitis C, which is caused by infection with the hepatitis C virus (HCV), is a global health problem. Using a mouse model of hepatitis C, we examined the therapeutic effects of a recombinant vaccinia virus (rVV) that encodes an HCV protein. We generated immunocompetent mice that each expressed multiple HCV proteins via a Cre/loxP switching system and established several distinct attenuated rVV strains. The HCV core protein was expressed consistently in the liver after polyinosinic acid–polycytidylic acid injection, and these mice showed chronic hepatitis C-related pathological findings (hepatocyte abnormalities, accumulation of glycogen, steatosis), liver fibrosis, and hepatocellular carcinoma. Immunization with one rVV strain (rVV-N25), which encoded nonstructural HCV proteins, suppressed serum inflammatory cytokine levels and alleviated the symptoms of pathological chronic hepatitis C within 7 days after injection. Furthermore, HCV protein levels in liver tissue also decreased in a CD4 and CD8 T-cell-dependent manner. Consistent with these results, we showed that rVV-N25 immunization induced a robust CD8 T-cell immune response that was specific to the HCV nonstructural protein 2. We also demonstrated that the onset of chronic hepatitis in CN2-29(+/−)/MxCre(+/−) mice was mainly attributable to inflammatory cytokines, (tumor necrosis factor) TNF-α and (interleukin) IL-6. Thus, our generated mice model should be useful for further investigation of the immunological processes associated with persistent expression of HCV proteins because these mice had not developed immune tolerance to the HCV antigen. In addition, we propose that rVV-N25 could be developed as an effective therapeutic vaccine. PMID:23284733
Immunization with a recombinant vaccinia virus that encodes nonstructural proteins of the hepatitis C virus suppresses viral protein levels in mouse liver.

PubMed

Sekiguchi, Satoshi; Kimura, Kiminori; Chiyo, Tomoko; Ohtsuki, Takahiro; Tobita, Yoshimi; Tokunaga, Yuko; Yasui, Fumihiko; Tsukiyama-Kohara, Kyoko; Wakita, Takaji; Tanaka, Toshiyuki; Miyasaka, Masayuki; Mizuno, Kyosuke; Hayashi, Yukiko; Hishima, Tsunekazu; Matsushima, Kouji; Kohara, Michinori

2012-01-01

Chronic hepatitis C, which is caused by infection with the hepatitis C virus (HCV), is a global health problem. Using a mouse model of hepatitis C, we examined the therapeutic effects of a recombinant vaccinia virus (rVV) that encodes an HCV protein. We generated immunocompetent mice that each expressed multiple HCV proteins via a Cre/loxP switching system and established several distinct attenuated rVV strains. The HCV core protein was expressed consistently in the liver after polyinosinic acid-polycytidylic acid injection, and these mice showed chronic hepatitis C-related pathological findings (hepatocyte abnormalities, accumulation of glycogen, steatosis), liver fibrosis, and hepatocellular carcinoma. Immunization with one rVV strain (rVV-N25), which encoded nonstructural HCV proteins, suppressed serum inflammatory cytokine levels and alleviated the symptoms of pathological chronic hepatitis C within 7 days after injection. Furthermore, HCV protein levels in liver tissue also decreased in a CD4 and CD8 T-cell-dependent manner. Consistent with these results, we showed that rVV-N25 immunization induced a robust CD8 T-cell immune response that was specific to the HCV nonstructural protein 2. We also demonstrated that the onset of chronic hepatitis in CN2-29((+/-))/MxCre((+/-)) mice was mainly attributable to inflammatory cytokines, (tumor necrosis factor) TNF-α and (interleukin) IL-6. Thus, our generated mice model should be useful for further investigation of the immunological processes associated with persistent expression of HCV proteins because these mice had not developed immune tolerance to the HCV antigen. In addition, we propose that rVV-N25 could be developed as an effective therapeutic vaccine.
Pathogenesis of Hepatic Encephalopathy

PubMed Central

Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

2012-01-01

Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy. PMID:23316223
Expression of hepatic lipid droplets is decreased in the nitrofen model of congenital diaphragmatic hernia.

PubMed

Takahashi, Hiromizu; Kutasy, Balazs; Friedmacher, Florian; Takahashi, Toshiaki; Puri, Prem

2016-02-01

Prenatal mortality in newborn infants with congenital diaphragmatic hernia (CDH) has been attributed to increased amounts of liver hernia ion through the diaphragmatic defect. Antenatal studies in human and rodent fetus with CDH further demonstrated a contribution of the developing liver in the pathogenesis of CDH. The abnormal hepatic growth in experimental animal models, therefore, indicates a disruption of normal liver development in CDH. However, the underlying structural, histological and functional changes in the liver of animals with CDH remain unclear. We design this study to test the hypothesis that the morphological and cellular liver development is altered in the nitrogen-induced CDH model. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Livers and chest were harvested on D21 and divided into two groups: control (n = 8), nitrofen with CDH (CDH, n = 8). Haematoxylin-eosin (Straub et al. Histopathology 68:617-631, 2013) staining was performed to evaluate underlying morphological changes. Apoptosis was checked by using TUNEL staining and apoptotic cell number was counted on 16-16 slides in 25 fields by two independent viewers. Hepatic lipid droplet expressions were evaluated by hepatic adipose differentiation-related protein (ARDP) expression. Compared to controls markedly increased hypertrophy was seen in CDH group. Significantly increased apoptotic cell numbers were detected in CDH group compared to controls (5.1 ± 1.5 vs 2.1 ± 0.6) (p < 0.05). The relative mRNA expression levels of ARDP were significantly reduced in CDH group compared to controls. Immunohistochemistry showed markedly decreased hepatic ADRP immunoreactivity in CDH fetuses compared to controls. Our findings provide strong evidence of hepatic hypertrophy and increased cell apoptosis in the liver of nitrofen-induced CDH. These morphological changes may affect liver lipid droplet expression function.
Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

PubMed Central

Diaz-Castroverde, Sabela; Gómez-Hernández, Almudena; Fernández, Silvia; García-Gómez, Gema; Di Scala, Marianna; González-Aseguinolaza, Gloria; Fernández-Millán, Elisa; González-Rodríguez, Águeda; García-Bravo, María; Chambon, Pierre; Álvarez, Carmen; Perdomo, Liliana; Beneit, Nuria; Benito, Manuel

2016-01-01

ABSTRACT Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte-specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus. PMID:27562101
Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model.

PubMed

Ohba, Kenji; Sinha, Rohit Anthony; Singh, Brijesh Kumar; Iannucci, Liliana Felicia; Zhou, Jin; Kovalik, Jean-Paul; Liao, Xiao-Hui; Refetoff, Samuel; Sng, Judy Chia Ghee; Leow, Melvin Khee-Shing; Yen, Paul Michael

2017-06-01

Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Adult male mice were treated with daily injections of T3 (20 μg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Although TH receptor (TRα and TRβ) mRNAs decreased slightly after chronic T3 treatment, only TRβ protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRβ protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Decreased hepatic TRβ protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRβ protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations.
Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

PubMed Central

Ohba, Kenji; Sinha, Rohit Anthony; Singh, Brijesh Kumar; Iannucci, Liliana Felicia; Zhou, Jin; Kovalik, Jean-Paul; Liao, Xiao-Hui; Refetoff, Samuel; Sng, Judy Chia Ghee; Leow, Melvin Khee-Shing; Yen, Paul Michael

2017-01-01

Background: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Methods: Adult male mice were treated with daily injections of T3 (20 μg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Results: Although TH receptor (TRα and TRβ) mRNAs decreased slightly after chronic T3 treatment, only TRβ protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRβ protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Conclusions: Decreased hepatic TRβ protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRβ protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations. PMID:28457184
Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xing, Xiaomang; Li, Danyang; Chen, Dilong

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose,more » insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in SHR. • MA inhibited hepatic DGAT2 expression at the mRNA and protein levels. • MA did not affect expression of the genes responsible for fatty acid synthesis. • MA ameliorates fructose-induced fatty liver by inhibiting hepatic DGAT2 in rats.« less
Protective effect of human serum amyloid P on CCl4-induced acute liver injury in mice.

PubMed

Cong, Min; Zhao, Weihua; Liu, Tianhui; Wang, Ping; Fan, Xu; Zhai, Qingling; Bao, Xiaoli; Zhang, Dong; You, Hong; Kisseleva, Tatiana; Brenner, David A; Jia, Jidong; Zhuang, Hui

2017-08-01

Human serum amyloid P (hSAP), a member of the pentraxin family, inhibits the activation of fibrocytes in culture and inhibits experimental renal, lung, skin and cardiac fibrosis. As hepatic inflammation is one of the causes of liver fibrosis, in the present study, we investigated the hepatoprotective effects of hSAP against carbon tetrachloride (CCl4)-induced liver injury. Our data indicated that hSAP attenuated hepatic histopathological abnormalities and significantly decreased inflammatory cell infiltration and pro-inflammatory factor expression. Moreover, CCl4-induced apoptosis in the mouse liver was inhibited by hSAP, as measured by terminal-deoxynucleotidyl transferase mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 expression. hSAP significantly restored the expression of B cell lymphoma/leukemia (Bcl)-2 and suppressed the expression of Bcl-2-associated X protein (Bax) in vivo. The number of hepatocytes in early apoptosis stained with Annexin V was significantly reduced by 28-30% in the hSAP treatment group compared with the CCl4 group, and the expression of Bcl-2 was increased, whereas the expression of Bax and cleaved caspase-3 were significantly inhibited in the hSAP pre-treatment group compared with the CCl4 group. hSAP administration also inhibited the migration and activation of hepatic stellate cells (HSCs) in CCl4-injured liver and suppressed the activation of isolated primary HSCs induced by transforming growth factor (TGF)-β1 in vitro. Collectively, these findings suggest that hSAP exerts a protective effect againts CCl4-induced hepatic injury by suppressing the inflammatory response and hepatocyte apoptosis, potentially by inhibiting HSC activation.
Protective effect of human serum amyloid P on CCl4-induced acute liver injury in mice

PubMed Central

Cong, Min; Zhao, Weihua; Liu, Tianhui; Wang, Ping; Fan, Xu; Zhai, Qingling; Bao, Xiaoli; Zhang, Dong; You, Hong; Kisseleva, Tatiana; Brenner, David A.; Jia, Jidong; Zhuang, Hui

2017-01-01

Human serum amyloid P (hSAP), a member of the pentraxin family, inhibits the activation of fibrocytes in culture and inhibits experimental renal, lung, skin and cardiac fibrosis. As hepatic inflammation is one of the causes of liver fibrosis, in the present study, we investigated the hepatoprotective effects of hSAP against carbon tetrachloride (CCl4)-induced liver injury. Our data indicated that hSAP attenuated hepatic histopathological abnormalities and significantly decreased inflammatory cell infiltration and pro-inflammatory factor expression. Moreover, CCl4-induced apoptosis in the mouse liver was inhibited by hSAP, as measured by terminal-deoxynucleotidyl transferase mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 expression. hSAP significantly restored the expression of B cell lymphoma/leukemia (Bcl)-2 and suppressed the expression of Bcl-2-associated X protein (Bax) in vivo. The number of hepatocytes in early apoptosis stained with Annexin V was significantly reduced by 28–30% in the hSAP treatment group compared with the CCl4 group, and the expression of Bcl-2 was increased, whereas the expression of Bax and cleaved caspase-3 were significantly inhibited in the hSAP pre-treatment group compared with the CCl4 group. hSAP administration also inhibited the migration and activation of hepatic stellate cells (HSCs) in CCl4-injured liver and suppressed the activation of isolated primary HSCs induced by transforming growth factor (TGF)-β1 in vitro. Collectively, these findings suggest that hSAP exerts a protective effect againts CCl4-induced hepatic injury by suppressing the inflammatory response and hepatocyte apoptosis, potentially by inhibiting HSC activation. PMID:28627620
Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort.

PubMed

Arnold, David T; Bentham, Louise M; Jacob, Ruth P; Lilford, Richard J; Girling, Alan J

2011-03-03

Liver function tests (LFTs) are ordered in large numbers in primary care, and the Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study was set up to assess their usefulness in patients with no pre-existing or self-evident liver disease. All patients were tested for chronic viral hepatitis thereby providing an opportunity to compare various strategies for detection of this serious treatable disease. This study uses data from the BALLETS cohort to compare various testing strategies for viral hepatitis in patients who had received an abnormal LFT result. The aim was to inform a strategy for identification of patients with chronic viral hepatitis. We used a cost-minimisation analysis to define a base case and then calculated the incremental cost per case detected to inform a strategy that could guide testing for chronic viral hepatitis. Of the 1,236 study patients with an abnormal LFT, 13 had chronic viral hepatitis (nine hepatitis B and four hepatitis C). The strategy advocated by the current guidelines (repeating the LFT with a view to testing for specific disease if it remained abnormal) was less efficient (more expensive per case detected) than a simple policy of testing all patients for viral hepatitis without repeating LFTs. A more selective strategy of viral testing all patients for viral hepatitis if they were born in countries where viral hepatitis was prevalent provided high efficiency with little loss of sensitivity. A notably high alanine aminotransferase (ALT) level (greater than twice the upper limit of normal) on the initial ALT test had high predictive value, but was insensitive, missing half the cases of viral infection. Based on this analysis and on widely accepted clinical principles, a "fast and frugal" heuristic was produced to guide general practitioners with respect to diagnosing cases of viral hepatitis in asymptomatic patients with abnormal LFTs. It recommends testing all patients where a clear clinical indication of infection is present (e.g. evidence of intravenous drug use), followed by testing all patients who originated from countries where viral hepatitis is prevalent, and finally testing those who have a notably raised ALT level (more than twice the upper limit of normal). Patients not picked up by this efficient algorithm had a risk of chronic viral hepatitis that is lower than the general population.
Hepatitis C virus core protein triggers abnormal porphyrin metabolism in human hepatocellular carcinoma cells.

PubMed

Nakano, Takafumi; Moriya, Kyoji; Koike, Kazuhiko; Horie, Toshiharu

2018-01-01

Porphyria cutanea tarda (PCT), the most common of the human porphyrias, arises from a deficiency of uroporphyrinogen decarboxylase. Studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with PCT. While these observations implicate HCV infection as a risk factor for PCT pathogenesis, the mechanism of interaction between the virus and porphyrin metabolism is unknown. This study aimed to assess the effect of HCV core protein on intracellular porphyrin metabolism to elucidate the link between HCV infection and PCT. The accumulation and excretion of porphyrins after treatment with 5-aminolevulinic acid, a porphyrin precursor, were compared between cells stably expressing HCV core protein and controls. Cells expressing HCV core protein had lower amounts of intracellular protoporphyrin IX and heme and had higher amounts of excreted coproporphyrin III, the oxidized form of coproporphyrinogen III, compared with controls. These observations suggest that HCV core protein affects porphyrin metabolism and facilitates the export of excess coproporphyrinogen III and/or coproporphyrin III, possibly via porphyrin transporters. Real-time PCR analysis revealed that the presence of HCV core protein increased the mRNA expression of porphyrin exporters ABCG2 and FLVCR1. Western blot analysis showed a higher expression level of FLVCR1, but not ABCG2, as well as a higher expression level of mature ALAS1, which is the rate-limiting enzyme in the heme synthesis pathway, in HCV core protein-expressing cells compared with controls. The data indicate that HCV core protein induced abnormal intracellular porphyrin metabolism, with an over-excretion of coproporphyrin III. These findings may partially account for the susceptibility of HCV-infected individuals to PCT development.
MicroRNA-21 regulates hepatic glucose metabolism by targeting FOXO1.

PubMed

Luo, Ailing; Yan, Haibo; Liang, Jichao; Du, Chunyuan; Zhao, Xuemei; Sun, Lijuan; Chen, Yong

2017-09-05

Abnormal activation of hepatic gluconeogenesis is a major contributor to fasting hyperglycemia in type 2 diabetes; however, the potential role of microRNAs in gluconeogenesis remains unclear. Here, we showed that hepatic expression levels of microRNA-21 (miR-21) were decreased in db/db and high-fat diet (HFD)-induced diabetic mice. Adenovirus-mediated overexpression of miR-21 decreased the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and inhibited glucose production in primary mouse hepatocytes. Silencing of miR-21 reversed this effect. Overexpression of miR-21 in the livers of db/db and HFD-induced mice was able to suppress hepatic gluconeogenesis, subsequently decreasing blood glucose levels and improving glucose and insulin intolerance. Furthermore, overexpression of miR-21 in primary mouse hepatocytes and mouse livers decreased the protein levels of FOXO1 and increased hepatic insulin sensitivity. By contrast, silencing of miR-21 increased the protein levels of FOXO1, subsequently leading to a decrease in insulin sensitivity and impaired glucose intolerance in C57BL/6 mice fed with high-fat diet for 4weeks. Finally, we confirmed that FOXO1 was a potential target of miR-21. These results suggest that miR-21 is a critical regulator in hepatic gluconeogenesis and may provide a novel therapeutic target for treating insulin resistance and type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.
Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

PubMed

Ganji, Shobha H; Kukes, Gary D; Lambrecht, Nils; Kashyap, Moti L; Kamanna, Vaijinath S

2014-02-15

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.
Transient elastography as a noninvasive assessment tool for hepatopathies of different etiology in pediatric type 1 diabetes mellitus.

PubMed

Elkabbany, Zeinab A; Elbarbary, Nancy S; Ismail, Eman A; Mohamed, Nesrine A; Ragab, Dina; Abdel Alem, Shereen; Ezzat, Yasmine M; Maurice, Sarah S; Hashem, Noha U

2017-01-01

To identify the prevalence and effect of hepatopathies of different etiologies among pediatric patients with type 1 diabetes mellitus (T1DM) using transient elastography (TE) and its relation to glycemic control. One hundred T1DM patients were studied focusing on liver functions, fasting lipid profile, hemoglobin A1c (HbA1c), hepatitis C virus (HCV), serum immunoglobulins, autoimmune antibodies; anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver kidney microsomal antibody (anti-LKM). Abdominal ultrasound was performed and TE was done for patients with HCV, positive autoimmune antibody and/or abnormal ultrasound findings. Thirty-one patients were found to have one or more hepatic abnormalities; clinical hepatomegaly in 8%, elevated alanine aminotransferase (ALT) in 10%, HCV in 6%, autoimmune hepatitis (AIH) in 11% (10 were positive for ASMA and 2 were positive for ANA while anti-LKM antibodies were negative) and abnormal hepatic ultrasound in 20% (12 non-alcoholic fatty liver disease, 5 AIH, 2 HCV, 1 Mauriac syndrome). Mean liver stiffness in those 31 patients was 7.0±2.1kPa (range, 3.1-11.8kPa); 24 were Metavir F0-F1, 7 were F2-F3 while none was F4. Type 1 diabetic patients with abnormal hepatic ultrasound had higher fasting blood glucose, HbA1c and total cholesterol than those with normal findings. Liver stiffness was significantly higher in patients with abnormal liver ultrasound compared with normal sonography. Liver stiffness was positively correlated to HbA1c and ALT. Hepatic abnormalities are prevalent in T1DM and related to poor metabolic control. TE provides a non-invasive method for detection of hepatopathy-induced fibrosis. Copyright © 2017 Elsevier Inc. All rights reserved.
Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

PubMed

Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis C; Kathiresan, Sekar; Cohen, David E; Whetstine, Johnathan; Chung, Raymond T; Fernández-Hernando, Carlos; Kaplan, Lee M; Bernards, Andre; Gerszten, Robert E; Näär, Anders M

2015-11-01

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.
Treatment of rats with Jiangzhi Capsule improves liquid fructose-induced fatty liver: modulation of hepatic expression of SREBP-1c and DGAT-2.

PubMed

Zhao, Yuanyang; Pan, Yongquan; Yang, Yifan; Batey, Robert; Wang, Jianwei; Li, Yuhao

2015-06-02

Jiangzhi Capsule is an Australian listed patented traditional Chinese medicine and has been used for management of lipid abnormalities over the past 10 years. To obtain a better understanding regarding Jiangzhi Capsule, the present study investigated the effects and underlying mechanisms of Jiangzhi Capsule on chronic fructose overconsumption-induced lipid abnormalities. Male rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. Treatment with Jiangzhi Capsule (100 mg/kg) attenuated fructose-induced excessive triglyceride accumulation and Oil Red O-stained area in the liver. This effect was accompanied by amelioration of hyperinsulinemia. There was no significant difference in intakes of fructose and chow, and body weight between fructose control and fructose Jiangzhi Capsule-treated groups. Mechanistically, Jiangzhi Capsule downregulated fructose-stimulated hepatic overexpression of sterol regulatory element binding protein (SREBP)-1/1c at the mRNA and protein levels. Accordingly, the SREBP-1c downstream genes, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, were also inhibited. In addition, acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver was also inhibited after Jiangzhi Capsule treatment. In contrast, Jiangzhi Capsule affected neither carbohydrate response element binding protein, peroxisome proliferator-activated receptor (PPAR)-gamma and DGAT-1, nor PPAR-alpha and its target genes. These findings demonstrate the anti-steatotic action of Jiangzhi Capsule in fructose-fed rats, and modulation of hepatic SREBP-1c and DGAT-2 involved in hepatic de novo synthesis of fatty acids and triglyceride, respectively. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule supporting its application for the prevention and/or treatment of fatty liver and its associated disorders in clinical practice.

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver.

PubMed

Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

2014-10-15

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. Copyright © 2014 Elsevier Inc. All rights reserved.
Abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren's syndrome.

PubMed

Montaño-Loza, Aldo J; Crispín-Acuña, José Carlos; Remes-Troche, José María; Uribe, Misael

2007-01-01

Patients with primary Sjögren's syndrome may present liver involvement. Our goals were to establish the prevalence of abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren's syndrome and correlate their presence with other clinical and laboratory features. Ninety-five patients with diagnosis of primary Sjögren's syndrome were studied. Data on gender, age, clinical features, liver biochemistries, tests of inflammation and autoimmunity, and concomitant diseases were collected. Forty-two patients (44%) had abnormal hepatic biochemistries, and of these 19 patients (20%) had clinical liver disease. Patients with abnormal hepatic biochemistries had higher frequency of autoimmune hypotiroidism, arthritis, vasculitis, Raynaud's phenomenon, higher sedimentation rate,and higher frequency of antinuclear and antimitochondrial antibodies than patients with normal liver biochemistries (P < 0.05 for each). Patients with clinical liver disease had higher frequency of arthritis, vasculitis, and higher frequency of antimitochondrial antibodies than patients without clinical liver disease (P < 0.05 for each). Twenty-one patients had diagnosis of a specific liver disease, such as hepatitis C virus infection (n = 11), autoimmune hepatitis (n = 2), primary biliary cirrhosis (n =5),nonalcoholic fatty liver disease (n = 2), and hepatitis B virus infection (n = 1). In half of patients with liver involvement a definitive cause could not be identified. Liver involvement is frequently found in patients with primary Sjögren's syndrome, and its presence is associated with clinical features of systemic disease, and markers of autoimmunity and inflammation. There may be a subgroup of patients with liver involvement secondary to primary Sjögren's syndrome.
Hepatic damage in newborns from female rats exposed to the pesticide derivative ethylenethiourea.

PubMed

Lemos, Patrícia Veruska Ribeiro Barbosa; Martins, José Luiz; Lemos, Sidney Pereira Pinto; Santos, Fernando Leandro dos; Silva, Sílvio Romero Gonçalves e

2012-12-01

To evaluate hepatic morphological-histological abnormalities in newborns from female rats exposed to ethylenethiourea. A randomized study was conducted on fifty-five newborn Wistar rats were studied: 34 in the experimental group, whose mothers had been exposed to 1% ethylenethiourea; and 21 in the control group, whose mothers had received 0.9% physiological solution. The solution was administered via gavage on the 11(th) day of gestation. Cesarean section was performed on the 20(th) day of gestation. The newborns' livers were examined and any morphological-histological abnormalities were registered. The presence of megakaryocytes was quantified in 50 microscope fields, as the total number of these cells per mm(2). The entire experimental group presented abnormalities of embryonic formation, with musculoskeletal anomalies, digestive system anomalies, hepatic congestion and friability, hydrops and delayed intrauterine growth. The histopathological analysis showed that morphological-histological hepatic destructuring had occurred in all entire experimental with removal of the hepatic trabeculae and severe hepatic megakaryocytosis. The mean megakaryocyte density ranged from 107.9 to 114.2 per mm(2), and it was eight times greater than in the control group, thus characterizing a situation of extramedullary hematopoiesis. The fetal exposure to ethylenethiourea caused hepatic damage characterized by severe extramedullary hematopoiesis.
Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report.

PubMed

McGuire, Helen M; Shklovskaya, Elena; Edwards, Jarem; Trevillian, Paul R; McCaughan, Geoffrey W; Bertolino, Patrick; McKenzie, Catriona; Gourlay, Ralph; Gallagher, Stuart J; Fazekas de St Groth, Barbara; Hersey, Peter

2018-04-01

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4 + T cells were profoundly depleted by ATG, while CD8 + T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4 + T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4 - CCR6 - effector/memory CD4 + T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4 + rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.
The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reue, K.; Rehnmark, S.; Cohen, R.D.

1997-07-01

Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and thesemore » droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.« less
Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

PubMed Central

Krygier, Darin S; Steinbrecher, Urs P; Petric, Martin; Erb, Siegfried R; Chung, Stephen W; Scudamore, Charles H; Buczkowski, Andrzej K; Yoshida, Eric M

2009-01-01

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation. PMID:19705505
Insulin protects against hepatic damage postburn.

PubMed

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.
Insulin Protects against Hepatic Damage Postburn

PubMed Central

Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

2011-01-01

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509
Parenteral nutrition dysregulates bile salt homeostasis in a rat model of parenteral nutrition-associated liver disease.

PubMed

Koelfat, Kiran V K; Schaap, Frank G; Hodin, Caroline M J M; Visschers, Ruben G J; Svavarsson, Björn I; Lenicek, Martin; Shiri-Sverdlov, Ronit; Lenaerts, Kaatje; Olde Damink, Steven W M

2017-10-01

Parenteral nutrition (PN), a lifesaving therapy in patients with intestinal failure, has been associated with hepatobiliary complications including steatosis, cholestasis and fibrosis, collectively known as parenteral nutrition-associated liver disease (PNALD). To date, the pathogenesis of PNALD is poorly understood and therapeutic options are limited. Impaired bile salt homeostasis has been proposed to contribute PNALD. The objective of this study was to establish a PNALD model in rats and to evaluate the effects of continuous parenteral nutrition (PN) on bile salt homeostasis. Rats received either PN via the jugular vein or received normal diet for 3, 7 or 14 days. Serum biochemistry, hepatic triglycerides, circulating bile salts and C4, IL-6 and TNF-alpha, and lipogenic and bile salt homeostatic gene expression in liver and ileum were assessed. PN increased hepatic triglycerides already after 3 days of administration, and resulted in conjugated bilirubin elevation after 7 or more days. This indicates PN-induced steatosis and impaired canalicular secretion of bilirubin, the latter which is in line with reduced hepatic expression of Mrp2 mRNA. There was no histological evidence for liver inflammation after PN administration, and circulating levels of pro-inflammatory cytokines IL-6 and TNF-α, were comparable in all groups. Hepatic expression of Fxr mRNA was decreased after 7 days of PN, without apparent effect on expression of Fxr targets Bsep and Shp. Nonetheless, Cyp7a1 expression was reduced after 7 days of PN, indicative for lowered bile salt synthesis. Circulating levels of C4 (marker of bile salt synthesis) were also decreased after 3, 7 and 14 days of PN. Levels of circulating bile salts were not affected by PN. This study showed that PN in rats caused early mild steatosis and cholestasis, while hepatic and systemic inflammation were not present. The onset of these abnormalities was associated with alterations in bile salt synthesis and transport. This animal model serves as an experimental model to further investigate the pathogenesis of PNALD inflicted by steatosis and cholestasis. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Conjugated Bilirubin Upregulates TIM-3 Expression on CD4+CD25+ T Cells: Anti-Inflammatory Implications for Hepatitis A Virus Infection.

PubMed

Trujillo-Ochoa, Jorge L; Corral-Jara, Karla F; Charles-Niño, Claudia L; Panduro, Arturo; Fierro, Nora A

2018-04-01

Bilirubin (BR), a metabolite with increased concentrations in plasma during viral hepatitis, has been recognized as a potential immune-modulator. We recently reported that conjugated BR (CB) augments regulatory T cell (Treg) suppressor activity during acute hepatitis A virus (HAV) infection. However, the mechanisms related to the effects of CB on Treg function in the course of hepatotropic viral diseases have not been elucidated. T cell immunoglobulin domain and mucin domain 3 (TIM-3), via its interactions with galectin-9 (GAL-9), is a receptor associated with enhanced Treg function. Thus, TIM-3 expression may be related to the crosstalk between CB and Tregs during HAV infection. Herein, in vitro treatment with high concentrations of CB upregulated TIM-3 expression on Tregs from healthy donors. CB treatment in vitro did not induce de novo Treg generation, and in vitro stimulation with TGF-β, which shows increased secretion during HAV infection, resulted in a trend toward increased TIM-3 expression on Tregs and CD4 + T lymphocytes (TLs) from healthy donors. Interestingly, an upregulation of TIM-3 expression on CD4 + CD25 + T cells and an increase in the proportion of CD4 + TLs expressing GAL-9 were found in HAV-infected patients with abnormal CB values relative to healthy controls. In addition, a statistically significantly reduction in IL-17F production was observed after treatment of CD4 + TLs from healthy donors with high doses of CB in vitro. In summary, our results suggest that CB might regulate Treg activity via a TIM-3-mediated mechanism, ultimately leading to an anti-inflammatory hepatoprotective effect.
Micronuclei and other erythrocyte nuclear abnormalities in fishes from the Great Lakes Basin, USA

USGS Publications Warehouse

Braham, Ryan P.; Blazer, Vicki S.; Shaw, Cassidy H.; Mazik, Patricia M.

2017-01-01

Biological markers (biomarkers) sensitive to genotoxic and mutagenic contamination in fishes are widely used to identify exposure effects in aquatic environments. The micronucleus assay was incorporated into a suite of indicators to assess exposure to genotoxic and mutagenic contamination at five Great Lakes Areas of Concern (AOCs), as well as one non-AOC (reference) site. The assay allowed enumeration of micronuclei as well as other nuclear abnormalities for both site and species comparisons. Erythrocyte abnormality data was also compared to skin and liver tumor prevalence and hepatic transcript abundance. Erythrocyte abnormalities were observed at all sites with variable occurrence and severity among sites and species. Benthic-oriented brown bullhead (Ameiurus nebulosus) and white sucker (Catostomus commersonii) expressed lower rates of erythrocyte abnormalities, but higher rates of skin and liver neoplasms, when compared to pelagic-oriented largemouth bass (Micropterus salmoides) or smallmouth bass (Micropterus dolomieu) at the same site. The reduced erythrocyte abnormalities, increased transcript abundance associated with Phase I and II toxicant responsive pathways, and increased neoplastic lesions among benthic-oriented taxa may indicate the development of contaminant resistance of these species to more acute effects.
Clinical, biochemical, serological, histological and ultrastructural features of liver disease in drug abusers.

PubMed Central

Weller, I V; Cohn, D; Sierralta, A; Mitcheson, M; Ross, M G; Montano, L; Scheuer, P; Thomas, H C

1984-01-01

Heroin abusers are frequently found to have abnormal liver function tests and hepatic histology. Hepatitis viruses A, B, and NANB, other drugs or drug contaminants and excessive alcohol consumption are factors thought to contribute. One hundred and sixteen heroin abusers attending a London treatment centre were studied. Sixty two (53%) had a raised aspartate transaminase. This was not explained by current infection with hepatitis A and B, cytomegalo or Epstein-Barr viruses, excessive alcohol consumption (greater than 80 g/day) or concomitant drug taking. Abnormal liver function tests were as frequent in those with markers of current or past HBV infection as those without and there was evidence that both HBV infection and the cause of the abnormal liver function tests were acquired in the first few years of intravenous drug abuse. Liver biopsies from eight patients showed chronic hepatitis with a mild lobular and portal inflammatory infiltrate, fatty change and prominent sinusoidal cells. Electron microscopy showed cytoplasmic trilaminar tubular structures and dense fused membranes in dilated endoplasmic reticulum. These clinical, biochemical, serological, and histological features would suggest a major role for NANB virus infection in the aetiology of hepatitis in heroin abusers. Images Fig. 2 Fig. 3 Fig. 4 PMID:6423458
Hepatic inclusions during interferon therapy in chronic viral hepatitis.

PubMed

Schaff, Z; Hoofnagle, J H; Grimley, P M

1986-01-01

Two types of cytomembranous abnormalities were identified for the first time in liver biopsies from patients with chronic active type B hepatitis during treatment with recombinant alpha-interferon. Tubuloreticular inclusions were present in the hepatic endothelial cells, Kupffer cells and perisinusoidal cells of liver biopsies from both patients, and they were absent in liver biopsies obtained before treatment. Cylindrical confronting lamellae, having "test tube" or "ring-shape" forms were observed in the cytoplasm both of Kupffer cells and macrophages in the second liver biopsy of one of the patients. The findings suggest that interferon can be involved in the pathogenesis of both cytomembranous abnormalities, but that additional biological factors may play a role in formation of the cylindrical confronting lamellae.
S-ADENOSYLMETHIONINE IN LIVER HEALTH, INJURY, AND CANCER

PubMed Central

Lu, Shelly C.; Mato, José M.

2013-01-01

S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well. PMID:23073625
Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

PubMed Central

Henao-Mejia, Jorge; Elinav, Eran; Jin, Cheng-Cheng; Hao, Liming; Mehal, Wajahat Z.; Strowig, Till; Thaiss, Christoph A.; Kau, Andrew L.; Eisenbarth, Stephanie C.; Jurczak, Michael J.; Camporez, Joao-Paulo; Shulman, Gerald I.; Gordon, Jeffrey I.; Hoffman, Hal M.; Flavell, Richard A.

2012-01-01

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty percent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different animal models reveal that inflammasome deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic TNF-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient animals to wild type mice results in exacerbation of hepatic steatosis, glucose intolerance, and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. PMID:22297845
Prevalence and factors associated with the presence of abnormal function liver tests in patients with ulcerative colitis.

PubMed

Yamamoto-Furusho, Jesús K; Sánchez-Osorio, Magdalena; Uribe, Misael

2010-01-01

To investigate the prevalence of abnormal function liver tests and risk factors associated with their development in Mexican patients with UC. A total of 200 patients with confirmed diagnosis of UC were evaluated prospectively during a one year period from January 1, 2007 to December 31, 2008. A total of 94 females and 106 males patients with UC were analyzed. The age at diagnosis was 31.4 ± 13.2 years and the mean of disease duration was 6.7 ± 5.2 years. We found a high prevalence of abnormal function livers tests in 40% of UC patients. The pattern of abnormal function liver test was hepatitis in 70%, cholestatic (20%) and mixed (10%). The most common cause of abnormal function liver test was transient elevation in 50 patients (63%) followed by fatty liver disease (11.2%), primary sclerosing cholangitis (6.3%), drug-toxicity (6%) and others (13.5%) including chronic hepatitis C, total parenteral nutrition, granulomatous and ischemic hepatitis. In the multivariate logistic regression model, active disease, colectomy and abdominal sepsis were factors that persisted associated with the development of abnormal liver tests in UC patients. A high prevalence of abnormal function liver tests (40%) was found in Mexican UC patients is likely to be related to active disease, colectomy and the presence of sepsis.
Cavernous Transformation of Portal Vein Secondary to Portal Vein Thrombosis: A Case Report

PubMed Central

Ramos, Radhames; Park, Yoojin; Shazad, Ghulamullah; A.Garcia, Christine; Cohen, Ronny

2012-01-01

There are few reported cases of cavernous transformation of the portal vein (CTPV) in adults. We present a case of a 58 year-old male who was found to have this complication due to portal vein thrombosis (PVT). A 58-year old African American male with chronic alcohol and tobacco use presented with a 25-day history of weakness, generalized malaise, nausea and vomiting associated with progressively worsening anorexia and weight loss. The patient was admitted for severe anemia in conjunction with abnormal liver function tests and electrolyte abnormalities, and to rule out end stage liver disease or hepatic malignancy. The work-up for anemia showed no significant colon abnormalities, cholecystitis, liver cirrhosis, or liver abnormalities but could not rule out malignancy. An esophageogastroduodenoscopy (EGD) was suspicious for a mass compressing the stomach and small bowel. After further work-up, the hepatic mass has been diagnosed as a cavernous transformation of the portal vein (CTPV), a very rare complication of portal vein thrombosis (PVT). Cavernous Transformation of the Portal Vein (CTPV) is a rare and incurable complication of portal vein thrombosis (PVT) that should be considered as one of the differential diagnoses of a hepatic mass. Keywords Cavernous transformation of the portal vein; Portal vein thrombosis; Portal hypertension; Hyperbilirubinemia; Hepatic mass PMID:22383935
Abnormal splenic artery diameter/hepatic artery diameter ratio in cirrhosis-induced portal hypertension

PubMed Central

Zeng, Dao-Bing; Dai, Chuan-Zhou; Lu, Shi-Chun; He, Ning; Wang, Wei; Li, Hong-Jun

2013-01-01

AIM: To determine an optimal cutoff value for abnormal splenic artery diameter/proper hepatic artery diameter (S/P) ratio in cirrhosis-induced portal hypertension. METHODS: Patients with cirrhosis and portal hypertension (n = 770) and healthy volunteers (n = 31) underwent volumetric computed tomography three-dimensional vascular reconstruction to measure the internal diameters of the splenic artery and proper hepatic artery to calculate the S/P ratio. The cutoff value for abnormal S/P ratio was determined using receiver operating characteristic curve analysis, and the prevalence of abnormal S/P ratio and associations between abnormal S/P ratio and major complications of portal hypertension were studied using logistic regression. RESULTS: The receiver operating characteristic analysis showed that the cutoff points for abnormal splenic artery internal diameter and S/P ratio were > 5.19 mm and > 1.40, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 74.2%, 45.2%, 97.1%, and 6.6%, respectively. The prevalence of an abnormal S/P ratio in the patients with cirrhosis and portal hypertension was 83.4%. Patients with a higher S/P ratio had a lower risk of developing ascites [odds ratio (OR) = 0.708, 95%CI: 0.508-0.986, P = 0.041] and a higher risk of developing esophageal and gastric varices (OR = 1.483, 95%CI: 1.010-2.175, P = 0.044) and forming collateral circulation (OR = 1.518, 95%CI: 1.033-2.230, P = 0.034). After splenectomy, the portal venous pressure and maximum and mean portal venous flow velocities were reduced, while the flow rate and maximum and minimum flow velocities of the hepatic artery were increased (P < 0.05). CONCLUSION: The prevalence of an abnormal S/P ratio is high in patients with cirrhosis and portal hypertension, and it can be used as an important marker of splanchnic hemodynamic disturbances. PMID:23483462
Functional proteomics of nonalcoholic steatohepatitis: Mitochondrial proteins as targets of S-adenosylmethionine

PubMed Central

Santamaría, Enrique; Avila, Matías A.; Latasa, M. Ujue; Rubio, Angel; Martín-Duce, Antonio; Lu, Shelly C.; Mato, José M.; Corrales, Fernando J.

2003-01-01

Recent work shows that S-adenosylmethionine (AdoMet) helps maintain normal liver function as chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. The mechanisms by which these nontraditional functions of AdoMet occur are unknown. Here, we use knockout mice deficient in hepatic AdoMet synthesis (MAT1A−/−) to study the proteome of the liver during the development of steatohepatitis. One hundred and seventeen protein spots, differentially expressed during the development of steatohepatitis, were selected and identified by peptide mass fingerprinting. Among them, 12 proteins were found to be affected from birth, when MAT1A−/− expression is switched on in WT mouse liver, to the rise of histological lesions, which occurs at ≈8 months. Of the 12 proteins, 4 [prohibitin 1 (PHB1), cytochrome c oxidase I and II, and ATPase β-subunit] have known roles in mitochondrial function. We show that the alteration in expression of PHB1 correlates with a loss of mitochondrial function. Experiments in isolated rat hepatocytes indicate that AdoMet regulates PHB1 content, thus suggesting ways by which steatohepatitis may be induced. Importantly, we found the expression of these mitochondrial proteins was abnormal in ob/ob mice and obese patients who are at risk for nonalcoholic steatohepatitis. PMID:12631701
Genome-wide differences in hepatitis C- vs alcoholism-associated hepatocellular carcinoma

PubMed Central

Derambure, Céline; Coulouarn, Cédric; Caillot, Frédérique; Daveau, Romain; Hiron, Martine; Scotte, Michel; François, Arnaud; Duclos, Celia; Goria, Odile; Gueudin, Marie; Cavard, Catherine; Terris, Benoit; Daveau, Maryvonne; Salier, Jean-Philippe

2008-01-01

AIM: To look at a comprehensive picture of etiology-dependent gene abnormalities in hepatocellular carcinoma in Western Europe. METHODS: With a liver-oriented microarray, transcript levels were compared in nodules and cirrhosis from a training set of patients with hepatocellular carcinoma (alcoholism, 12; hepatitis C, 10) and 5 controls. Loose or tight selection of informative transcripts with an abnormal abundance was statistically valid and the tightly selected transcripts were next quantified by qRTPCR in the nodules from our training set (12 + 10) and a test set (6 + 7). RESULTS: A selection of 475 transcripts pointed to significant gene over-representation on chromosome 8 (alcoholism) or -2 (hepatitis C) and ontology indicated a predominant inflammatory response (alcoholism) or changes in cell cycle regulation, transcription factors and interferon responsiveness (hepatitis C). A stringent selection of 23 transcripts whose differences between etiologies were significant in nodules but not in cirrhotic tissue indicated that the above dysregulations take place in tumor but not in the surrounding cirrhosis. These 23 transcripts separated our test set according to etiologies. The inflammation-associated transcripts pointed to limited alterations of free iron metabolism in alcoholic vs hepatitis C tumors. CONCLUSION: Etiology-specific abnormalities (chromosome preference; differences in transcriptomes and related functions) have been identified in hepatocellular carcinoma driven by alcoholism or hepatitis C. This may open novel avenues for differential therapies in this disease. PMID:18350606

Occult Hepatitis B Virus Among the Patients With Abnormal Alanine Transaminase

PubMed Central

Makvandi, Manoochehr; Neisi, Niloofar; Khalafkhany, Davod; Makvandi, Kamyar; Hajiani, Eskandar; Shayesteh, Ali Akbar; Masjedi Zadeh, Abdolrahim; Sina, Amir Hosein; Hamidifard, Mojtaba; Rasti, Mojtaba; Aryan, Ehsan; Ahmadi, Kambiz; Yad Yad, Mohammad Jafar

2014-01-01

Background: The occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the sera or in the liver biopsy and the absence of hepatitis B surface antigen (HBsAg) by serological test. Objectives: The current study aimed to evaluate the occult HBV infection by polymerase chain reaction (PCR) and determine HBV genotyping among the patients with abnormal alanine transaminase (ALT) in Ahvaz city, Iran. Patients and Methods: The sera of 120 patients, 54 (45%) females and 66 (55%) males, with abnormal ALT 40-152 IU were collected. All the patients were negative for HBsAg for more than one year. The patients` sera were tested by PCR using primers specified for the S region of HBV. Then the positive PCR products were sequenced to determine HBV genotyping and phylogenic tree. Results: Of these 120 subjects, 12 (10%) patients including 6 (5%) males and 6 (5%) females were found positive for HBV DNA by PCR, which indicated the presence of occult HBV infection among these patients. The sequencing results revealed that genotype D was predominant with sub-genotyping D1 among OBI patients. Conclusions: Occult hepatitis B infection is remarkably prevalent in Ahvaz, Iran, and should be considered as a potential risk factor for the transmission of Hepatitis B Virus throughout the community by the carriers. PMID:25485052
Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review.

PubMed

Desbois, Anne-Claire; Cacoub, Patrice

2017-03-07

To summarise the literature data on hepatitis C virus (HCV)-infected patients concerning the prevalence of glucose abnormalities and associated risk. We conducted a PubMed search and selected all studies found with the key words "HCV" or "hepatitis C virus" and "diabetes" or "insulin resistance". We included only comparative studies written in English or in French, published from January 2000 to April 2015. We collected the literature data on HCV-infected patients concerning the prevalence of glucose abnormalities [diabetes mellitus (DM) and insulin resistance (IR)] and associated risk [ i.e ., severe liver fibrosis, response to antivirals, and the occurrence of hepatocellular carcinoma (HCC)]. HCV infection is significantly associated with DM/IR compared with healthy volunteers and patients with hepatitis B virus infection. Glucose abnormalities were associated with advanced liver fibrosis, lack of sustained virologic response to interferon alfa-based treatment and with a higher risk of HCC development. As new antiviral therapies may offer a cure for HCV infection, such data should be taken into account, from a therapeutic and preventive point of view, for liver and non-liver consequences of HCV disease. The efficacy of antidiabetic treatment in improving the response to antiviral treatment and in decreasing the risk of HCC has been reported by some studies but not by others. Thus, the effects of glucose abnormalities correction in reducing liver events need further studies. Glucose abnormalities are strongly associated with HCV infection and show a negative impact on the main liver related outcomes.
Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease.

PubMed

Guo, Rui; Liong, Emily C; So, Kwok Fai; Fung, Man-Lung; Tipoe, George L

2015-04-01

Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD. We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor gamma expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy. Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.
In Vitro and in Vivo Analysis of the Binding of the C Terminus of the HDL Receptor Scavenger Receptor Class B, Type I (SR-BI), to the PDZ1 Domain of Its Adaptor Protein PDZK1*

PubMed Central

Kocher, Olivier; Birrane, Gabriel; Tsukamoto, Kosuke; Fenske, Sara; Yesilaltay, Ayce; Pal, Rinku; Daniels, Kathleen; Ladias, John A. A.; Krieger, Monty

2010-01-01

The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys14-Xaa4-Asn19-Tyr-Gly-Phe-Phe-Leu24), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI (503VLQEAKL509). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (Kd) of the K14A and F22A mutants were 3.2 and 4.0 μm, respectively, similar to 2.6 μm measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI (505QEAKL509) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10–20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1. PMID:20739281
In vitro and in vivo Analysis of the Binding of the C Terminus of the HDL Receptor Scavenger Receptor Class B type I (SR-BI) to the PDZ1 Domain of its Cytoplasmic Adaptor Protein PDZK1

DOE Office of Scientific and Technical Information (OSTI.GOV)

O Kocher; G Birrane; K Tsukamoto

2011-12-31

The PDZ1 domain of the four PDZ domain-containing protein PDZK1 has been reported to bind the C terminus of the HDL receptor scavenger receptor class B, type I (SR-BI), and to control hepatic SR-BI expression and function. We generated wild-type (WT) and mutant murine PDZ1 domains, the mutants bearing single amino acid substitutions in their carboxylate binding loop (Lys(14)-Xaa(4)-Asn(19)-Tyr-Gly-Phe-Phe-Leu(24)), and measured their binding affinity for a 7-residue peptide corresponding to the C terminus of SR-BI ((503)VLQEAKL(509)). The Y20A and G21Y substitutions abrogated all binding activity. Surprisingly, binding affinities (K(d)) of the K14A and F22A mutants were 3.2 and 4.0 ?M,more » respectively, similar to 2.6 ?M measured for the WT PDZ1. To understand these findings, we determined the high resolution structure of WT PDZ1 bound to a 5-residue sequence from the C-terminal SR-BI ((505)QEAKL(509)) using x-ray crystallography. In addition, we incorporated the K14A and Y20A substitutions into full-length PDZK1 liver-specific transgenes and expressed them in WT and PDZK1 knock-out mice. In WT mice, the transgenes did not alter endogenous hepatic SR-BI protein expression (intracellular distribution or amount) or lipoprotein metabolism (total plasma cholesterol, lipoprotein size distribution). In PDZK1 knock-out mice, as expected, the K14A mutant behaved like wild-type PDZK1 and completely corrected their hepatic SR-BI and plasma lipoprotein abnormalities. Unexpectedly, the 10-20-fold overexpressed Y20A mutant also substantially, but not completely, corrected these abnormalities. The results suggest that there may be an additional site(s) within PDZK1 that bind(s) SR-BI and mediate(s) productive SR-BI-PDZK1 interaction previously attributed exclusively to the canonical binding of the C-terminal SR-BI to PDZ1.« less
Gene Therapy for Diabetes Mellitus in Rats by Hepatic Expression of Insulin

NASA Astrophysics Data System (ADS)

Kolodka, Tadeusz M.; Finegold, Milton; Moss, Larry; Woo, Savio L. C.

1995-04-01

Type 1 diabetes mellitus is caused by severe insulin deficiency secondary to the autoimmune destruction of pancreatic β cells. Patients need to be controlled by periodic insulin injections to prevent the development of ketoacidosis, which can be fatal. Sustained, low-level expression of the rat insulin 1 gene from the liver of severely diabetic rats was achieved by in vivo administration of a recombinant retroviral vector. Ketoacidosis was prevented and the treated animals exhibited normoglycemia during a 24-hr fast, with no evidence of hypoglycemia. Histopathological examination of the liver in the treated animals showed no apparent abnormalities. Thus, the liver is an excellent target organ for ectopic expression of the insulin gene as a potential treatment modality for type 1 diabetes mellitus by gene therapy.
Coagulation disorders in dogs with hepatic disease.

PubMed

Prins, M; Schellens, C J M M; van Leeuwen, M W; Rothuizen, J; Teske, E

2010-08-01

Liver disease has been associated with abnormalities in haemostasis. In this study, coagulation times, platelet counts, platelet activity parameters, activities of individual coagulation factors, D-dimers, antithrombin (AT) and protein C activity were measured in 42 dogs with histologically confirmed liver disease. Outcome was correlated with histological diagnosis. One or more coagulation abnormalities were present in 57% of dogs with hepatic disease. Activated partial thromboplastin time was significantly prolonged in dogs with chronic hepatitis (CH), with or without cirrhosis. Mean platelet numbers, AT and factor IX activity were significantly lower in dogs with CH plus cirrhosis, compared to dogs with other hepatopathies. D-dimers were not significantly increased in any group. Only three dogs, all with different histological diagnoses, satisfied the criteria for disseminated intravascular coagulation (DIC). Haemostatic abnormalities were primarily seen in dogs with cirrhosis and this may be due to reduced synthesis rather than increased consumption of coagulation factors. Copyright (c) 2009 Elsevier Ltd. All rights reserved.
Reticulocyte Count Test

MedlinePlus

... Acid-Fast Bacillus (AFB) Testing Activated Clotting Time Acute Viral Hepatitis Panel Adenosine Deaminase Adrenocorticotropic Hormone (ACTH) ... Guillain-Barré Syndrome Hashimoto Thyroiditis Heart Attack and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis ...
Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats

PubMed Central

Tian, Yu-Feng; He, Chih-Tsueng; Chen, Yu-Ting; Hsieh, Po-Shiuan

2013-01-01

AIM: To examine the effect of α-lipoic acid (LA) on mild portal endotoxemia-induced steatohepatitis and associated pancreatic abnormalities in fructose-fed rats. METHODS: Rats were randomly assigned into two groups with a regular or 60% fructose-enriched diet for 8 wk. After fructose feeding for 4 wk, rats were further divided into four subgroups: with intraportal saline (FPV), with intraportal saline plus administration of LA (FPV + LA), with lipopolysaccharide (LPS) infusion (FPLPS), and with LPS infusion plus administration of LA (FPLPS + LA). Rats were treated with LPS using intraportal infusion while LA was administered orally. Metabolite levels, superoxide levels, inflammatory markers, malondialdehyde content, glutathione content and toll-like receptor 4 (TLR4) gene expression were all measured using standard biochemical techniques. Pancreatic insulin secretion was evaluated by a hyperglycemic clamp technique. Histology of liver and pancreas tissues were evaluated using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Fructose-induced elevation in plasma C-reactive protein, amylase, superoxide, white blood cell count as well as in hepatic and pancreatic contents of malondialdehyde, tumor necrosis factor alpha and interleukin-6 were increased in animals treated with LPS and reversed with LA administration. The augmented hepatic gene expression of TLR4 in fructose-fed rats was further increased in those with intraportal LPS infusion, which was partially reversed by LA administration. Pathological examination showed inflammatory changes and leukocyte infiltration in hepatic and pancreatic islets of animals treated with LPS but were rarely observed in those with LA treatment. In addition to affects on the liver, impaired pancreatic insulin secretion seen in fructose-fed rats was deteriorated in with LPS treatment and partially reversed with LA administration. CONCLUSION: These data suggest LA could significantly suppress mild portal-endotoxemia but not fructose-induced liver and pancreatic abnormalities in a rodent model for metabolic syndrome. PMID:23687413
Index of Glossary Terms

MedlinePlus

... Acid-Fast Bacillus (AFB) Testing Activated Clotting Time Acute Viral Hepatitis Panel Adenosine Deaminase Adrenocorticotropic Hormone (ACTH) ... Guillain-Barré Syndrome Hashimoto Thyroiditis Heart Attack and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis ...
BCR-ABL1: Test

MedlinePlus

... Acid-Fast Bacillus (AFB) Testing Activated Clotting Time Acute Viral Hepatitis Panel Adenosine Deaminase Adrenocorticotropic Hormone (ACTH) ... Guillain-Barré Syndrome Hashimoto Thyroiditis Heart Attack and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis ...
White Blood Cell Count

MedlinePlus

... Acid-Fast Bacillus (AFB) Testing Activated Clotting Time Acute Viral Hepatitis Panel Adenosine Deaminase Adrenocorticotropic Hormone (ACTH) ... Guillain-Barré Syndrome Hashimoto Thyroiditis Heart Attack and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis ...
Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota.

PubMed

Shanmugam, Nanda Kumar N; Trebicka, Estela; Fu, Ling-Lin; Shi, Hai Ning; Cherayil, Bobby J

2014-08-01

States of chronic inflammation such as inflammatory bowel disease are often associated with dysregulated iron metabolism and the consequent development of an anemia that is caused by maldistribution of iron. Abnormally elevated expression of the hormone hepcidin, the central regulator of systemic iron homeostasis, has been implicated in these abnormalities. However, the mechanisms that regulate hepcidin expression in conditions such as inflammatory bowel disease are not completely understood. To clarify this issue, we studied hepcidin expression in mouse models of colitis. We found that dextran sulfate sodium-induced colitis inhibited hepcidin expression in wild-type mice but upregulated it in IL-10-deficient animals. We identified two mechanisms contributing to this difference. Firstly, erythropoietic activity, as indicated by serum erythropoietin concentrations and splenic erythropoiesis, was higher in the wild-type mice, and pharmacologic inhibition of erythropoiesis prevented colitis-associated hepcidin downregulation in these animals. Secondly, the IL-10 knockout mice had higher expression of multiple inflammatory genes in the liver, including several controlled by STAT3, a key regulator of hepcidin. The results of cohousing and fecal transplantation experiments indicated that the microbiota was involved in modulating the expression of hepcidin and other STAT3-dependent hepatic genes in the context of intestinal inflammation. Our observations thus demonstrate the importance of erythropoietic activity and the microbiota in influencing hepcidin expression during colitis and provide insight into the dysregulated iron homeostasis seen in inflammatory diseases. Copyright © 2014 by The American Association of Immunologists, Inc.
WBC (White Blood Cell) Differential Count

MedlinePlus

... Acid-Fast Bacillus (AFB) Testing Activated Clotting Time Acute Viral Hepatitis Panel Adenosine Deaminase Adrenocorticotropic Hormone (ACTH) ... Guillain-Barré Syndrome Hashimoto Thyroiditis Heart Attack and Acute Coronary Syndrome Heart Disease Hemochromatosis Hemoglobin Abnormalities Hepatitis ...
Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine–homocysteine S-methyltransferase

PubMed Central

Sparks, Janet D.; Collins, Heidi L.; Chirieac, Doru V.; Cianci, Joanne; Jokinen, Jenny; Sowden, Mark P.; Galloway, Chad A.; Sparks, Charles E.

2006-01-01

We have previously reported a positive correlation between the expression of BHMT (betaine–homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639–645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion. PMID:16396637
Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice.

PubMed

Tsuneki, Hiroshi; Tokai, Emi; Nakamura, Yuya; Takahashi, Keisuke; Fujita, Mikio; Asaoka, Takehiro; Kon, Kanta; Anzawa, Yuuki; Wada, Tsutomu; Takasaki, Ichiro; Kimura, Kumi; Inoue, Hiroshi; Yanagisawa, Masashi; Sakurai, Takeshi; Sasaoka, Toshiyasu

2015-02-01

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Acute pancreatitis in cats with hepatic lipidosis.

PubMed

Akol, K G; Washabau, R J; Saunders, H M; Hendrick, M J

1993-01-01

The purpose of this study was to characterize the incidence, clinical features, and prognosis of acute pancreatitis in cats with hepatic lipidosis. Of 13 cats histologically diagnosed with hepatic lipidosis between July 1988, and November 1989, 5(38%) were also histologically diagnosed with acute pancreatitis. In cats with hepatic lipidosis alone, the signalment, history, physical examination, and clinicopathologic findings were generally indistinguishable from those of cats with concurrent acute pancreatitis except that cats with acute pancreatitis were more likely to be cachectic and to have coagulation abnormalities. Hepatomegaly was seen on abdominal radiographs in both groups. Of the 5 cats with concurrent acute pancreatitis, abdominal ultrasonography detected 1 cat with a hypoechoic pancreas and 5 with peritoneal effusion; those abnormalities were not seen in cats without concurrent acute pancreatitis. Cats with concurrent acute pancreatitis had only a 20% recovery rate, compared with a 50% recovery rate in cats with hepatic lipidosis alone. We conclude that cats with hepatic lipidosis should be rigorously evaluated for concurrent acute pancreatitis because of 1) the rate of disease coincidence, 2) the inability of signalment, history, physical examination, and clinicopathologic findings to adequately distinguish between hepatic lipidosis and acute pancreatitis, 3) the worse prognosis associated with concurrent acute pancreatitis, and 4) the opposing nutritional strategies for hepatic lipidosis and acute pancreatitis.
The number of metabolic abnormalities associated with the risk of gallstones in a non-diabetic population.

PubMed

Tsai, Chung-Hung; Wu, Jin-Shang; Chang, Yin-Fan; Lu, Feng-Hwa; Yang, Yi-Ching; Chang, Chih-Jen

2014-01-01

To evaluate whether metabolic syndrome is associated with gallstones, independent of hepatitis C infection or chronic kidney disease (CKD), in a non-diabetic population. A total of 8,188 Chinese adult participants that underwent a self-motivated health examination were recruited into the final analysis after excluding the subjects who had a history of cholecystectomy, diabetes mellitus, or were currently using antihypertensive or lipid-lowering agents. Gallstones were defined by the presence of strong intraluminal echoes that were gravity-dependent or that attenuated ultrasound transmission. A total of 447 subjects (5.5%) had gallstones, with 239 (5.1%) men and 208 (6.0%) women. After adjusting for age, gender, obesity, education level, and lifestyle factors, included current smoking, alcohol drinking, regular exercise, hepatitis B, hepatitis C, and CKD, there was a positive association between metabolic syndrome and gallstones. Moreover, as compared to subjects without metabolic abnormalities, subjects with one, two, and three or more suffered from a 35, 40, and 59% higher risk of gallstones, respectively. Non-diabetic subjects with metabolic syndrome had a higher risk of gallstones independent of hepatitis C or CKD, and a dose-dependent effect of metabolic abnormalities also exists.
[The clinical features and natural history of post-transfusion hepatitis C].

PubMed

Chong, Yu-tian; Lin, Chao-shuang; Zhao, Zhi-xin; Lin, Guo-li; Li, Jian-guo; Gao, Zhi-liang

2006-03-01

To study the clinical features and natural history of post-transfusion hepatitis C (PTHC). Ninety-nine post-transfusion hepatitis C patients were analyzed using retrospective and prospective study and follow-up. (1) Ninety-nine post-transfusion HCV patients were infected during 1989-1994, mostly between 1990-1992. (2) Ninety patients were diagnosed as chronic hepatitis C, and 9 as hepatic cirrhosis (period of compensation). (3) The intervals between their transfusions and their initial diagnoses of PTHC were 7.4+/-6.6 years in all 99 patients, and the intervals in 9 cirrhosis patients were 12.7+/-5.8 years. (4) Among 63 male patients, 59 cases were chronic hepatitis C and 4 were cirrhosis while among 36 female patients, 31 were chronic hepatitis C and 5 were cirrhosis. There was no significant difference of the ratio for hepatitis C and cirrhosis between the male and female patients (P>0.05). (5) Repeat abnormal liver function occurred accompanied with a fluctuation of ALT elevation in those patients with cirrhosis. (6) No patient developed hepatic carcinoma during the study period. (1) The possibility of HCV infection by transfusion has declined greatly since 1995 in Guangzhou. (2) Nine of the 99 (9.1%) chronic HCV-infected patients developed a compensated cirrhosis after 12.7+/-5.8 years. (3) For those PTHC patients with repeat abnormal liver functions, interferon combined with ribavirin is recommended to prevent the development of cirrhosis.
Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging

PubMed Central

Fujisawa, Koichi; Terai, Shuji; Matsumoto, Toshihiko; Takami, Taro; Yamamoto, Naoki; Nishina, Hiroshi; Furutani-Seiki, Makoto; Sakaida, Isao

2015-01-01

Maid is a helix-loop-helix protein that is involved in cell proliferation. In order to further elucidate its physiological functions, we studied Maid activity in two small fish model systems. We found that Maid expression was greatest in zebrafish liver and that it increased following partial hepatectomy. Maid levels were also high in hepatic preneoplastic foci induced by treatment of zebrafish with diethylnitrosamine (DEN), but low in hepatocellular carcinomas (HCC), mixed tumors, and cholangiocarcinomas developing in these animals. In DEN-treated transgenic medaka overexpressing Maid, hepatic BrdU uptake and proliferation were reduced. After successive breedings, Maid transgenic medaka exhibited decreased movement and a higher incidence of abnormal spine curvature, possibly due to the senescence of spinal cord cells. Taken together, our results suggest that Maid levels can influence the progression of liver cancer. In conclusion, we found that Maid is important regulator of hepatocarconogenesis and aging. PMID:26107180

Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism

PubMed Central

van Herwaarden, Antonius E.; Wagenaar, Els; van der Kruijssen, Cornelia M.M.; van Waterschoot, Robert A.B.; Smit, Johan W.; Song, Ji-Ying; van der Valk, Martin A.; van Tellingen, Olaf; van der Hoorn, José W.A.; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.

2007-01-01

Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a–/–) mice lacking all functional Cyp3a genes. Cyp3a–/– mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a–/– mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems. PMID:17975676
Remote reprogramming of hepatic circadian transcriptome by breast cancer.

PubMed

Hojo, Hiroaki; Enya, Sora; Arai, Miki; Suzuki, Yutaka; Nojiri, Takashi; Kangawa, Kenji; Koyama, Shinsuke; Kawaoka, Shinpei

2017-05-23

Cancers adversely affect organismal physiology. To date, the genes within a patient responsible for systemically spreading cancer-induced physiological disruption remain elusive. To identify host genes responsible for transmitting disruptive, cancer-driven signals, we thoroughly analyzed the transcriptome of a suite of host organs from mice bearing 4T1 breast cancer, and discovered complexly rewired patterns of circadian gene expression in the liver. Our data revealed that 7 core clock transcription factors, represented by Rev-erba and Rorg, exhibited abnormal daily expression rhythm in the liver of 4T1-bearing mice. Accordingly, expression patterns of specific set of downstream circadian genes were compromised. Osgin1, a marker for oxidative stress, was an example. Specific downstream genes, including E2f8, a transcriptional repressor that controls cellular polyploidy, displayed a striking pattern of disruption, "day-night reversal." Meanwhile, we found that the liver of 4T1-bearing mice suffered from increased oxidative stress. The tetraploid hepatocytes population was concomitantly increased in 4T1-bearing mice, which has not been previously appreciated as a cancer-induced phenotype. In summary, the current study provides a comprehensive characterization of the 4T1-affected hepatic circadian transcriptome that possibly underlies cancer-induced physiological alteration in the liver.
Expression of β-catenin protein in hepatocellular carcinoma and its relationship with alpha-fetoprotein.

PubMed

Ren, Ya-Jun; Huang, Tao; Yu, Hong-Lu; Zhang, Li; He, Qian-Jin; Xiong, Zhi-Fan; Peng, Hua

2016-12-01

This study aimed to investigate the expression of β-catenin in hepatocellular carcinoma (HCC) tissues and its relationship with α-fetoprotein (AFP) in HCC. Immunohistochemistry was used to determine the expression of β-catenin in normal liver tissues (n=10), liver cirrhosis tissues (n=20), and primary HCC tissues (n=60). The relationship between β-catenin expression and clinical parameters of HCC was investigated. Real-time PCR and Western blotting were used to detect the mRNA and protein expression levels of β-catenin in the liver cancer cell line SMMC-7721 transfected with a plasmid encoding AFP, and also the mRNA and protein expression levels of β-catenin were measured in the liver cancer cell line Huh7 before and after the transfection with AFP shRNA plasmids. The results showed that β-catenin was only expressed on the cell membrane in normal liver tissues. Its localization to the cytoplasm and nucleus of cells was observed in a small proportion of cirrhotic tissues or adjacent HCC tissues, and such ectopic expression of β-catenin was predominant in HCC tissues. The abnormal expression of β-catenin was correlated with serum AFP levels, cancer cell differentiation and vascular invasion (P<0.05). Additionally, the increased expression of AFP resulted in the upregulation of β-catenin mRNA and protein levels, while knockdown of AFP with AFP shRNA led to significantly decreased β-catenin mRNA and protein levels (P<0.05). It was suggested that the abnormal expression of β-catenin is implicated in hepatic carcinogenesis and development. AFP can lead to increased expression of β-catenin, which may account for the poor prognosis of AFP-associated HCC patients.
Micronuclei and other erythrocyte nuclear abnormalities in fishes from the Great Lakes Basin, USA

PubMed Central

Braham, Ryan P.; Shaw, Cassidy H.; Mazik, Patricia M.; Umbuzeiro, G.

2017-01-01

Biological markers (biomarkers) sensitive to genotoxic and mutagenic contamination in fishes are widely used to identify exposure effects in aquatic environments. The micronucleus assay was incorporated into a suite of indicators to assess exposure to genotoxic and mutagenic contamination at five Great Lakes Areas of Concern (AOCs), as well as one non‐AOC (reference) site. The assay allowed enumeration of micronuclei as well as other nuclear abnormalities for both site and species comparisons. Erythrocyte abnormality data was also compared to skin and liver tumor prevalence and hepatic transcript abundance. Erythrocyte abnormalities were observed at all sites with variable occurrence and severity among sites and species. Benthic‐oriented brown bullhead (Ameiurus nebulosus) and white sucker (Catostomus commersonii) expressed lower rates of erythrocyte abnormalities, but higher rates of skin and liver neoplasms, when compared to pelagic‐oriented largemouth bass (Micropterus salmoides) or smallmouth bass (Micropterus dolomieu) at the same site. The reduced erythrocyte abnormalities, increased transcript abundance associated with Phase I and II toxicant responsive pathways, and increased neoplastic lesions among benthic‐oriented taxa may indicate the development of contaminant resistance of these species to more acute effects. Environ. Mol. Mutagen. 58:570–581, 2017. © 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society PMID:28868735
Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease.

PubMed

Sajan, Mini P; Hansen, Barbara C; Higgs, Margaret G; Kahn, C Ron; Braun, Ursula; Leitges, Michael; Park, Collin R; Diamond, David M; Farese, Robert V

2018-01-01

Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ 1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ 1-40/42 , β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), β-secretase, and Aβ 1-40/42 , and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ 1-40/42 . Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-ι/λ activation by insulin, metformin, or expression of constitutive PKC-ι provoked increases in β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt inhibitor. PKC-λ/ι provokes increases in brain β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau. Excessive signaling via PKC-λ/ι may link hyperinsulinemia and other PKC-λ/ι activators to pathological and functional abnormalities in Alzheimer's disease. Published by Elsevier Inc.
Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone.

PubMed

Holness, Mark J; Bulmer, Karen; Smith, Nicholas D; Sugden, Mary C

2003-02-01

Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-alpha (PPARalpha). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-alpha. Heterodimerization partners for retinoid X receptors (RXRs) include PPARalpha and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-alpha activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARalpha activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARalpha, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARalpha or TR with the RXR receptor and that effects of PPARalpha activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.
Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis

PubMed Central

Kondo, Yoshitaka; Masutomi, Hirofumi; Noda, Yoshihiro; Ozawa, Yusuke; Takahashi, Keita; Handa, Setsuko; Maruyama, Naoki; Shimizu, Takahiko; Ishigami, Akihito

2014-01-01

Superoxide dismutase 1 (SOD1) is an antioxidant enzyme that converts superoxide anion radicals into hydrogen peroxide and molecular oxygen. The senescence marker protein-30 (SMP30) is a gluconolactonase that functions as an antioxidant protein in mammals due to its involvement in ascorbic acid (AA) biosynthesis. SMP30 also participates in Ca2+ efflux by activating the calmodulin-dependent Ca2+-pump. To reveal the role of oxidative stress in lipid metabolism defects occurring in non-alcoholic fatty liver disease pathogenesis, we generated SMP30/SOD1-double knockout (SMP30/SOD1-DKO) mice and investigated their survival curves, plasma and hepatic lipid profiles, amounts of hepatic oxidative stress, and hepatic protein levels expressed by genes related to lipid metabolism. While SMP30/SOD1-DKO pups had no growth retardation by 14 days of age, they did have low plasma and hepatic AA levels. Thereafter, 39% and 53% of male and female pups died by 15–24 and 89 days of age, respectively. Compared to wild type, SMP30-KO and SOD1-KO mice, by 14 days SMP30/SOD1-DKO mice exhibited: (1) higher plasma levels of triglyceride and aspartate aminotransferase; (2) severe accumulation of hepatic triglyceride and total cholesterol; (3) higher levels of superoxide anion radicals and thiobarbituric acid reactive substances in livers; and (4) decreased mRNA and protein levels of Apolipoprotein B (ApoB) in livers – ApoB is an essential component of VLDL secretion. These results suggest that high levels of oxidative stress due to concomitant deficiency of SMP30 and/or AA, and SOD1 cause abnormal plasma lipid metabolism, hepatic lipid accumulation and premature death resulting from impaired VLDL secretion. PMID:25003023
Hepatic, metabolic and toxicity evaluation of repeated oral administration of SnS2 nanoflowers in mice.

PubMed

Bai, Disi; Li, Qingzhao; Xiong, Yanjie; Wang, Chao; Shen, Peijun; Bai, Liyuan; Yuan, Lu; Wu, Ping

2018-05-02

Tin sulphide (SnS2) nanoflowers (NFs) with highly photocatalytic activity for wastewater treatment may lead to potential health hazards via oral routes of human exposure. No studies have reported the hepatic effects of SnS2 NFs on the metabolic function and hepatotoxicity. In this study, we examined the hepatic effects of the oral administration of SnS2 NFs (250-1000 mg/kg) to ICR mice for 14 d, with the particle size ranging from 50 to 200 nm. Serum and liver tissue samples were assayed using biochemical analysis, liver histopathology and metabolic gene expression. The different sizes of SnS2 NFs (250 mg/kg dose), such as 50, 80 and 200 nm, did not induce any adverse hepatic effect related to biochemical parameters or histopathology in the treated mice compared with controls. The oral administration of 50-nm SnS2 NFs at doses of 250, 500 and 1000 mg/kg for 14 d produced dose-dependent hepatotoxicity and inflammatory responses in treated mice. Furthermore, the expression of metabolic genes in the liver tissues was altered, supporting the SnS2 NF-related hepatotoxic phenotype. The oral administration of SnS2 NFs also produced abnormal microstructures in the livers of the treated mice. Taken together, these data indicate that the increased risk of hepatotoxicity in SnS2 NF-treated mice was independent of the particle size but was dependent on their dose. The no-observed-adverse effect level was <250 mg/kg for the 50-nm SnS2 NFs. Our study provides an experimental basis for the safe application of SnS2 NFs.
The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

PubMed Central

Selvaraj, Saravanakumar; Oh, Jung-Hwa; Spanel, Reinhard; Länger, Florian; Han, Hyoung-Yun; Lee, Eun-Hee; Yoon, Seokjoo; Borlak, Jürgen

2017-01-01

Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes. Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system. PMID:29296203
Long-term obestatin treatment of mice type 2 diabetes increases insulin sensitivity and improves liver function.

PubMed

Kołodziejski, Paweł A; Pruszyńska-Oszmałek, Ewa; Strowski, Mathias Z; Nowak, Krzysztof W

2017-06-01

Obestatin and ghrelin are peptides encoded by the preproghrelin gene. Obestatin inhibits food intake, in addition to regulation of glucose and lipid metabolism. Here, we test the ability of obestatin at improving metabolic control and liver function in type 2 diabetic animals (type 2 diabetes mellitus). The effects of chronic obestatin treatment of mice with experimentally induced type 2 diabetes mellitus on serum levels of glucose and lipids, and insulin sensitivity are characterized. In addition, alterations of hepatic lipid and glycogen contents are evaluated. Obestatin reduced body weight and decreased serum glucose, fructosamine, and β-hydroxybutyrate levels, as well as total and low-density lipoprotein fractions of cholesterol. In addition, obestatin increased high-density lipoproteins cholesterol levels and enhanced insulin sensitivity in mice with type 2 diabetes mellitus. Moreover, obestatin diminished liver mass, hepatic triglycerides and cholesterol contents, while glycogen content was higher in livers of healthy and mice with type 2 diabetes mellitus treated with obestatin. These changes were accompanied by reduction of increased alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transpeptidase in T2DM mice with type 2 diabetes mellitus. Obestatin increased adiponectin levels and reduced leptin concentration. Obestatin influenced the expression of genes involved in lipid and carbohydrate metabolism by increasing Fabp5 and decreasing G6pc, Pepck, Fgf21 mRNA in the liver. Obestatin increased both, AKT and AMPK phosphorylation, and sirtuin 1 (SIRT1) protein levels as well as mRNA expression in the liver. Obestatin improves metabolic abnormalities in type 2 diabetes mellitus, restores hepatic lipid contents and decreases hepatic enzymes. Therefore, obestatin could potentially have a therapeutic relevance in treating of insulin resistance and metabolic dysfunctions in type 2 diabetes mellitus.
The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver.

PubMed

Yin, Chunyue; Evason, Kimberley J; Maher, Jacquelyn J; Stainier, Didier Y R

2012-11-01

Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play vital roles in liver development and injury. Our knowledge of HSC biology is limited by the paucity of in vivo data. HSCs and sinusoidal endothelial cells (SECs) reside in close proximity, and interactions between these two cell types are potentially critical for their development and function. Here, we introduce a transgenic zebrafish line, Tg(hand2:EGFP), that labels HSCs. We find that zebrafish HSCs share many similarities with their mammalian counterparts, including morphology, location, lipid storage, gene-expression profile, and increased proliferation and matrix production, in response to an acute hepatic insult. Using the Tg(hand2:EGFP) line, we conducted time-course analyses during development to reveal that HSCs invade the liver after SECs do. However, HSCs still enter the liver in mutants that lack most endothelial cells, including SECs, indicating that SECs are not required for HSC differentiation or their entry into the liver. In the absence of SECs, HSCs become abnormally associated with hepatic biliary cells, suggesting that SECs influence HSC localization during liver development. We analyzed factors that regulate HSC development and show that inhibition of vascular endothelial growth factor signaling significantly reduces the number of HSCs that enter the liver. We also performed a pilot chemical screen and identified two compounds that affect HSC numbers during development. Our work provides the first comprehensive description of HSC development in zebrafish and reveals the requirement of SECs in HSC localization. The Tg(hand2:EGFP) line represents a unique tool for in vivo analysis and molecular dissection of HSC behavior. Copyright © 2012 American Association for the Study of Liver Diseases.
Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet.

PubMed

Strekalova, Tatyana; Evans, Matthew; Costa-Nunes, Joao; Bachurin, Sergey; Yeritsyan, Naira; Couch, Yvonne; Steinbusch, Harry M W; Eleonore Köhler, S; Lesch, Klaus-Peter; Anthony, Daniel C

2015-08-01

An association between metabolic abnormalities, hypercholesterolemia and affective disorders is now well recognized. Less well understood are the molecular mechanisms, both in brain and in the periphery, that underpin this phenomenon. In addition to hepatic lipid accumulation and inflammation, C57BL/6J mice fed a high-cholesterol diet (0.2%) to induce non-alcoholic fatty liver disease (NAFLD), exhibited behavioral despair, anxiogenic changes, and hyperlocomotion under bright light. These abnormalities were accompanied by increased expression of transcript and protein for Toll-like receptor 4, a pathogen-associated molecular pattern (PAMP) receptor, in the prefrontal cortex and the liver. The behavioral changes and Tlr4 expression were reversed ten days after discontinuation of the high-cholesterol diet. Remarkably, the dietary fat content and body mass of experimental mice were unchanged, suggesting a specific role for cholesterol in the molecular and behavioral changes. Expression of Sert and Cox1 were unaltered. Together, our study has demonstrated for the first time that high consumption of cholesterol results in depression- and anxiety-like changes in C57BL/6J mice and that these changes are unexpectedly associated with the increased expression of TLR4, which suggests that TLR4 may have a distinct role in the CNS unrelated to pathogen recognition. Copyright © 2015 Elsevier Inc. All rights reserved.
Hepatic encephalopathy: An approach to its multiple pathophysiological features

PubMed Central

Perazzo, Juan Carlos; Tallis, Silvina; Delfante, Amalia; Souto, Pablo Andrés; Lemberg, Abraham; Eizayaga, Francisco Xavier; Romay, Salvador

2012-01-01

Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two- to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics. PMID:22489256
Radiocolloid liver imaging in tuberculous hepatitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Essop, A.R.; Posen, J.A.; Savitch, I.

1984-02-01

Twenty of 22 patients with tuberculous hepatitis had abnormal Tc-99m tin colloid liver scans. However, in the majority of the patients the changes were mild and nonspecific. The most frequent scintigraphic picture was a decreased uptake of the radiocolloid by the liver, with shunting to the spleen and bone marrow. The decreased hepatic uptake was usually mildly heterogeneous, but it was sometimes homogeneous, and in five patients obvious defects were present. The liver was enlarged in six patients and the spleen in six patients. Increased extrahepatic uptake of the radiocolloid was the only abnormality in five patients. The severity ofmore » the scintigraphic changes did not correlate with the following histologic findings: number of granulomas, degree of associated fibrosis, degree of hepatocyte swelling, or extent of fatty change.« less
Dietary Tributyrin Supplementation Attenuates Insulin Resistance and Abnormal Lipid Metabolism in Suckling Piglets with Intrauterine Growth Retardation

PubMed Central

He, Jintian; Dong, Li; Xu, Wen; Bai, Kaiwen; Lu, Changhui; Wu, Yanan; Huang, Qiang; Zhang, Lili; Wang, Tian

2015-01-01

Intrauterine growth retardation (IUGR) is associated with insulin resistance and lipid disorder. Tributyrin (TB), a pro-drug of butyrate, can attenuate dysfunctions in body metabolism. In this study, we investigated the effects of TB supplementation on insulin resistance and lipid metabolism in neonatal piglets with IUGR. Eight neonatal piglets with normal birth weight (NBW) and 16 neonatal piglets with IUGR were selected, weaned on the 7th day, and fed basic milk diets (NBW and IUGR groups) or basic milk diets supplemented with 0.1% tributyrin (IT group, IUGR piglets) until day 21 (n = 8). Relative parameters for lipid metabolism and mRNA expression were measured. Piglets with IUGR showed higher (P < 0.05) concentrations of insulin in the serum, higher (P < 0.05) HOMA-IR and total cholesterol, triglycerides (TG), non-esterified fatty acid (NEFA) in the liver, and lower (P < 0.05) enzyme activities (hepatic lipase [HL], lipoprotein lipase [LPL], total lipase [TL]) and concentration of glycogen in the liver than the NBW group. TB supplementation decreased (P < 0.05) the concentrations of insulin, HOMA-IR, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in the serum, and the concentrations of TG and NEFA in the liver, and increased (P < 0.05) enzyme activities (HL, LPL, and TL) and concentration of glycogen in the liver of the IT group. The mRNA expression for insulin signal transduction pathway and hepatic lipogenic pathway (including transcription factors and nuclear factors) was significantly (P < 0.05) affected in the liver by IUGR, which was efficiently (P < 0.05) attenuated by diets supplemented with TB. TB supplementation has therapeutic potential for attenuating insulin resistance and abnormal lipid metabolism in IUGR piglets by increasing enzyme activities and upregulating mRNA expression, leading to an early improvement in the metabolic efficiency of IUGR piglets. PMID:26317832
Enhancement of Programmed Death Ligand 2 on Hepatitis C Virus Infected Hepatocytes by Calcineurin Inhibitors

PubMed Central

Koike, Kazuko; Takaki, Akinobu; Yagi, Takahito; Iwasaki, Yoshiaki; Yasunaka, Tetsuya; Sadamori, Hiroshi; Shinoura, Susumu; Umeda, Yuzo; Yoshida, Ryuichi; Sato, Daisuke; Nobuoka, Daisuke; Utsumi, Masashi; Miyake, Yasuhiro; Ikeda, Fusao; Shiraha, Hidenori; Fujiwara, Toshiyoshi; Yamamoto, Kazuhide

2015-01-01

Background Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2. Methods The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines. Results The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity. Conclusions The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C. PMID:25675203
Thyroid stimulating hormone increases hepatic gluconeogenesis via CRTC2.

PubMed

Li, Yujie; Wang, Laicheng; Zhou, Lingyan; Song, Yongfeng; Ma, Shizhan; Yu, Chunxiao; Zhao, Jiajun; Xu, Chao; Gao, Ling

2017-05-05

Epidemiological evidence indicates that thyroid stimulating hormone (TSH) is positively correlated with abnormal glucose levels. We previously reported that TSH has direct effects on gluconeogenesis. However, the underlying molecular mechanism remains unclear. In this study, we observed increased fasting blood glucose and glucose production in a mouse model of subclinical hypothyroidism (only elevated TSH levels). TSH acts via the classical cAMP/PKA pathway and CRTC2 regulates glucose homeostasis. Thus, we explore whether CRTC2 is involved in the process of TSH-induced gluconeogenesis. We show that TSH increases CRTC2 expression via the TSHR/cAMP/PKA pathway, which in turn upregulates hepatic gluconeogenic genes. Furthermore, TSH stimulates CRTC2 dephosphorylation and upregulates p-CREB (Ser133) in HepG2 cells. Silencing CRTC2 and CREB decreases the effect of TSH on PEPCK-luciferase, the rate-limiting enzyme of gluconeogenesis. Finally, the deletion of TSHR reduces the levels of the CRTC2:CREB complex in mouse livers. This study demonstrates that TSH activates CRTC2 via the TSHR/cAMP/PKA pathway, leading to the formation of a CRTC2:CREB complex and increases hepatic gluconeogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.
Placental expression of asialoglycoprotein receptor associated with Hepatitis B virus transmission from mother to child.

PubMed

Vyas, Ashish Kumar; Ramakrishna, Usha; Sen, Bijoya; Islam, Mojahidul; Ramakrishna, Gayatri; Patra, Sharda; Rastogi, Archana; Sarin, Shiv Kumar; Trehanpati, Nirupma

2018-04-30

Asialoglycoprotein receptor expression on hepatocytes has been associated with endocytosis, binding and uptake of hepatitis B virus. The role of asialoglycoprotein receptor in hepatitis B virus vertical transmission and its expression on placenta has not yet been studied. Thirty-four HBsAg+ve and 13 healthy pregnant mothers along with their newborns were enrolled. The former were categorized into transmitting and non-transmitting mothers based on their newborns being hepatitis B surface antigen and hepatitis B virus DNA positive. Expression of asialoglycoprotein receptor and hepatitis B surface antigen in placenta and isoform of asialoglycoprotein receptor on dendritic cell in peripheral and cord blood dendritic cells were analysed using flowcytometry, immune histochemistry, immune florescence and qRT-PCR. Twelve HBsAg+ve mothers transmitted hepatitis B virus to their newborns whereas the rest (n = 22) did not. Hepatitis B virus-transmitting mothers showed increased expression of asialoglycoprotein receptor in trophoblasts of placenta. Immunofluorescence microscopy revealed colocalization of hepatitis B surface antigen and asialoglycoprotein receptor in placenta as well as in DCs of transmitting mothers. There was no significant difference in the expression of asialoglycoprotein receptor on peripheral blood mononuclear cells or chord blood mononuclear cells between the 2 groups. However, hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed increased mRNA levels of isoform of asialoglycoprotein receptor on dendritic cell in peripheral blood mononuclear cells. Hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed an increased expression of isoform of asialoglycoprotein receptor on dendritic cell on circulating dendritic cells compared to hepatitis B virus non-transmitting mothers and their negative newborns. This study revealed that increased expression of asialoglycoprotein receptor in placenta and colocalization with hepatitis B surface antigen strongly indicates its role in intrauterine transmission of hepatitis B virus. Asialoglycoprotein receptor-blocking strategy can be used for therapeutic intervention of vertical transmission. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Risk factors for abnormal liver function tests in patients with ileal pouch-anal anastomosis for underlying inflammatory bowel disease.

PubMed

Navaneethan, Udayakumar; Remzi, Feza H; Nutter, Benjamin; Fazio, Victor W; Shen, Bo

2009-10-01

Liver involvement is common in patients with inflammatory bowel disease (IBD). However, the frequency and the significance of liver function test (LFT) abnormalities in patients with ileal pouch-anal anastomosis (IPAA) for underlying IBD have not been studied. The aim of this study was to evaluate the prevalence and to identify risk factors for abnormal LFTs in patients with IPAA and underlying IBD. All patients were identified from our prospectively maintained Pouchitis Database between 2002 and 2008. Abnormal LFTs were classified as the following: (i) any abnormal elevation of transaminases, and/or alkaline phosphatase (ALP), and/or bilirubin; (ii) hepatitis, if there was more than twice the elevation of transaminases; and (iii) cholestatic, if there was more than 1.5 times elevation of ALP. Clinical, endoscopic, and histological variables were assessed using Cox proportional hazard models for evaluating risk for abnormal LFTs. A total of 545 IPAA patients with underlying IBD were identified from the database, of which 373 patients who had LFTs done after their pouch surgery were included. This included 346 patients with ulcerative colitis, 25 with indeterminate colitis, and 2 with Crohn's colitis before surgery. Their mean age was 45.9+/-13.8 years. A total of 65 patients (17.4%) (40 men, 25 women, median age: 47 years) had abnormal LFTs. Of the patients, 52 (13.9%) had abnormal transaminases, whereas 15 (4%) were classified as having hepatitis. Thirty-five (9.4%) patients had an abnormal ALP level, with 18 (4.8%) classified as cholestatic. The most common cause of an abnormal LFT was transient elevation in 32 (49.2%) patients, followed by fatty liver (fatty change on imaging with body mass index (BMI) > or =25 kg/m(2) in the absence of other causes, including alcohol abuse and drug-induced hepatitis) in 10 (15.4%), drug-induced abnormal LFTs in 7 (10.7%), and chronic hepatitis B or C in 6 (9.2%). Primary sclerosing cholangitis (PSC) was responsible for abnormal LFTs in 10 patients (15.4%). Cox proportional hazard model analysis showed that BMI (hazard ratio (HR)=1.07, 95% confidence interval (95% CI): 1.02, 1.12; P=0.003), the presence of PSC (HR=4.49, 95% CI: 1.45, 13.89; P=0.009), autoimmune disorder (HR=2.54, 95% CI: 1.09, 5.93; P=0.031), a family history of IBD (HR=2.32, 95% CI: 1.29, 4.17; P=0.005), and extensive colitis before colectomy (HR=4.59, 95% CI: 2.04, 10.33; P<0.001) predicted any abnormal LFTs. Abnormal LFTs were common in patients with IPAA in this cohort. The presence of co-existing autoimmune disorder, a family history of IBD, extensive colitis before colectomy, the presence of PSC, and a high BMI appear to be a significant risk factors for abnormal LFTs. Whether abnormal LFTs affect health-related quality of life, pouch survival, and selection of pouch-related medical therapy requires further investigation.
Expression patterns of STAT3, ERK and estrogen-receptor α are associated with development and histologic severity of hepatic steatosis: a retrospective study.

PubMed

Choi, Euno; Kim, Won; Joo, Sae Kyung; Park, Sunyoung; Park, Jeong Hwan; Kang, Yun Kyung; Jin, So-Young; Chang, Mee Soo

2018-04-03

Hepatic steatosis renders hepatocytes vulnerable to injury, resulting in the progression of preexisting liver disease. Previous animal and cell culture studies implicated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription-3 (STAT3), extracellular signal-regulated kinase (ERK) and estrogen-receptor α in the pathogenesis of hepatic steatosis and disease progression. However, to date there have been few studies performed using human liver tissue to study hepatic steatosis. We examined the expression patterns of mTOR, STAT3, ERK and estrogen-receptor α in liver tissues from patients diagnosed with hepatic steatosis. We reviewed the clinical and histomorphological features of 29 patients diagnosed with hepatic steatosis: 18 with non-alcoholic fatty liver disease (NAFLD), 11 with alcoholic fatty acid disease (AFLD), and a control group (16 biliary cysts and 22 hepatolithiasis). Immunohistochemistry was performed on liver tissue using an automated immunostainer. The histologic severity of hepatic steatosis was evaluated by assessing four key histomorphologic parameters common to NAFLD and AFLD: steatosis, lobular inflammation, ballooning degeneration and fibrosis. mTOR, phosphorylated STAT3, phosphorylated pERK, estrogen-receptor α were found to be more frequently expressed in the hepatic steatosis group than in the control group. Specifically, mTOR was expressed in 78% of hepatocytes, and ERK in 100% of hepatic stellate cells, respectively, in patients with NAFLD. Interestingly, estrogen-receptor α was diffusely expressed in hepatocytes in all NALFD cases. Phosphorylated (active) STAT3 was expressed in 73% of hepatocytes and 45% of hepatic stellate cells in patients with AFLD, and phosphorylated (active) ERK was expressed in hepatic stellate cells in all AFLD cases. Estrogen-receptor α was expressed in all AFLD cases (focally in 64% of AFLD cases, and diffusely in 36%). Phosphorylated STAT3 expression in hepatocytes and hepatic stellate cells correlated with severe lobular inflammation, severe ballooning degeneration and advanced fibrosis, whereas diffusely expressed estrogen-receptor α correlated with a mild stage of fibrosis. Our data indicate ERK activation and estrogen-receptor α may be relevant in the development of hepatic steatosis. However, diffuse expression of estrogen-receptor α would appear to impede disease progression, including hepatic fibrosis. Finally, phosphorylated STAT3 may also contribute to disease progression.

Peritoneal manifestations of fascioliasis on CT images: a new observation.

PubMed

Song, Kyoung Doo; Lim, Jae Hoon; Kim, Mi Jeong; Jang, Yun Jin; Kim, Jae Woon; Cho, Seung Hyun; Kwon, Jung Hyeok

2013-08-01

To describe peritoneal manifestations of fascioliasis on CT. We reviewed CT images in 31 patients with fascioliasis confirmed by enzyme-linked immunosorbent assay (ELISA) (n = 24) or surgery (n = 7). Image analyses were performed to identify hepatic, biliary, and peritoneal abnormalities. Hepatic abnormalities were seen in 28 (90.3 %) of the 31 patients. The most common finding was caves sign, which was present in 25 (80.1 %) patients. Three patients (9.7 %) presented with biliary abnormalities exhibiting dilatation and enhancing wall thickening of the bile duct, wall thickening of the gallbladder, and elongated structures in the bile duct or gallbladder. Peritoneal abnormalities were seen in 14 (45.2 %) of the 31 patients. The most common peritoneal abnormality was mesenteric or omental infiltration, which was seen in 9 (29.0 %) patients. Other peritoneal findings included lymph node enlargement (n = 7), ascites (n = 7), thickening of ligamentum teres (n = 2), and peritoneal mass (n = 2). Peritoneal manifestations of fascioliasis are relatively common, and CT findings include mesenteric or omental infiltration, lymph node enlargement, ascites, thickening of the ligamentum teres, and peritoneal masses.
Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression.

PubMed

Gonsebatt, M E; Del Razo, L M; Cerbon, M A; Zúñiga, O; Sanchez-Peña, L C; Ramírez, P

2007-09-01

Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.
Gene expression profile associated with superimposed non-alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C.

PubMed

Younossi, Zobair M; Afendy, Arian; Stepanova, Maria; Hossain, Noreen; Younossi, Issah; Ankrah, Kathy; Gramlich, Terry; Baranova, Ancha

2009-10-01

Hepatic steatosis occurs in 40-70% of patients chronically infected with hepatitis C virus [chronic hepatitis C (CH-C)]. Hepatic steatosis in CH-C is associated with progressive liver disease and a low response rate to antiviral therapy. Gene expression profiles were examined in CH-C patients with and without hepatic steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis. This study included 65 CH-C patients who were not receiving antiviral treatment. Total RNA was extracted from peripheral blood mononuclear cells, quantified and used for one-step reverse transcriptase-polymerase chain reaction to profile 153 mRNAs that were normalized with six 'housekeeping' genes and a reference RNA. Multiple regression and stepwise selection assessed differences in gene expression and the models' performances were evaluated. Models predicting the grade of hepatic steatosis in patients with CH-C genotype 3 involved two genes: SOCS1 and IFITM1, which progressively changed their expression level with the increasing grade of steatosis. On the other hand, models predicting hepatic steatosis in non-genotype 3 patients highlighted MIP-1 cytokine encoding genes: CCL3 and CCL4 as well as IFNAR and PRKRIR. Expression levels of PRKRIR and SMAD3 differentiated patients with and without superimposed NASH only in the non-genotype 3 cohort (area under the receiver operating characteristic curve=0.822, P-value 0.006]. Gene expression signatures related to hepatic fibrosis were not genotype specific. Gene expression might predict moderate to severe hepatic steatosis, NASH and fibrosis in patients with CH-C, providing potential insights into the pathogenesis of hepatic steatosis and fibrosis in these patients.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xuejiao, E-mail: liuxuejiao0615@163.com; Institute for Liver Diseases, Anhui Medical University, Hefei 230032; Wu, Yuting

Background: NLRC5, as the largest member of NLRs family, has recently been identified as a critical regulator of immune responses through negatively regulating NF-κB which is associated with the development of hepatic fibrosis. However, the expression and potential roles of NLRC5 in hepatic fibrosis and its reversal are still to be defined. Methods: C57BL/6 mice were treatment with carbon tetrachloride (CCl{sub 4}) induce hepatic fibrosis and its reversal. In vitro, models of hepatic fibrosis and its reversal are established by the treatment with TGF-β and MDI. The expression of NLRC5 was determined by RT-PCR, Western blot and immunohistochemistry. Consequently, NLRC5more » was overexpressed or knockdown by transfecting PEGFP-C2-NLRC5 or NLRC5-siRNA respectively in the reversal of hepatic fibrosis, and the expression of fibrogenic genes such as α-SMA and Col1α1 was quantified. The NF-κB activity was detected as well. Results: Immunohistochemistry, RT-PCR and Western blot analysis with liver tissues and primary HSCs showed that NLRC5 was highly expressed in hepatic fibrosis and correspondingly decreased in the reversal stage. The differential expression of NLRC5 was confirmed in vitro. Enforced NLRC5 expression increased the expression of α-SMA and Col1α1, and blockade of NLRC5 reduced the fibrotic response. While the opposite expression of phosphorylated NF-kB p65 and phospho-IκBα was found. Conclusion: NLRC5 is differentially expressed in hepatic tissues and hepatic stellate cells during hepatic fibrosis and its reversal. All the data indicated that NLRC5 may play a crucial role in regulating the reversal of hepatic fibrosis through NF-κB signaling pathway. - Highlights: • The activated HSCs can be reverted to quiescent HSCs by MDI treatment. • NLRC5 expressed differentially during different stages of hepatic fibrosis and its reversal. • Enforced NLRC5 in reverted LX-c cells boosted the expression of α-SMA and Col1α1. • Blockade of NLRC5 diminished α-SMA and Col1α1 expression. • NLRC5 might provide a novel therapeutic approach for liver fibrosis.« less
Cocoa butter and safflower oil elicit different effects on hepatic gene expression and lipid metabolism in rats.

PubMed

Gustavsson, Carolina; Parini, Paolo; Ostojic, Jovanca; Cheung, Louisa; Hu, Jin; Zadjali, Fahad; Tahir, Faheem; Brismar, Kerstin; Norstedt, Gunnar; Tollet-Egnell, Petra

2009-11-01

The aim of this study was to compare the effects of cocoa butter and safflower oil on hepatic transcript profiles, lipid metabolism and insulin sensitivity in healthy rats. Cocoa butter-based high-fat feeding for 3 days did not affect plasma total triglyceride (TG) levels or TG-rich VLDL particles or hepatic insulin sensitivity, but changes in hepatic gene expression were induced that might lead to increased lipid synthesis, lipotoxicity, inflammation and insulin resistance if maintained. Safflower oil increased hepatic beta-oxidation, was beneficial in terms of circulating TG-rich VLDL particles, but led to reduced hepatic insulin sensitivity. The effects of safflower oil on hepatic gene expression were partly overlapping with those exerted by cocoa butter, but fewer transcripts from anabolic pathways were altered. Increased hepatic cholesterol levels and increased expression of hepatic CYP7A1 and ABCG5 mRNA, important gene products in bile acid production and cholesterol excretion, were specific effects elicited by safflower oil only. Common effects on gene expression included increased levels of p8, DIG-1 IGFBP-1 and FGF21, and reduced levels of SCD-1 and SCD-2. This indicates that a lipid-induced program for hepatic lipid disposal and cell survival was induced by 3 days of high-fat feeding, independent on the lipid source. Based on the results, we speculate that hepatic TG infiltration leads to reduced expression of SCD-1, which might mediate either neutral, beneficial or unfavorable effects on hepatic metabolism upon high-fat feeding, depending on which fatty acids were provided by the diet.
18F-FDG PET/CT Equivalent of the Hepatic Hot Spot Sign With CT Correlation.

PubMed

Jundt, Michael C; Broski, Stephen M; Binkovitz, Larry A

2018-05-01

A 43-year-old woman presented with an FDG-avid mediastinal Ewing sarcoma invading and nearly occluding the superior vena cava. Geographic increased FDG uptake in hepatic segment IVA was the only other site of nonphysiologic FDG activity. This focal activity was without an underlying mass, had atypical morphology for a hepatic metastasis, and correlated well with prior CT findings of abnormal segment IVA enhancement resulting from the recruitment of portocaval collaterals. In the correct setting, the F-FDG hepatic hot spot should be considered in the differential of a focal FDG-avid hepatic lesion in segment IVA.
Hepatitis C virus core protein induces hepatic steatosis via Sirt1-dependent pathway.

PubMed

Zhang, Chuanhai; Wang, Jingjing; Zhang, Hanlin; Liu, Shunai; Lee, Hyuek Jong; Jin, Wanzhu; Cheng, Jun

2018-05-01

Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied. Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression. Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Expression of CD163 in the liver of patients with viral hepatitis.

PubMed

Hiraoka, Atsushi; Horiike, Norio; Akbar, Sk Md Fazle; Michitaka, Kojiro; Matsuyama, Takami; Onji, Morikazu

2005-01-01

CD163 is a marker of activated macrophages, and increased levels of soluble CD163 have been detected in sera obtained from patients with hepatitis. The aim of this study was to detect the expression of CD163 in the liver from patients with viral hepatitis. Frozen sections of liver specimens were obtained from 5 patients with acute viral hepatitis (AH) and from 23 patients with chronic viral hepatitis (CH). The expression of CD163 in the liver was determined immunohistochemically using monoclonal antibody to human CD163. Double immunostaining was done to assess those cell types that express CD163 in the liver. The frequencies of CD163-positive cells were significantly higher both in the portal areas and in the hepatic lobules in the liver of patients with AH compared to those with CH (p < 0.05). Double immunostaining revealed that most of the CD163-positive cells were macrophages and Kupffer cells, because they expressed CD68. The expression of CD163 was very low in endothelial cells and liver stellate cells. This study shows that macrophages are activated in hepatitis liver.
Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy.

PubMed

Cichoż-Lach, Halina; Michalak, Agata

2013-01-07

Hepatic encephalopathy is a medical phenomenon that is described as a neuropsychiatric manifestation of chronic or acute liver disease that is characterized by psychomotor, intellectual and cognitive abnormalities with emotional/affective and behavioral disturbances. This article focuses on the underlying mechanisms of the condition and the differences between hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. Hepatic encephalopathy is a serious condition that can cause neurological death with brain edema and intracranial hypertension. It is assumed that approximately 60%-80% of patients with liver cirrhosis develop hepatic encephalopathy. This review explores the complex mechanisms that lead to hepatic encephalopathy. However, noncirrhotic hyperammonemic encephalopathy is not associated with hepatic diseases and has a completely different etiology. Noncirrhotic hyperammonemic encephalopathy is a severe occurrence that is connected with multiple pathogeneses.
Comparing functional metabolic effects of marginal and sufficient selenium supply in sheep.

PubMed

Humann-Ziehank, Esther; Renko, Kostja; Mueller, Andreas S; Roehrig, Petra; Wolfsen, Jacqueline; Ganter, Martin

2013-10-01

This study was performed to characterise key data of long-term ovine Se metabolism and to work out the best biomarker of Se status. An upgrade from marginal (<0.05 mg Se/kg diet, 'Se-') to sufficient (0.2mg Se/kg diet, 'Se+') nutritional Se supply using sodium selenite was monitered biweekly by analysing Se concentration, glutathione peroxidase (Gpx) activity and routine biochemistry in blood/serum over 2 years. Se, Cu, Zn, cytosolic Gpx and thioredoxin reductase (TrxR) activity were measured in the liver (biopsies/post-mortem). Se, Gpx, TrxR, glutathione-S-transferase-alpha (aGST) and iodothyronine deiodinase (Dio1) were analysed in the kidney, heart muscle and thyroid. Relative mRNA expression of hepatic aGST1 and Gpx1 was determined. Improvement of Se supply strongly increased serum and liver Se concentration within 10 and 20 days, respectively followed by a plateau. Whereas the achievement of a maximum whole blood Gpx activity was reached after 3 months, serum Gpx3 activity increased with high variations. Hepatic Gpx activity reached a maximum during days 100-200, decreasing thereafter. Distinct group differences in Se and cytosolic Gpx activity were evident in all organs (except Se in kidney). TrxR and Dio1 activity was affected only in the liver. The Se- sheep showed an ongoing decrease in serum Se concentration within 2 years, whereas liver Se remained almost unaffected. High relative Gpx1 mRNA expression in the Se+ group was consensual to high hepatic Gpx activity. Relative mRNA expression of hepatic aGST1 was higher in the Se- sheep. Clinical signs and abnormalities in routine biochemistry were absent. In summary, the best biomarker of Se deprivation and nutritional Se upgrade, respectively was Se in serum. Moreover, hepatic Se concentrations reliably reflected the upgrade of Se supply within days. Whole blood Gpx reacts slowly depending on newly formed erythrocytes restricting its diagnostic use. Vital organs are affected by Se deficiency due to a decrease of cytosolic Gpx activity attenuating the antioxidative system. Cellular up-regulation of aGST1 mRNA expression in the Se- group is assumed to partially compensate for the decreased antioxidant defence due to a loss in Gpx activity. This sheep model appears advantageous for long-term studies on sub-clinical metabolic effects in experimental modifiable nutritional Se supply. Copyright © 2013 Elsevier GmbH. All rights reserved.
Liver transplantation for fulminant hepatitis at Stanford University.

PubMed

Lu, Amy; Monge, Humberto; Drazan, Kenneth; Millan, Maria; Esquivel, Carlos O

2002-01-01

To review the clinical characteristics and outcomes of 26 patients evaluated for liver transplantation for fulminant hepatic failure at Stanford University and Lucile Packard Children's Hospital in an attempt to identify risk factors and prognostic predictors of survival. A retrospective review of the records of 26 consecutive patients who were evaluated for possible liver transplantation for acute liver failure from May 1, 1995, to January 1, 2000. Pretransplant patient demographics and clinical characteristics were collected, and the data were analyzed by univariate and multivariate analysis. Clinical assessment of encephalopathy did not predict outcome. Patients with abnormal computed tomography (CT) of the brain had a twofold increase in mortality compared with those patients with normal studies (p = 0.03). Patients requiring mechanical ventilation and continuous venovenous hemofiltration (CVVH) also had a poor prognosis. Predictors of poor outcome after fulminant hepatic failure include abnormal CT scan, mechanical ventilation, and requirement for hemofiltration.
Hepatic blood flow measurement III. Total hepatic blood flow measured by ICG clearance and electromagnetic flowmeters in a canine septic shock model.

PubMed Central

Nxumalo, J L; Teranaka, M; Schenk, W G

1978-01-01

The validity of the ICG clearance method for the measurement of THBF in abnormal circulatory states remains questionable. In this study THBF measured by this method is compared with the electromagnetic flow technique in a canine spetic model. Good correlation is demonstrated between the two in normal control animals. However, in the septic animals the ICG underestimated the electromagnetic flow result by 20%. This is true in both the high and the low cardiac output septic shock pictures that emerge. In the septic animals, the total hepatic blood flow as measured by the ICG was almost equal to the portal vein flow alone measured by the electromagnetic flowmeters suggesting that this was the quantity it was measuring in this abnormal state. Pathophysiologic mechanisms that may explain the discrepancy are given. PMID:637587
Diagnostic Value of Anti-Hepatitis C Virus (HCV) Core Immunoglobulin M in Recurrence of HCV Infection after Orthotopic Liver Transplantation†

PubMed Central

Casino, Carmela; Lilli, Daniela; Rivanera, Daniela; Comanducci, Antonella; Rossi, Massimo; Casciaro, Giovanni; Pecorella, Irene; Alfani, Dario; Mancini, Carlo

1999-01-01

The significance of anti-hepatitis C virus (HCV) core immunoglobulin M (IgM) and its relationship with genotypes, alanine aminotransferase abnormality, and histological data were studied for 18 patients who had undergone orthotopic liver transplantation due to HCV-related end-stage disease. During follow-up, IgM response seemed to be associated with the recurrence of HCV infection but did not correlate with abnormal alanine aminotransferase levels and histological data. In addition, the results of this study indicated that the detection of HCV RNA is critical for diagnosis of reinfection in liver transplantation. PMID:10405433
Abnormal histopathology, fat percent and hepatic apolipoprotein A I and apolipoprotein B100 mRNA expression in fatty liver hemorrhagic syndrome and their improvement by soybean lecithin.

PubMed

Song, Yalu; Ruan, Jiming; Luo, Junrong; Wang, Tiancheng; Yang, Fei; Cao, Huabin; Huang, Jianzhen; Hu, Guoliang

2017-10-01

To investigate the etiopathogenesis of fatty liver hemorrhagic syndrome (FLHS) and the protective effects of soybean lecithin against FLHS in laying hens, 135 healthy 300-day-old Hyline laying hens were randomly divided into groups: control (group 1), diseased (group 2), and protected (group 3). Each group contained 45 layers with 3 replicates. The birds in these 3 groups were fed a control diet, a high-energy/low-protein (HELP) diet or the HELP diet supplemented with 3% soybean lecithin instead of maize. The fat percent in the liver was calculated. Histopathological changes in the liver were determined by staining, and the mRNA expression levels of apolipoproteinA I (apoA I) and apolipoprotein B100 (apoB100) in the liver were determined by RT-PCR. The results showed that the fat percent in the liver of group 2 was much higher (P < 0.01) than that of group 1 and group 2 on d 30 and 60. The histology of the liver in group 2 on d 30 and 60 displayed various degrees of liver lesions, while the hepatocytes showed a normal structure in group 3 with mild microvesicular steatosis in the liver cell on d 30 and 60. The mRNA expression levels of apoA I and apoB100 in the livers were variable throughout the experiment. The expression level of apoA I in group 2 significantly decreased on d 60 (P < 0.05); the expression level of apoB100 slightly increased on d 30 in group 2, while it sharply decreased on d 60. Compared to group 1, the expression level of apoB100 showed no significant difference in group 3 (P < 0.05). This study indicated that FLHS induced pathological changes and abnormal expression of apoA I and apoB100 in the livers of laying hens and that soybean lecithin alleviated these abnormal changes. © 2017 Poultry Science Association Inc.
Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.

PubMed

Priyadarshini, Emayavaramban; Anuradha, Carani Venkatraman

2017-02-01

High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.
Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy.

PubMed

Köşkderelioğlu, Aslı; Ortan, Pınar; Ari, Alpay; Gedizlioğlu, Muhteşem

2016-03-01

To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in favor of peripheral nerve injury of various types and optic neuropathy of the axonal type.
Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy

PubMed Central

KÖŞKDERELİOĞLU, Aslı; ORTAN, Pınar; ARI, Alpay; GEDİZLİOĞLU, Muhteşem

2016-01-01

Introduction To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. Methods Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. Results Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. Conclusion Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in favor of peripheral nerve injury of various types and optic neuropathy of the axonal type. PMID:28360761
Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

PubMed Central

Almatrafi, Manal Mused; Vergara-Jimenez, Marcela; Murillo, Ana Gabriela; Norris, Gregory H.; Blesso, Christopher N.; Fernandez, Maria Luz

2017-01-01

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver. PMID:28640194
Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism.

PubMed

Almatrafi, Manal Mused; Vergara-Jimenez, Marcela; Murillo, Ana Gabriela; Norris, Gregory H; Blesso, Christopher N; Fernandez, Maria Luz

2017-06-22

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group ( p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group ( p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls ( p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.
Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB–mediated mechanism

PubMed Central

Qiu, Jia; Thapaliya, Samjhana; Runkana, Ashok; Yang, Yu; Tsien, Cynthia; Mohan, Maradumane L.; Narayanan, Arvind; Eghtesad, Bijan; Mozdziak, Paul E.; McDonald, Christine; Stark, George R.; Welle, Stephen; Naga Prasad, Sathyamangla V.; Dasarathy, Srinivasan

2013-01-01

Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB–dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients. PMID:24145431

Protective Effect of Procyanidin B2 against CCl4-Induced Acute Liver Injury in Mice.

PubMed

Yang, Bing-Ya; Zhang, Xiang-Yu; Guan, Sheng-Wen; Hua, Zi-Chun

2015-07-03

Procyanidin B2 has demonstrated several health benefits and medical properties. However, its protective effects against CCl4-induced hepatotoxicity have not been clarified. The present study aimed to investigate the hepatoprotective effects of procyanidin B2 in CCl4-treated mice. Our data showed that procyanidin B2 significantly decreased the CCl4-induced elevation of serum alanine aminotransferase activities, as well as improved hepatic histopathological abnormalities. Procyanidin B2 also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD, CAT and GSH-Px. Further research demonstrated that procyanidin B2 decreased the expression of TNF-α, IL-1β, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), as well as inhibited the translocation of nuclear factor-kappa B (NF-κB) p65 from the cytosol to the nuclear fraction in mouse liver. Moreover, CCl4-induced apoptosis in mouse liver was measured by (terminal-deoxynucleotidyl transferase mediated nick end labeling) TUNEL assay and the cleaved caspase-3. Meanwhile, the expression of apoptosis-related proteins Bax and Bcl-xL was analyzed by Western blot. Results showed that procyanidin B2 significantly inhibited CCl4-induced hepatocyte apoptosis, markedly suppressed the upregulation of Bax expression and restored the downregulation of Bcl-xL expression. Overall, the findings indicated that procyanidin B2 exhibited a protective effect on CCl4-induced hepatic injury by elevating the antioxidative defense potential and consequently suppressing the inflammatory response and apoptosis of liver tissues.
Low-dose ethanol aggravates allergic dermatitis in mice.

PubMed

Sakazaki, Fumitoshi; Ogino, Hirofumi; Arakawa, Tomohiro; Okuno, Tomofumi; Ueno, Hitoshi

2014-08-01

Alcohol injures dendritic cells and suppresses cellular immunity, while some evidence indicates that drinking alcohol aggravates allergic asthma. This study investigated the effect of low doses of ethanol in enhancing allergic reactions in the skin of mice. Liquid food containing alcohol was administered to conventional NC/Nga mice to induce alcoholic hepatic steatosis, and spontaneous dermatitis was evaluated. BALB/c mice were administered approximately 1 g/kg body weight of ethanol by gavage, and contact hypersensitivity (CHS) or active cutaneous anaphylaxis (ACA) was induced. Spleens were collected 24 h after the elicitation of CHS and mRNA expressions of interferon (IFN)-γ, interleukin (IL)-4, IL-6, IL-10, and IL-18 were measured by quantitative RT-PCR. Alcohol-containing diet exaggerated spontaneous dermatitis in conventional NC/Nga mice and contact hypersensitivity in BALB/c mice. Ethanol administered by gavage for 5 days enhanced contact hypersensitivity in BALB/c mice. Ethanol administration with gavage also enhanced ACA of BALB/c mice. Ethanol did not affect mRNA expression of IFN-γ and IL-4, but did enhance IL-6, IL-10, and IL-18 mRNA expression. Histological evaluation revealed an absence of hepatic steatosis in mice administered ethanol by gavage for 5 days. In ethanol-administered mice, inflamed areas presented as lesions or a local extreme accumulation of mononuclear cells in the epidermis. These findings suggest that ethanol enhances the expression of inflammatory cytokines independently from T helper (Th)1/Th2 cytokine phenotypes, causing abnormalities in the epidermis resulting in exacerbated allergic reactivity. Copyright © 2014 Elsevier Inc. All rights reserved.
Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-κB-mediated mechanism.

PubMed

Qiu, Jia; Thapaliya, Samjhana; Runkana, Ashok; Yang, Yu; Tsien, Cynthia; Mohan, Maradumane L; Narayanan, Arvind; Eghtesad, Bijan; Mozdziak, Paul E; McDonald, Christine; Stark, George R; Welle, Stephen; Naga Prasad, Sathyamangla V; Dasarathy, Srinivasan

2013-11-05

Loss of muscle mass, or sarcopenia, is nearly universal in cirrhosis and adversely affects patient outcome. The underlying cross-talk between the liver and skeletal muscle mediating sarcopenia is not well understood. Hyperammonemia is a consistent abnormality in cirrhosis due to impaired hepatic detoxification to urea. We observed elevated levels of ammonia in both plasma samples and skeletal muscle biopsies from cirrhotic patients compared with healthy controls. Furthermore, skeletal muscle from cirrhotics had increased expression of myostatin, a known inhibitor of skeletal muscle accretion and growth. In vivo studies in mice showed that hyperammonemia reduced muscle mass and strength and increased myostatin expression in wild-type compared with postdevelopmental myostatin knockout mice. We postulated that hyperammonemia is an underlying link between hepatic dysfunction in cirrhosis and skeletal muscle loss. Therefore, murine C2C12 myotubes were treated with ammonium acetate resulting in intracellular concentrations similar to those in cirrhotic muscle. In this system, we demonstrate that hyperammonemia stimulated myostatin expression in a NF-κB-dependent manner. This finding was also observed in primary murine muscle cell cultures. Hyperammonemia triggered activation of IκB kinase, NF-κB nuclear translocation, binding of the NF-κB p65 subunit to specific sites within the myostatin promoter, and stimulation of myostatin gene transcription. Pharmacologic inhibition or gene silencing of NF-κB abolished myostatin up-regulation under conditions of hyperammonemia. Our work provides unique insights into hyperammonemia-induced myostatin expression and suggests a mechanism by which sarcopenia develops in cirrhotic patients.
HIV-associated anal dysplasia: experience from a multiethnic-HIV clinic in Hawaii.

PubMed

Payam, Ahoora; Shiramizu, Bruce; Shikuma, Cecilia; Milne, Cris; Terada, Kevin; Kajioka, Eric; Ka'opua, Lana Sue; Cassel, Kevin; Chow, Dominic

2011-01-01

To assess the proportion as well as predictors of anal dysplasia in HIV-infected Asian/Pacific Islanders. This was a retrospective chart review evaluating the proportion of anal dysplasia among a multiethnic population from an ambulatory university-based HIV clinic in Hawaii. Demographic, clinical, and virologic parameters were examined with respect to abnormal anal Pap smear. Variables included: Pap smear results (outcome variable), cytology results, age, self-reported ethnicity, CD4/ nadir CD4 counts, HIV viral load, antiretroviral therapy use, Hepatitis B and C co-infections, history of sexually transmitted diseases, personal history of cancer, tobacco use, alcohol use, intravenous drug abuse, family history of cancer, and history of genital/anal warts. There were no significant differences in rates of abnormal Pap smear among the ethnic groups. Abnormal Pap smears were associated with history of genital warts (7% normal vs. 18% abnormal, p=.01) and alcohol consumption (16% vs. 27%, p=.05). Hepatitis B infection and current anti-retroviral therapy (ART) were associated with normal Pap cytology (9.7% vs. 0%, p=.03) and (96.8% vs. 86.5%, p=.05) respectively. No differences in the proportion of abnormal Pap smears were seen among ethnic groups followed within an ambulatory HIV clinic.
Involvement of adenosine monophosphate-activated protein kinase in the influence of timed high-fat evening diet on the hepatic clock and lipogenic gene expression in mice.

PubMed

Huang, Yan; Zhu, Zengyan; Xie, Meilin; Xue, Jie

2015-09-01

A high-fat diet may result in changes in hepatic clock gene expression, but potential mechanisms are not yet elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine protein kinase that is recognized as a key regulator of energy metabolism and certain clock genes. Therefore, we hypothesized that AMPK may be involved in the alteration of hepatic clock gene expression under a high-fat environment. This study aimed to examine the effects of timed high-fat evening diet on the activity of hepatic AMPK, clock genes, and lipogenic genes. Mice with hyperlipidemic fatty livers were induced by orally administering high-fat milk via gavage every evening (19:00-20:00) for 6 weeks. Results showed that timed high-fat diet in the evening not only decreased the hepatic AMPK protein expression and activity but also disturbed its circadian rhythm. Accordingly, the hepatic clock genes, including clock, brain-muscle-Arnt-like 1, cryptochrome 2, and period 2, exhibited prominent changes in their expression rhythms and/or amplitudes. The diurnal rhythms of the messenger RNA expression of peroxisome proliferator-activated receptorα, acetyl-CoA carboxylase 1α, and carnitine palmitoyltransferase 1 were also disrupted; the amplitude of peroxisome proliferator-activated receptorγcoactivator 1α was significantly decreased at 3 time points, and fatty liver was observed. These findings demonstrate that timed high-fat diet at night can change hepatic AMPK protein levels, activity, and circadian rhythm, which may subsequently alter the circadian expression of several hepatic clock genes and finally result in the disorder of hepatic lipogenic gene expression and the formation of fatty liver. Copyright © 2015 Elsevier Inc. All rights reserved.
Hypoglycemic and hypolipidemic effects of triterpenoid-enriched Jamun (Eugenia jambolana Lam.) fruit extract in streptozotocin-induced type 1 diabetic mice.

PubMed

Xu, Jialin; Liu, Tingting; Li, Yuanyuan; Yuan, Chunhui; Ma, Hang; Seeram, Navindra P; Liu, Feifei; Mu, Yu; Huang, Xueshi; Li, Liya

2018-06-20

The edible berries of Eugenia jambolana Lam. (known as Jamun) are consumed in various parts of the world. Our previous studies revealed that a triterpenoid-enriched Jamun fruit extract (TJFE) showed beneficial effects on glucose homeostasis in non-diabetic mice. Herein, the anti-diabetic effects of TJFE (100 mg kg-1 by oral gavage for ten days) were evaluated in streptozotocin (STZ)-induced type 1 diabetic mice. TJFE significantly attenuated STZ-induced hyperglycemia and glucose intolerance, suppressed the abnormal elevation of hepatic gluconeogenesis, and improved dyslipidemia in the mice. Histopathology and mechanism-based studies revealed that TJFE preserved the architecture and function of pancreatic islets, attenuated insulin secretion deficiency, enhanced insulin/Akt signaling transduction, reduced lipogenic gene expression, and prevented the abnormal activation of Erk MAPK in the liver tissues of the STZ-induced diabetic mice. The current study adds to previously published data supporting the potential beneficial effects of this edible fruit on diabetes management.
Secondhand smoke induces hepatic apoptosis and fibrosis in hamster fetus.

PubMed

Huang, Chien-Wei; Horng, Chi-Ting; Huang, Chih-Yang; Cho, Ta-Hsiung; Tsai, Yi-Chang; Chen, Li-Jeng; Hsu, Tsai-Ching; Tzang, Bor-Show

2016-09-01

Secondhand smoke (SHS) is an important health issue worldwide. Inhaling SHS during pregnancy could cause abnormalities in the internal tissues of newborns, which may then impair fetal development and even cause severe intrauterine damage and perinatal death. However, the understanding of cytopathic mechanisms of SHS by maternal passive smoking on fetus liver during pregnancy is still limited. This study analyzed the effects of high-dose SHS (SHSH) on fetus liver using a maternal passive smoking animal model. Experiments showed that hepatic matrix metalloproteinase-9 activity and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells were significantly increased in livers from fetuses of hamsters treated with SHSH. Similarly, expressions of both extrinsic and intrinsic apoptotic molecules were significantly higher in livers from fetuses of hamsters exposed to SHSH. Additionally, significantly increased inflammatory proteins, including transforming growth factor β, inducible nitric oxide synthase, and interleukin 1β, and fibrotic signaling molecules, including phosphorylated Smad2/3, SP1, and α-smooth muscle actin, were observed in the fetus livers from hamsters treated with SHSH. This study revealed that SHSH not only increased apoptosis through intrinsic and extrinsic pathways in the livers of fetuses from hamsters exposed to SHSH but also augmented hepatic fibrosis via Smad2/3 signaling. © The Author(s) 2015.
Apocynin alleviated hepatic oxidative burden and reduced liver injury in hypercholesterolaemia.

PubMed

Lu, Long-Sheng; Wu, Chau-Chung; Hung, Li-Man; Chiang, Meng-Tsan; Lin, Ching-Ting; Lin, Chii-Wann; Su, Ming-Jai

2007-05-01

This study addressed the effects of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, on hepatic oxidative burden and liver injury during diet-induced hypercholesterolaemia. Male Wistar rats were fed a 4% cholesterol-enriched diet for 3 weeks. Apocynin was administered in drinking water concurrently. The high-cholesterol diet (HC) significantly increased the serum level of cholesterol and hepatic cholesterol ester deposition, and these parameters were similar between the HC and high-cholesterol diet plus apocynin (HCA) groups. The HC group showed abnormal liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (Alk-P)] as well as increased Evans blue extravasation and macrophages infiltration. Apocynin treatment could suppress these inflammation-related parameters. In vivo measurement of NADPH-derived cellular autofluorescence suggested that HC increased oxidative stress in hepatocytes. Biochemical analysis of redox status including thiobarbituric acid reactive substances, reduced glutathione, and oxidized glutathione also confirmed the phenomenon. Apocynin treatment was able to alleviate these indices of oxidative burden owing to HC. Furthermore, apocynin-abrogated HC induced gp91(phox) expression, suggesting the involvement of NADPH oxidase in the pathogenesis. We concluded that apocynin suppressed NADPH oxidase activation and subsequent liver injuries owing to high-cholesterol intake in rats. The impacts of cholesterol metabolism disorders on pathogenesis and progression of steatohepatitis warrant further clinical investigation.
Hepatic glucose sensing is required to preserve β cell glucose competence

PubMed Central

Seyer, Pascal; Vallois, David; Poitry-Yamate, Carole; Schütz, Frédéric; Metref, Salima; Tarussio, David; Maechler, Pierre; Staels, Bart; Lanz, Bernard; Grueter, Rolf; Decaris, Julie; Turner, Scott; da Costa, Anabela; Preitner, Frédéric; Minehira, Kaori; Foretz, Marc; Thorens, Bernard

2013-01-01

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr–/– mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. PMID:23549084
Effect of Nigella sativa fixed and essential oils on antioxidant status, hepatic enzymes, and immunity in streptozotocin induced diabetes mellitus

PubMed Central

2014-01-01

Background Nigella sativa fixed (NSFO) and essential (NSEO) oils have been used to treat diabetes mellitus and its complications. Present study was undertaken to explore and validate these folkloric uses. Methods Sprague dawley rats having streptozotocin (STZ) induced diabetes mellitus were used to assess the role of NSFO and NSEO in the management of diabetes complications. Parameters investigated were antioxidant potential, oxidative stress, and the immunity by in vivo experiments. Results The results indicated that STZ decreased the glutathione contents (25.72%), while NSFO and NSEO increased the trait significantly (P < 0.05). Experimental diets increased the tocopherol contents (P < 0.01) and enhanced the expression of hepatic enzymes (P < 0.01). Correlation matrix further indicated that antioxidant potential is positively associated (P < 0.05) responsible for the modulation of hepatic enzymes and the decrease of the nitric oxide production thus controlling the diabetes complications. Conclusions Overall, results of present study supported the traditional use of N. sativa and its derived products as a treatment for hyperglycemia and allied abnormalities. Moreover, N. sativa fixed and essential oils significantly ameliorate free radicals and improve antioxidant capacity thus reducing the risk of diabetic complications. PMID:24939518
Toxin-Induced Autoimmune Hepatitis Caused by Raw Cashew Nuts.

PubMed

Crismale, James F; Stueck, Ashley; Bansal, Meena

2016-08-01

A 64-year-old man with no past medical history presented with abnormally elevated liver enzymes 1 year after developing a diffuse rash thought to be related to eating large quantities of raw cashew nuts. Liver biopsy was performed, which revealed features concerning for drug- or toxin-induced autoimmune hepatitis. The patient began treatment with azathioprine and prednisone, and liver enzymes normalized. We describe a unique case of a toxin-induced autoimmune hepatitis precipitated not by a drug or dietary supplement but by a food product.
Micronuclei and other erythrocyte nuclear abnormalities in fishes from the Great Lakes Basin, USA.

PubMed

Braham, Ryan P; Blazer, Vicki S; Shaw, Cassidy H; Mazik, Patricia M

2017-10-01

Biological markers (biomarkers) sensitive to genotoxic and mutagenic contamination in fishes are widely used to identify exposure effects in aquatic environments. The micronucleus assay was incorporated into a suite of indicators to assess exposure to genotoxic and mutagenic contamination at five Great Lakes Areas of Concern (AOCs), as well as one non-AOC (reference) site. The assay allowed enumeration of micronuclei as well as other nuclear abnormalities for both site and species comparisons. Erythrocyte abnormality data was also compared to skin and liver tumor prevalence and hepatic transcript abundance. Erythrocyte abnormalities were observed at all sites with variable occurrence and severity among sites and species. Benthic-oriented brown bullhead (Ameiurus nebulosus) and white sucker (Catostomus commersonii) expressed lower rates of erythrocyte abnormalities, but higher rates of skin and liver neoplasms, when compared to pelagic-oriented largemouth bass (Micropterus salmoides) or smallmouth bass (Micropterus dolomieu) at the same site. The reduced erythrocyte abnormalities, increased transcript abundance associated with Phase I and II toxicant responsive pathways, and increased neoplastic lesions among benthic-oriented taxa may indicate the development of contaminant resistance of these species to more acute effects. Environ. Mol. Mutagen. 58:570-581, 2017. © 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. © 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
Coeliac disease and the liver: spectrum of liver histology, serology and treatment response at a tertiary referral centre.

PubMed

Majumdar, Kaushik; Sakhuja, Puja; Puri, Amarender Singh; Gaur, Kavita; Haider, Aiman; Gondal, Ranjana

2018-05-01

Coeliac disease (CD) is a gluten-sensitive enteropathy diagnosed on the basis of ESPGHAN criteria and clinical response to gluten-free diet (GFD). Histological abnormalities on liver biopsy have been noted in CD but have seldom been described. To assess the histological spectrum of 'coeliac hepatitis' and possibility of reversal of such features after a GFD. Twenty-five patients with concomitant CD and hepatic derangement were analysed for clinical profile, laboratory investigations and duodenal and liver biopsy. A histological comparison of pre- and post-GFD duodenal and liver biopsies was carried out, wherever possible. Fifteen patients presenting with CD subsequently developed abnormal liver function tests; 10 patients presenting with liver disease were found to have tissue positive transglutaminase in 70% and antigliadin antibodies in 60%. Serological markers for autoimmune liver disease (AILD) were positive in eight patients. Liver histology ranged from mild reactive hepatitis, chronic hepatitis, steatosis to cirrhosis. Liver biopsies after a GFD were available in six cases, of which five showed a decrease in steatosis, portal and lobular inflammation and fibrosis score. Coeliac hepatitis could be a distinct entity and the patients may present with either CD or secondary hepatic derangement. Evaluation for the presence of CD is recommended for patients presenting with AILD, unexplained transaminasaemia or anaemia. This is one of the very few studies demonstrating the continuum of liver histological changes in 'coeliac hepatitis'. Trial of a GFD may result in clinicopathological improvement of 'coeliac hepatitis'. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Reversible severe hepatitis in anorexia nervosa: a case report and overview.

PubMed

Ramsoekh, Dewkoemar; Taimr, Pavel; Vanwolleghem, Thomas

2014-04-01

Mildly elevated transaminases are often observed in anorexia nervosa patients, but severe hepatitis is less common. We suggest that hypoperfusion is the pathogenetic factor that causes severe hepatitis in a patient with a very poor nutritional status and present an overview of previous case reports. In our patient, early initiation of intravenous fluids resulted in rapid recovery of the liver test abnormalities, despite minimal oral caloric intake, the refusal of enteral feeding and the development of a hypoglycemic coma. Two months after admission, transaminases had normalized. Reversible severe hepatitis has been described in most of the cases, with only one anorexia nervosa-related fatal hepatitis. In general, both adequate hydration and gradual enteral feeding with monitoring of electrolytes are essential in the management of anorexia patients with severe hepatitis.
Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

PubMed Central

Jaeger, Doris; Schoiswohl, Gabriele; Hofer, Peter; Schreiber, Renate; Schweiger, Martina; Eichmann, Thomas O.; Pollak, Nina M.; Poecher, Nadja; Grabner, Gernot F.; Zierler, Kathrin A.; Eder, Sandra; Kolb, Dagmar; Radner, Franz P.W.; Preiss-Landl, Karina; Lass, Achim; Zechner, Rudolf; Kershaw, Erin E.; Haemmerle, Guenter

2015-01-01

Background & Aims Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Methods Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. Results Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. Conclusions AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. PMID:25733154
Polysome Profiling in Liver Identifies Dynamic Regulation of Endoplasmic Reticulum Translatome by Obesity and Fasting

PubMed Central

Fu, Suneng; Fan, Jason; Blanco, Joshua; Gimenez-Cassina, Alfredo; Danial, Nika N.; Watkins, Steve M.; Hotamisligil, Gökhan S.

2012-01-01

Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)–associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity. PMID:22927828
Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.

PubMed

Fu, Suneng; Fan, Jason; Blanco, Joshua; Gimenez-Cassina, Alfredo; Danial, Nika N; Watkins, Steve M; Hotamisligil, Gökhan S

2012-08-01

Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)-associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity.
Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression.

PubMed

Kotiya, Deepak; Jaiswal, Bharti; Ghose, Sampa; Kaul, Rachna; Datta, Kasturi; Tyagi, Rakesh K

2016-01-01

The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-α along with NF-κB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-α, NF-κB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer.
Glucose abnormalities in Asian patients with chronic hepatitis C.

PubMed

Bo, Qingyan; Orsenigo, Roberto; Wang, Junyi; Griffel, Louis; Brass, Clifford

2015-01-01

Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin.
Glucose abnormalities in Asian patients with chronic hepatitis C

PubMed Central

Bo, Qingyan; Orsenigo, Roberto; Wang, Junyi; Griffel, Louis; Brass, Clifford

2015-01-01

Many studies have demonstrated a potential association between type 2 diabetes (T2D) and hepatitis C virus infection in Western countries, while similar evidence is limited in Asia. We compared the prevalence of glucose abnormalities (impaired fasting glucose [IFG] and T2D) and their risk factors between Asian and non-Asian chronic hepatitis C (CHC) patients, and evaluated whether glucose abnormalities impacted the viral responses to peginterferon plus ribavirin treatment (current standard of care in most Asian countries). This study retrospectively analyzed data of 1,887 CHC patients from three Phase II/III studies with alisporivir (DEB025) as treatment for CHC. The chi-square test was used to compare the prevalence of IFG/T2D between Asian and non-Asian CHC patients, and logistic regression was used to adjust for sex, age, and cirrhosis status. Risk factors for IFG/T2D were evaluated using univariate and multivariate analysis. Our results indicated that the prevalence of IFG/T2D was high in both Asian and non-Asian CHC patients (23.0% vs 20.9%), and no significant difference was found between these two populations (adjusted odds ratio: 1.3, 95% confidence interval: 0.97, 1.7; P=0.08). Age, sex, and cirrhosis status were risk factors for IFG/T2D in both populations, while body mass index was positively associated with IFG/T2D in non-Asian but not in Asian participants. No significant differences in sustained virological response rates were seen between patients with normal fasting glucose and patients with IFG/T2D for both populations. These results demonstrate that the prevalence of glucose abnormalities in Asian CHC patients was similar to that in non-Asians, and glucose abnormalities had no impact on viral response to peginterferon plus ribavirin. PMID:26609222

[An investigation of trichloroethylene-induced effects on histone methylation in L-02 hepatic cells].

PubMed

Deng, R X; Ren, X H; Ruan, J W; Zheng, J; Zhong, J C; Lu, W X; Zou, X Q; Liu, J J

2017-04-06

Objective: To further explore TCE-induced hepatotoxicity and its mechanisms by identification of trichloroethylene (TCE) induced abnormal histone methylation in human liver cells. Methods: L-02 cells were treated with 0 and 8 mmol/L TCE for 24 h. Histones were extracted by acid. Liquid chromatography electrospray ionization tandem mass spectrometry (ESI-LC-MS/MS) were used to identify and quantify TCE related histone methylations. TCE induced abnormal methylation of H3K79 me2 and H3K79 me3 were validated by Western blot analysis. The further analysis of the function of histone abnormal methylation modifications were done by single cell gel electrophoresis (SCGE) and Western blot analysis of p53 and ɤH2AX. Results: After treatment with TCE for 24 h in L-02 cells, the 36 TCE related histone methylation sites in 28 peptide segments were identified by MS. After treatment with TCE in concentrations of 0 and 8.0 mmol/L in L-02 cells for 24 h, the relative expression level of histone H3K79 me3 were 1.00±0.06, 0.70±0.09 ( t= 15.01, P= 0.015); the relative expression level of histone H3K79 me2 were 1.00±0.05, 0.74±0.07 ( t= 16.69, P= 0.018); the Olive Tail Moment about DNA damage were 1.46±0.28, 3.12± 0.68 ( t= 15.22, P= 0.018); the relative expression levels of p53 were 1.00±0.04, 1.24±0.04 ( t= 18.71, P= 0.012); and the relative expression levels of ɤH2AX were 1.00 ± 0.03, 1.56 ± 0.11 ( t= 8.32, P= 0 045). Conclusion: TCE can induce changes in the relative expression level of H3K79 me2 and H3K79 me3 in L-02 cell, and induce DNA damage, suggesting that TCE may induce changes in the relative expression level of H3K79 me2 and H3K79 me3 by DNA damage.
Angiostrongylus vasorum Causing Severe Granulomatous Hepatitis with Concurrent Multiple Acquired PSS.

PubMed

Cook, Simon; Priestnall, Simon L; Blake, Damer; Meeson, Richard L

2015-01-01

A 14 mo old female Jack Russell terrier presented with a 12 hr history of vomiting and inappetence. She was subsequently diagnosed with multiple acquired portosystemic shunts during an exploratory celiotomy. Gross and histopathological hepatic abnormalities were consistent with chronic disease, including features suggestive of portal hypertension that was potentially caused by migrating and resident Angiostrongylus vasorum larvae. Fecal analysis and polymerase chain reaction of hepatic tissue confirmed the presence of Angiostrongylus vasorum . The dog recovered clinically following empirical treatment and supportive care. A lack of parasite burden was confirmed 9 wk postdiagnosis; however, serum biochemical analysis at that time was suggestive of ongoing hepatic dysfunction.
Theoretical basis of a beneficial role for vitamin D in viral hepatitis

PubMed Central

Lương, Khanh vinh quốc; Nguyễn, Lan Thi Hoàng

2012-01-01

Abnormal bone metabolism and dysfunction of the calcium-parathyroid hormone-vitamin D axis have been reported in patients with viral hepatitis. Some studies suggested a relationship between vitamin D and viral hepatitis. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to the pathology of viral hepatitis (i.e., the major histocompatibility complex class II molecules, the vitamin D receptor, cytochrome P450, the renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, and the proteins regulated by the Sp1 promoter gene). Vitamin D also exerts its effects on viral hepatitis via non-genomic factors, i.e., matrix metalloproteinase, endothelial vascular growth factor, prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D could have a beneficial role in viral hepatitis. Calcitriol is best used for viral hepatitis because it is the active form of the vitamin D3 metabolite. PMID:23082050
Hepatitis E virus infection presenting with paraesthesia.

PubMed

Bennett, Susan; Li, Kathy; Gunson, Rory N

2015-05-01

Hepatitis E virus infection is an emerging disease in developed countries. Acute and chronic infection has been reported, with chronic infection being increasingly reported in immunocompromised patients. Neurological disorders are an emerging manifestation of both acute and chronic hepatitis E virus infection. We report a 77-year-old female presented with paraesthesia and was found to have abnormal liver function tests. Serology was found to be positive for hepatitis E virus IgM, IgG and RNA. Liver function tests normalised after three weeks and her neurological symptoms completely resolved. To our knowledge, this is the first case in Scotland of hepatitis E virus presenting only with neurological symptoms. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure

PubMed Central

2004-01-01

The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1−/− mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver. The L-PDK1−/− mice were not insulin-intolerant, possessed normal levels of blood glucose and insulin under normal feeding conditions, but were markedly glucose-intolerant when injected with glucose. The L-PDK1−/− mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 h after injection of insulin. The glucose intolerance of the L-PDK1−/− mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconeogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1−/− mice died between 4–16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure. PMID:15554902
Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C

PubMed Central

Lens, Sabela; Calleja, Jose L; Campillo, Ana; Carrión, Jose A; Broquetas, Teresa; Perello, Christie; de la Revilla, Juan; Mariño, Zoe; Londoño, María-Carlota; Sánchez-Tapias, Jose M; Urbano-Ispizua, Álvaro; Forns, Xavier

2015-01-01

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications. PMID:25954117
Control of Hepatic Gluconeogenesis by the Promyelocytic Leukemia Zinc Finger Protein

PubMed Central

Chen, Siyu; Qian, Jinchun; Shi, Xiaoli; Gao, Tingting; Liang, Tingming

2014-01-01

The promyelocytic leukemia zinc finger (PLZF) protein is involved in major biological processes including energy metabolism, although its role remains unknown. In this study, we demonstrated that hepatic PLZF expression was induced in fasted or diabetic mice. PLZF promoted gluconeogenic gene expression and hepatic glucose output, leading to hyperglycemia. In contrast, hepatic PLZF knockdown improved glucose homeostasis in db/db mice. Mechanistically, peroxisome proliferator-activated receptor γ coactivator 1α and the glucocorticoid receptor synergistically activated PLZF expression. We conclude that PLZF is a critical regulator of hepatic gluconeogenesis. PLZF manipulation may benefit the treatment of metabolic diseases associated with gluconeogenesis. PMID:25333514
Developmental neurotoxicity targeting hepatic and cardiac sympathetic innervation: effects of organophosphates are distinct from those of glucocorticoids.

PubMed

Seidler, Frederic J; Slotkin, Theodore A

2011-05-30

Early-life exposure to organophosphate pesticides leads to subsequent hyperresponsiveness of β-adrenergic receptor-mediated cell signaling that regulates hepatic gluconeogenesis, culminating in metabolic abnormalities resembling prediabetes. In the current study, we evaluated the effects of chlorpyrifos or parathion on presynaptic sympathetic innervation to determine whether the postsynaptic signaling effects are accompanied by defects in neuronal input. We administered either chlorpyrifos or parathion to newborn rats using exposure paradigms known to elicit the later metabolic changes but found no alterations in either hepatic or cardiac norepinephrine levels in adolescence or adulthood. However, shifting chlorpyrifos exposure to the prenatal period did evoke changes: exposure early in gestation produced subsequent elevations in norepinephrine, whereas later gestational exposure produced significant deficits. We also distinguished the organophosphate effects from those of the glucocorticoid, dexamethasone, a known endocrine disruptor that leads to later-life metabolic and cardiovascular disruption. Postnatal exposure to dexamethasone elicited deficits in peripheral norepinephrine levels but prenatal exposure did not. Our results indicate that early-life exposure to organophosphates leads to subsequent abnormalities of peripheral sympathetic innervation through mechanisms entirely distinct from those of glucocorticoids, ruling out the possibility that the organophosphate effects are secondary to stress or disruption of the HPA axis. Further, the effects on innervation were separable from those on postsynaptic signaling, differing in critical period as well as tissue- and sex-selectivity. Organophosphate targeting of both presynaptic and postsynaptic β-adrenergic sites, each with different critical periods of vulnerability, thus sets the stage for compounding of hepatic and cardiac functional abnormalities. Copyright © 2011 Elsevier Inc. All rights reserved.
Congenital portosystemic shunts: prenatal manifestations with postnatal confirmation and follow-up.

PubMed

Han, Byoung Hee; Park, Sung Bin; Song, Mi Jin; Lee, Kyung Sang; Lee, Young-Ho; Ko, Sun Young; Lee, Yeon Kyung

2013-01-01

The purpose of this study was to evaluate prenatal sonographic findings that could be helpful for diagnosis of congenital intrahepatic portosystemic venous shunts and the follow-up results. Six neonates with congenital shunts between the portal vein and hepatic vein were enrolled in this study. Prenatal sonography was performed in 5 cases. We categorized the cases according to a previously published classification of intrahepatic portosystemic venous shunts and retrospectively reviewed the prenatal and postnatal sonographic examinations to identify findings that might be helpful for diagnosing shunts prenatally. Follow-up sonographic examinations were done until closure of the shunts. Clinical features were also determined. According to the original reports, intrahepatic portosystemic venous shunts were diagnosed by prenatal sonography in 2 of 5 cases. In the remaining 3 cases, there were suggestive abnormal findings on retrospective review, including an abnormal intrahepatic tubular structure, a prominent hepatic vein, and congestive heart failure. Postnatal sonography showed type 2 shunts in all 6 cases. In 1 case, there were 2 type 2 lesions between two branches of the left portal vein and the middle and left hepatic veins. On follow-up sonography, 5 of the 6 congenital shunts had spontaneously closed by 11 months of age. One case was treated with coil embolization during the neonatal period. Intrauterine growth restriction was the most commonly clinical feature prenatally. Findings such as an abnormal tubular structure, a prominent hepatic vein, and congestive heart failure can be important clues for identifying congenital intrahepatic portosystemic venous shunts on prenatal sonography. The use of prenatal and postnatal sonography is feasible for detection and evaluation of these shunts.
Lesions of the segmental and lobar hepatic ducts.

PubMed Central

Longmire, W P; Tompkins, R K

1975-01-01

Despite reports to the contrary, unobstructed drainage of 50% of an otherwise normal liver through either the right or left uninfected hepatic duct is adequate to restore normal liver function, even if the obstructed lobe remains in place. An undrained liver lobe, if present, may require no further treatment. As long as it is completely obstructed and uninfected, it will undergo a progressive asymptomatic atrophy. Cholangitis invariably develops behind a partial lobar ductal obstruction, producing jaundice, pruritis, and fever. Unless unobstructed, uninfected biliary flow can be achieved through a segmental or lobar duct, it is better that the duct be completely obstructed and the affected liver parenchyma allowed to atrophy, provided there is normal biliary flow from the residual 50% of liver. This concept is important in the management of injured anomalous segmental or lobar hepatic duct and in the palliative treatment of bile duct carcinoma. Localized intrahepatic infections communicating with abnormal biliary ducts will require hepatic resection of the infected parenchyma and ducts for cure. The abnormality may be saccular dilatation of the intrahepatic ductal system with abscess formation or intrahepatic abscess associated with stenosis of the ductal system from trauma to the duct, to the duct and liver, or to retained intrahepatic stones. Diffusely situated intrahepatic abscesses secondary to ductal abnormalities can be treated with systemic antibiotics, local drainage of a dmoninant abscess, and efforts to improve biliary drainage. Images Fig. 4. Fig. 5. Fig. 6. Fig. 8. Fig. 9. Fig. 10. Figs. 11A and B Figs. 12A and B. Fig. 13. Fig. 14. Fig. 15. Fig. 16. Fig. 17. PMID:1180585
Pulmonary changes in liver transplant candidates with hepatitis C cirrhosis.

PubMed

Al-Moamary, M S; Gorka, T; Al-Traif, I H; Al-Jahdali, H H; Al-Shimemeri, A A; Al-Kanway, B; Abdulkareeem, A A; Abdulkareeem, A A

2001-12-01

Several studies have shown that pulmonary abnormalities are common in patients with end-stage liver disease. However, most of these studies were conducted on patients with heterogeneous etiologies. Therefore, we studied these changes in a homogenous group of hepatitis C cirrhotic patients who were potential candidates for liver transplantation. The charts of 81 patients from King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia with hepatitis C cirrhosis who were evaluated for liver transplantation were reviewed. The following data was retrieved: echocardiography with micro-bubble study, arterial blood gases, and pulmonary function tests of 81 candidates and reviewed over 3 years from 1994 to 1997. The mean age was 53 (+/-9) years with male to female ratio of 1.4:1. Echocardiographic micro-bubble study, revealed 4 of 62 (7%) had an intrapulmonary shunt. Arterial blood gases results were pH of 7.44 (+/-0.4), partial arterial tension of carbon dioxide of 33 mm Hg (+/-4), partial arterial tension of oxygen of 84 mm Hg (+/-12), and alveolar-arterial gradient of 30 mm Hg (+/-10). Eleven percent had obstructive airway disease, 17% had restrictive lung impairment, and 43% had reduced diffusion capacity. Seventy five percent of patients with reduced diffusion capacity had normal lung volumes. Various pulmonary function test abnormalities did not lead to significant differences in arterial blood gases. Pulmonary changes were frequent in liver transplant candidates with hepatitis C virus cirrhosis with reduced diffusion capacity being the most. Apart from the effect of hepatopulmonary syndrome on arterial oxygenation, other pulmonary abnormalities were not significantly different.
Insights on augmenter of liver regeneration cloning and function

PubMed Central

Gatzidou, Elisavet; Kouraklis, Gregory; Theocharis, Stamatios

2006-01-01

Hepatic stimulator substance (HSS) has been referred to as a liver-specific but species non-specific growth factor. Gradient purification and sequence analysis of HSS protein indicated that it contained the augmenter of liver regeneration (ALR), also known as hepatopoietin (HPO). ALR, acting as a hepatotrophic growth factor, specifically stimulated proliferation of cultured hepatocytes as well as hepatoma cells in vitro, promoted liver regeneration and recovery of damaged hepatocytes and rescued acute hepatic failure in vivo. ALR belongs to the new Erv1/Alr protein family, members of which are found in lower and higher eukaryotes from yeast to man and even in some double-stranded DNA viruses. The present review article focuses on the molecular biology of ALR, examining the ALR gene and its expression from yeast to man and the biological function of ALR protein. ALR protein seems to be non-liver-specific as was previously believed, increasing the necessity to extend research on mammalian ALR protein in different tissues, organs and developmental stages in conditions of normal and abnormal cellular growth. PMID:16937489
Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids.

PubMed

Jiao, Li; Gan-Schreier, Hongying; Zhu, Xingya; Wei, Wang; Tuma-Kellner, Sabine; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee

2017-12-01

Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA 2 β is a homeostatic PLA 2 by playing a role in phospholipid metabolism and remodeling. Global iPLA 2 β -/- mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA 2 β deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA 2 β -/- mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA 2 β -/- mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1α, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRα and FXR. By LC/MS-MS profiling, iPLA 2 β deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA 2 β deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner. Copyright © 2017 Elsevier B.V. All rights reserved.
[Acute hepatitis following amiodarone administration].

PubMed

Tagliamonte, E; Cice, G; Ducceschi, V; Mayer, M S; Iacono, A

1997-09-01

A 61 year old man, treated with amiodarone since 1993 for resistant supraventricular arrhythmias, developed acute hepatitis after an intravenous amiodarone administration. Kidney and liver function tests were performed and pointed out abnormal results. Symptoms ascribable to hepatotoxicity were absent. These changes returned to normal levels within 20 days from withdrawal of the drug. Amiodarone hepatotoxicity can be related to prolonged therapy with a high dose. Intravenous amiodarone may cause acute hepatic disease, but it is suggested that polysorbate 80, a solvent added to the intravenous infusion, is a more likely cause of this complication.
Protectin DX suppresses hepatic gluconeogenesis through AMPK-HO-1-mediated inhibition of ER stress.

PubMed

Jung, Tae Woo; Kim, Hyung-Chun; Abd El-Aty, A M; Jeong, Ji Hoon

2017-06-01

Several studies have shown that protectins, which are ω-3 fatty acid-derived proresolution mediators, may improve insulin resistance. Recently, protectin DX (PDX) was documented to attenuate insulin resistance by stimulating IL-6 expression in skeletal muscle, thereby regulating hepatic gluconeogenesis. These findings made us investigate the direct effects of PDX on hepatic glucose metabolism in the context of diabetes. In the current study, we show that PDX regulates hepatic gluconeogenesis in a manner distinct from its indirect glucoregulatory activity via IL-6. We found that PDX stimulated AMP-activated protein kinase (AMPK) phosphorylation, thereby inducing heme oxygenase 1 (HO-1) expression. This induction blocked hepatic gluconeogenesis by suppressing endoplasmic reticulum (ER) stress in hepatocytes under hyperlipidemic conditions. These effects were significantly dampened by silencing AMPK or HO-1 expression with small interfering RNA (siRNA). We also demonstrated that administration of PDX to high fat diet (HFD)-fed mice resulted in increased hepatic AMPK phosphorylation and HO-1 expression, whereas hepatic ER stress was substantially attenuated. Furthermore, PDX treatment suppressed the expression of gluconeogenic genes, thereby decreasing blood glucose levels in HFD-fed mice. In conclusion, our findings suggest that PDX inhibits hepatic gluconeogenesis via AMPK-HO-1-dependent suppression of ER stress. Thus, PDX may be an effective therapeutic target for the treatment of insulin resistance and type 2 diabetes through the regulation of hepatic gluconeogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.
Roles of PPARγ/NF-κB signaling pathway in the pathogenesis of intrahepatic cholestasis of pregnancy.

PubMed

Zhang, Yan; Hu, Lingqing; Cui, Yan; Qi, Zhigang; Huang, Xiaoping; Cai, Liyi; Zhang, Ting; Yin, Yongxiang; Lu, Zhiyi; Xiang, Jingying

2014-01-01

Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood. To assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP. Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP. The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05). The higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.
Expression of hepatitis B virus 1.3-fold genome plasmid in an SV40 T-antigen-immortalized mouse hepatic cell line

PubMed Central

Song, Xiu-Guang; Bian, Peng-Fei; Yu, Shu-Li; Zhao, Xiu-Hua; Xu, Wei; Bu, Xue-Hui; Li, Xia; Ma, Li-Xian

2013-01-01

AIM: To investigate the expression of the hepatitis B virus (HBV) 1.3-fold genome plasmid (pHBV1.3) in an immortalized mouse hepatic cell line induced by SV40 T-antigen (SV40T) expression. METHODS: Mouse hepatic cells were isolated from mouse liver tissue fragments from 3-5 d old Kunming mice by the direct collagenase digestion method and cultured in vitro. The pRSV-T plasmid was transfected into mouse hepatic cells to establish an SV40LT-immortalized mouse hepatic cell line. The SV40LT-immortalized mouse hepatic cells were identified and transfected with the pHBV1.3 plasmid. The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in the supernatant were determined by an electrochemiluminescence immunoassay at 24, 48, 72 and 96 h after transfection. The expressions of HBsAg and hepatitis B c antigen (HBcAg) in the cells were investigated by indirect immunofluorescence analysis. The presence of HBV DNA replication intermediates in the transfected cells and viral particles in the supernatant of the transfected cell cultures was monitored using the Southern hybridization assay and transmission electronic microscopy, respectively. RESULTS: The pRSV-T plasmid was used to immortalize mouse hepatocytes and an SV40LT-immortalized mouse hepatic cell line was successfully established. SV40LT-immortalized mouse hepatic cells have the same morphology and growth characteristics as primary mouse hepatic cells can be subcultured and produce albumin and cytokeratin-18 in vitro. Immortalized mouse hepatic cells did not show the characteristics of tumor cells, as alpha-fetoprotein levels were comparable (0.58 ± 0.37 vs 0.61 ± 0.31, P = 0.37). SV40LT-immortalized mouse hepatic cells were then transfected with the pHBV1.3 plasmid, and it was found that the HBV genome replicated in SV40LT-immortalized mouse hepatic cells. The levels of HBsAg and HBeAg continuously increased in the supernatant after the transfection of pHBV1.3, and began to decrease 72 h after transfection. The expressions of HBsAg and HBcAg were observed in the pHBV1.3-transfected cells. HBV DNA replication intermediates were also observed at 72 h after transfection, including relaxed circular DNA, double-stranded DNA and single-stranded DNA. Furthermore, a few 42 nm Dane particles, as well as many 22 nm subviral particles with a spherical or filamentous shape, were detected in the supernatant. CONCLUSION: SV40T expression can immortalize mouse hepatic cells, and the pHBV1.3-transfected SV40T-immortalized mouse hepatic cell line can be a new in vitro cell model. PMID:24307795
Expression of hepatitis B virus 1.3-fold genome plasmid in an SV40 T-antigen-immortalized mouse hepatic cell line.

PubMed

Song, Xiu-Guang; Bian, Peng-Fei; Yu, Shu-Li; Zhao, Xiu-Hua; Xu, Wei; Bu, Xue-Hui; Li, Xia; Ma, Li-Xian

2013-11-28

To investigate the expression of the hepatitis B virus (HBV) 1.3-fold genome plasmid (pHBV1.3) in an immortalized mouse hepatic cell line induced by SV40 T-antigen (SV40T) expression. Mouse hepatic cells were isolated from mouse liver tissue fragments from 3-5 d old Kunming mice by the direct collagenase digestion method and cultured in vitro. The pRSV-T plasmid was transfected into mouse hepatic cells to establish an SV40LT-immortalized mouse hepatic cell line. The SV40LT-immortalized mouse hepatic cells were identified and transfected with the pHBV1.3 plasmid. The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in the supernatant were determined by an electrochemiluminescence immunoassay at 24, 48, 72 and 96 h after transfection. The expressions of HBsAg and hepatitis B c antigen (HBcAg) in the cells were investigated by indirect immunofluorescence analysis. The presence of HBV DNA replication intermediates in the transfected cells and viral particles in the supernatant of the transfected cell cultures was monitored using the Southern hybridization assay and transmission electronic microscopy, respectively. The pRSV-T plasmid was used to immortalize mouse hepatocytes and an SV40LT-immortalized mouse hepatic cell line was successfully established. SV40LT-immortalized mouse hepatic cells have the same morphology and growth characteristics as primary mouse hepatic cells can be subcultured and produce albumin and cytokeratin-18 in vitro. Immortalized mouse hepatic cells did not show the characteristics of tumor cells, as alpha-fetoprotein levels were comparable (0.58 ± 0.37 vs 0.61 ± 0.31, P = 0.37). SV40LT-immortalized mouse hepatic cells were then transfected with the pHBV1.3 plasmid, and it was found that the HBV genome replicated in SV40LT-immortalized mouse hepatic cells. The levels of HBsAg and HBeAg continuously increased in the supernatant after the transfection of pHBV1.3, and began to decrease 72 h after transfection. The expressions of HBsAg and HBcAg were observed in the pHBV1.3-transfected cells. HBV DNA replication intermediates were also observed at 72 h after transfection, including relaxed circular DNA, double-stranded DNA and single-stranded DNA. Furthermore, a few 42 nm Dane particles, as well as many 22 nm subviral particles with a spherical or filamentous shape, were detected in the supernatant. SV40T expression can immortalize mouse hepatic cells, and the pHBV1.3-transfected SV40T-immortalized mouse hepatic cell line can be a new in vitro cell model.
Liver-enriched transcription factors uncoupled from expression of hepatic functions in hepatoma cell lines.

PubMed Central

Chaya, D; Fougère-Deschatrette, C; Weiss, M C

1997-01-01

Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver. PMID:9343392
Liver-enriched transcription factors uncoupled from expression of hepatic functions in hepatoma cell lines.

PubMed

Chaya, D; Fougère-Deschatrette, C; Weiss, M C

1997-11-01

Among the liver-enriched transcription factors identified to date, only expression of hepatocyte nuclear factor 4 (HNF4) and hepatocyte nuclear factor 1 (HNF1) is in strict correlation with hepatic differentiation in cultured rat hepatoma cells. Indeed, differentiated hepatoma cells that stably express an extensive set of adult hepatic functions express liver-enriched transcription factors, while dedifferentiated cells that have lost expression of all these hepatic functions no longer express HNF4 and HNF1. We describe a new heritable phenotype, designated as uncoupled, in which there is a spontaneous dissociation between the expression of these transcription factors and that of the hepatic functions. Cells presenting this phenotype, isolated from differentiated hepatoma cells, cease to accumulate all transcripts coding for hepatic functions but nevertheless maintain expression of HNF4 and HNF1. Transitory transfection experiments indicate that these two factors present in these cells have transcriptional activity similar to that of differentiated hepatoma cells. Characterization of the appropriate intertypic cell hybrids demonstrates that this new phenotype is recessive to the dedifferentiated state and fails to be complemented by differentiated cells. These results indicate the existence of mechanisms that inhibit transcription of genes coding for hepatocyte functions in spite of the presence of functional HNF4 and HNF1. Cells of the uncoupled phenotype present certain properties of oval cells described for pathological states of the liver.

Analysis of disease-associated protein expression using quantitative proteomics—fibulin-5 is expressed in association with hepatic fibrosis.

PubMed

Bracht, Thilo; Schweinsberg, Vincent; Trippler, Martin; Kohl, Michael; Ahrens, Maike; Padden, Juliet; Naboulsi, Wael; Barkovits, Katalin; Megger, Dominik A; Eisenacher, Martin; Borchers, Christoph H; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

2015-05-01

Hepatic fibrosis and cirrhosis are major health problems worldwide. Until now, highly invasive biopsy remains the diagnostic gold standard despite many disadvantages. To develop noninvasive diagnostic assays for the assessment of liver fibrosis, it is urgently necessary to identify molecules that are robustly expressed in association with the disease. We analyzed biopsied tissue samples from 95 patients with HBV/HCV-associated hepatic fibrosis using three different quantification methods. We performed a label-free proteomics discovery study to identify novel disease-associated proteins using a subset of the cohort (n = 27). Subsequently, gene expression data from all available clinical samples were analyzed (n = 77). Finally, we performed a targeted proteomics approach, multiple reaction monitoring (MRM), to verify the disease-associated expression in samples independent from the discovery approach (n = 68). We identified fibulin-5 (FBLN5) as a novel protein expressed in relation to hepatic fibrosis. Furthermore, we confirmed the altered expression of microfibril-associated glycoprotein 4 (MFAP4), lumican (LUM), and collagen alpha-1(XIV) chain (COL14A1) in association to hepatic fibrosis. To our knowledge, no tissue-based quantitative proteomics study for hepatic fibrosis has been performed using a cohort of comparable size. By this means, we add substantial evidence for the disease-related expression of the proteins examined in this study.
Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein.

PubMed

Wu, Yun-Li; Peng, Xian-E; Zhu, Yi-Bing; Yan, Xiao-Li; Chen, Wan-Nan; Lin, Xu

2016-02-15

Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3β-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3β and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3β, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced pathogenesis of hepatic steatosis still remains to be elucidated. In this study, we found that expression of liver fatty acid binding protein (FABP1) was dramatically increased in the sera of HBV-infected patients and in both sera and liver tissues of HBV-transgenic mice. Forced expression of HBx led to FABP1 upregulation, whereas knockdown of FABP1 remarkably diminished lipid accumulation in both in vitro and in vivo models. It is possible that HBx promotes hepatic lipid accumulation through upregulating FABP1 in the development of HBV-induced nonalcoholic fatty liver disease. Therefore, inhibition of FABP1 might have therapeutic value in steatosis-associated chronic HBV infection. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Effect of dietary monosodium glutamate on HFCS-induced hepatic steatosis: expression profiles in the liver and visceral fat.

PubMed

Collison, Kate S; Maqbool, Zakia M; Inglis, Angela L; Makhoul, Nadine J; Saleh, Soad M; Bakheet, Razan H; Al-Johi, Mohammed A; Al-Rabiah, Rana K; Zaidi, Marya Z; Al-Mohanna, Futwan A

2010-06-01

It has previously been shown that patients with nonalcoholic fatty liver disease (NAFLD) exhibit alterations in both hepatic and adipose tissue metabolism, and the dietary factors that contribute to the pathogenesis of NAFLD are likely to be multifactorial. Using C57BL/6J mice, we examined whether chronic exposure to low-dose dietary monosodium glutamate (MSG), high-fructose corn syrup (HFCS), or a combination of the two, vs. control would affect metabolism and hepatic and visceral fat gene expression in adult male progeny. A maternal diet containing 20% HFCS and/or dietary MSG (97.2 +/- 6.3 mg/kg body weight (bw), provided in the drinking water) was offered ad libitum from 3 weeks before mating, and continued throughout gestation and weaning until the progeny reached 32 weeks of age. Liver and abdominal fat gene expression was compared with control animals fed isocaloric standard chow under identical conditions. HFCS induced hepatic steatosis and increased the expression of genes involved in carbohydrate and lipid metabolism. Conversely, dietary MSG elevated serum free fatty acids (FFAs), triglycerides (TGs), high-density lipoprotein-cholesterol (HDL-C), and insulin, together with the expression of hepatic genes involved in lipid metabolism and bile synthesis. The HFCS+MSG combination elevated hepatic TGs, serum FFAs, and TG levels. In visceral white adipose tissue, both MSG and HFCS diets increased the expression of transcription factor Srebf2 and decreased expression of Ppargc1a, while downregulating the expression of mitochondrial respiratory chain components. MSG increased the expression of several genes implicated in adipocytes differentiation. We hypothesize that HFCS may promote hepatic steatosis, whereas dietary MSG induces dyslipidemia and markers of insulin resistance.
[Esophageal motor disorders in cirrhotic patients with esophageal varices non-submitted to endoscopic treatment].

PubMed

Flores, Priscila Pollo; Lemme, Eponina Maria de Oliveira; Coelho, Henrique Sérgio Moraes

2005-01-01

The hepatic cirrhosis has as one of the main morbid-mortality causes, the portal hypertension with the development of esophageal varices, the possibility of a digestive hemorrhage and worsening of hepatic insufficiency. It is important to identify causal predictive or aggravating factors and if possible to prevent them. In the last years, it has been observed the association of esophageal motor disorders and gastro-esophageal reflux in cirrhotic patients with esophageal varices. To study the prevalence of the esophageal motility disorders and among them, the ineffective esophageal motility, in patients with hepatic cirrhosis and esophageal varices, without previous endoscopic therapeutic and the predictive factors. Prospectively, it has been evaluate 74 patients suffering from liver cirrhosis and esophagic varices, without previous endoscopic treatment. All of them were submitted to a clinical protocol, esophageal manometry and 55 patients also held the ambulatory esophageal pHmetry. Esophageal motility disorders have been found in 44 patients (60%). The most prevalent was the ineffective esophageal motility, observed in 28%. The abnormal reflux disease was diagnosed through the pHmetry in 35% of the patients. There were no correlation between the manometrical abnormality in general and the ineffective esophageal motility in particular and the esophageal or gastroesophageal reflux disease symptoms, the abnormal reflux, the disease seriousness, the ascites presence and the gauge of the varices. The majority of cirrhotic patients with non-treated esophageal varices present esophageal motor disorders. No predictive factor was found. The clinical relevance of these findings need more researches in the scope to define the real meaning of theses abnormalities.
[Development of immunologic deficiency conditions and sensitization in industrial workers and methodologic approach to their detection and evaluation].

PubMed

Dueva, L A; Ivanova, L A; Pavlova, T A

1989-01-01

The principal mechanisms forming the basis of detoxication abnormalities have been analysed using the data of research into the status of the hepatic monooxygenase enzyme system, which is responsible for the liver detoxication potential, and the literature reports. Irrespective of the pathology, a similar depression of the monooxygenase enzyme system of hepatocytes was revealed in acute stercoraceous peritonitis, acute ileus, burn disease, acute renal failure, and pyo-inflammatory conditions in the maxillofacial region. A pathogenetic model is proposed, which explains the mechanism of hepatic detoxication dysfunction in endogenous intoxications of different etiology. New approaches to the therapy of detoxication abnormalities in the conditions attended with endotoxemic syndrome are discussed proceeding from the pathogenetic mechanisms.
[Abnormal hepatic function tests in pregnancy: causes and consequences].

PubMed

Nemesánszky, Elemér

2013-07-21

The well-known normal ranges of laboratory parameters are altered due to the broad spectrum of physiological changes as well as proinflammatory and procoagulant effects of pregnancy. Hepatic disorders of any aetiology can cause potential problems during gravidity. Most frequently toxic-effects, hepatotrop viruses (such as hepatitis B and C), metabolic syndrome and diseases with autoimmune background can be observed. When dealing with "pregnancy-specific hepatic syndromes", it is very important to consider the "timing-factors" of pathologic changes and deterioration of clinical pictures as well. Due to the progress in cholestasis management, early termination of pregnancy can be avoided in many cases. As the overlap is really broad between various hepatic disorders, a multidisciplinary cooperation of different sub-disciplines is emphasized in order to achieve proper diagnosis and curative measures at early phase.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Levy, H.M.; Smith, R.

Two cases of thalassemia major are presented in which bone scintigraphy demonstrated diffuse hepatic uptake of Tc-99m diphosphonate. Although abnormal splenic and renal uptake of Tc-99m phosphates has been reported in patients with thalassemia major, hepatic uptake has not been reported previously. This scintigraphic finding is presumably due to increased iron deposition in the liver, resulting from increased iron turnover and retention in these patients and from multiple previous blood transfusions.
Hormetic modulation of hepatic insulin sensitivity by advanced glycation end products.

PubMed

Fabre, Nelly T; Thieme, Karina; Silva, Karolline S; Catanozi, Sérgio; Cavaleiro, Ana Mercedes; Pinto, Danilo A C; Okamoto, Maristela M; Morais, Mychel Raony P T; Falquetto, Bárbara; Zorn, Telma M; Machado, Ubiratan F; Passarelli, Marisa; Correa-Giannella, Maria Lúcia

2017-05-15

Because of the paucity of information regarding metabolic effects of advanced glycation end products (AGEs) on liver, we evaluated effects of AGEs chronic administration in (1) insulin sensitivity; (2) hepatic expression of genes involved in AGEs, glucose and fat metabolism, oxidative stress and inflammation and; (3) hepatic morphology and glycogen content. Rats received intraperitoneally albumin modified (AlbAGE) or not by advanced glycation for 12 weeks. AlbAGE induced whole-body insulin resistance concomitantly with increased hepatic insulin sensitivity, evidenced by activation of AKT, inactivation of GSK3, increased hepatic glycogen content, and decreased expression of gluconeogenesis genes. Additionally there was reduction in hepatic fat content, in expression of lipogenic, pro-inflamatory and pro-oxidative genes and increase in reactive oxygen species and in nuclear expression of NRF2, a transcription factor essential to cytoprotective response. Although considered toxic, AGEs become protective when administered chronically, stimulating AKT signaling, which is involved in cellular defense and insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.
Reduced Plasma HDL Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic ABCA1 Expression

PubMed Central

TANCEVSKI, IVAN; WEHINGER, ANDREAS; DEMETZ, EGON; ELLER, PHILIPP; DUWENSEE, KRISTINA; HUBER, JULIA; HOCHEGGER, KATHRIN; SCHGOER, WILFRIED; FIEVET, CATHERINE; STELLAARD, FRANS; RUDLING, MATS; PATSCH, JOSEF R.; RITSCH, ANDREAS

2010-01-01

The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of triiodothyronine (T3) upregulate hepatic expression of scavenger receptor-BI (SR-BI), resulting in increased clearance of plasma HDL-C. Here we show that severe hyperthyroidism in mice did not affect hepatic expression of SR-BI, but reduced hepatic expression of ATP-binding cassette transporter 1 (ABCA1), accompanied by a 40%-reduction of HDL-C. Sterol content of bile, liver and feces was markedly increased, accompanied by upregulation of hepatic CYP7A1, and ATP-binding cassette half-transporter ABCG5, which is known to promote biliary sterol secretion upon dimerization with ABCG8. Both control and hyperthyroid mice exerted identical plasma clearance of intravenously injected [3H] HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance, but rather its formation via hepatic ABCA1. PMID:18388200
Hepatic but not brain iron is rapidly chelated by deferasirox in aceruloplasminemia due to a novel gene mutation

PubMed Central

Finkenstedt, Armin; Wolf, Elisabeth; Höfner, Elmar; Gasser, Bethina Isasi; Bösch, Sylvia; Bakry, Rania; Creus, Marc; Kremser, Christian; Schocke, Michael; Theurl, Milan; Moser, Patrizia; Schranz, Melanie; Bonn, Guenther; Poewe, Werner; Vogel, Wolfgang; Janecke, Andreas R.; Zoller, Heinz

2010-01-01

Background & Aims Aceruloplasminemia is a rare autosomal recessive neurodegenerative disease associated with brain and liver iron accumulation which typically presents with movement disorders, retinal degeneration, and diabetes mellitus. Ceruloplasmin is a multi-copper ferroxidase that is secreted into plasma and facilitates cellular iron export and iron binding to transferrin. Results A novel homozygous ceruloplasmin gene mutation, c.2554+1G>T, was identified as the cause of aceruloplasminemia in three affected siblings. Two siblings presented with movement disorders and diabetes. Complementary DNA sequencing showed that this mutation causes skipping of exon 14 and deletion of amino acids 809–852 while preserving the open reading frame. Western blotting of liver extracts and sera of affected patients showed retention of the abnormal protein in the liver. Aceruloplasminemia was associated with severe brain and liver iron overload, where hepatic mRNA expression of the iron hormone hepcidin was increased, corresponding to the degree of iron overload. Hepatic iron concentration normalized after 3 and 5 months of iron chelation therapy with deferasirox, which was also associated with reduced insulin demands. During short term treatment there was no clinical or imaging evidence for significant effects on brain iron overload. Conclusions Aceruloplasminemia can show an incomplete clinical penetrance but is invariably associated with iron accumulation in the liver and in the brain. Iron accumulation in aceruloplasminemia is a result of defective cellular iron export, where hepcidin regulation is appropriate for the degree of iron overload. Iron chelation with deferasirox was effective in mobilizing hepatic iron but has no effect on brain iron. PMID:20801540
Soy isoflavones (Glycine max) ameliorate hypertriglyceridemia and hepatic steatosis in high fat-fed ovariectomized Wistar rats (an experimental model of postmenopausal obesity).

PubMed

Panneerselvam, Sankar; Packirisamy, Rajaa Muthu; Bobby, Zachariah; Elizabeth Jacob, Sajini; Sridhar, Magadi Gopalakrishna

2016-12-01

Obesity emerged as the major risk factor for metabolic syndrome. Postmenopausal women are more prone to develop obesity than premenopausal women. The absence of safe and effective conventional treatments for postmenopausal obesity has changed the focus to natural products as alternative remedy. We investigated the molecular basis of the effect of soy isoflavones (SIFs) on hypertriglyceridemia and hepatic steatosis in an animal model of postmenopausal obesity. Ovariectomized (OVX) and sham-operated Wistar rats were fed with high-fat diet (HFD) and normal diet for 8 weeks with and without SIF extract (150mg/kg body weight/day). Both OVX and HFD per se and when combined caused hypertriglyceridemia, hypercholesterolemia and atherogenic lipid profile. Proteomic studies revealed that both OVX and HFD caused overexpression of hepatic lipogenic proteins, such as LXR, SREBP1, PPARγ, ACC and FAS, in association with reduced expression of lipolytic proteins, such as FXR, PPARα, insig2 and SHP. Histological analysis showed fat accumulation and morphological abnormalities in the liver of OVX and HFD rats. All these metabolic derangements were further augmented when OVX was followed by HFD. In conclusion, these findings suggest that there was a synergism in the development of deranged lipid metabolism with the coexistence of postmenopausal state and the intake of fat-rich diet. SIF extract markedly alleviated the derangement of lipid metabolism suggesting the use of this natural phytoestrogen as a strategy for relieving dyslipidemia and hepatic steatosis associated with the postmenopausal women. Copyright © 2016 Elsevier Inc. All rights reserved.
Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome

PubMed Central

Riva, Alessia; Trombini, Paola; Mariani, Raffaella; Salvioni, Alessandra; Coletti, Sabina; Bonfadini, Silvia; Paolini, Valentina; Pozzi, Matteo; Facchetti, Rita; Bovo, Giorgio; Piperno, Alberto

2008-01-01

AIM: To re-evaluate the diagnostic criteria of insulin resistance hepatic iron overload based on clinical, biochemical and histopathological findings. METHODS: We studied 81 patients with hepatic iron overload not explained by known genetic and acquired causes. The metabolic syndrome (MS) was defined according to ATPIII criteria. Iron overload was assessed by liver biopsy. Liver histology was evaluated by Ishak’s score and iron accumulation by Deugnier’s score; steatosis was diagnosed when present in ≥ 5% of hepatocytes. RESULTS: According to transferrin saturation levels, we observed significant differences in the amount of hepatic iron overload and iron distribution, as well as the number of metabolic abnormalities. Using Receiving Operating Curve analysis, we found that the presence of two components of the MS differentiated two groups with a statistically significant different hepatic iron overload (P < 0.0001). Patients with ≥ 2 metabolic alterations and steatosis had lower amount of hepatic iron, lower transferrin saturation and higher sinusoidal iron than patients with < 2 MS components and absence of steatosis. CONCLUSION: In our patients, the presence of ≥ 2 alterations of the MS and hepatic steatosis was associated with a moderate form of iron overload with a prevalent sinusoidal distribution and a normal transferrin saturation, suggesting the existence of a peculiar pathogenetic mechanism of iron accumulation. These patients may have the typical dysmetabolic iron overload syndrome. By contrast, patients with transferrin saturation ≥ 60% had more severe iron overload, few or no metabolic abnormalities and a hemochromatosis-like pattern of iron overload. PMID:18720534
Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report.

PubMed

Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

2008-01-28

Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.
Hypothalamic pathogenesis of type 2 diabetes.

PubMed

Koshiyama, Hiroyuki; Hamamoto, Yoshiyuki; Honjo, Sachiko; Wada, Yoshiharu; Lkeda, Hiroki

2006-01-01

There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those lacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes.
Hepatic Stellate Cells Express Functional CXCR4: Role in Stromal Cell–Derived Factor-1α–Mediated Stellate Cell Activation

PubMed Central

Hong, Feng; Tuyama, Ana; Lee, Ting Fang; Loke, Johnny; Agarwal, Ritu; Cheng, Xin; Garg, Anita; Fiel, M. Isabel; Schwartz, Myron; Walewski, Jose; Branch, Andrea; Schecter, Alison D.; Bansal, Meena B.

2010-01-01

Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell–derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression of α-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. Conclusion HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α–induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches. PMID:19434726
Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.

PubMed

Jang, Jung Eun; Park, Han-Sol; Yoo, Hyun Ju; Baek, In-Jeoung; Yoon, Ji Eun; Ko, Myoung Seok; Kim, Ah-Ram; Kim, Hyoun Sik; Park, Hye-Sun; Lee, Seung Eun; Kim, Seung-Whan; Kim, Su Jung; Leem, Jaechan; Kang, Yu Mi; Jung, Min Kyo; Pack, Chan-Gi; Kim, Chong Jai; Sung, Chang Ohk; Lee, In-Kyu; Park, Joong-Yeol; Fernández-Checa, José C; Koh, Eun Hee; Lee, Ki-Up

2017-08-01

Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat +/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431). © 2017 by the American Association for the Study of Liver Diseases.
Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice

PubMed Central

Ai, Ding; Chen, Chiyuan; Han, Seongah; Ganda, Anjali; Murphy, Andrew J.; Haeusler, Rebecca; Thorp, Edward; Accili, Domenico; Horton, Jay D.; Tall, Alan R.

2012-01-01

Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9–/– mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy. PMID:22426206
Enhancing hepatic fibrosis in spontaneously hypertensive rats fed a choline-deficient diet: a follow-up report on long-term effects of oxidative stress in non-alcoholic fatty liver disease.

PubMed

Yamamoto, Hiroya; Kanno, Keishi; Ikuta, Takuya; Arihiro, Koji; Sugiyama, Akiko; Kishikawa, Nobusuke; Tazuma, Susumu

2016-05-01

We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress. © 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.
Role of the indoleamine-2,3-dioxygenase/kynurenine pathway of tryptophan metabolism in behavioral alterations in a hepatic encephalopathy rat model.

PubMed

Jiang, Xi; Xu, Lexing; Tang, Lin; Liu, Fuhe; Chen, Ziwei; Zhang, Jiajia; Chen, Lei; Pang, Cong; Yu, Xuefeng

2018-01-04

This study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats. Expression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-L-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats. Increased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment. Taken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE.
p53 in pure epithelioid PEComa: an immunohistochemistry study and gene mutation analysis.

PubMed

Bing, Zhanyong; Yao, Yuan; Pasha, Theresa; Tomaszewski, John E; Zhang, Paul J

2012-04-01

Pure epithelioid PEComa (PEP; so-called epithelioid angiomyolipoma) is rare and is more often associated with aggressive behaviors. The pathogenesis of PEP has been poorly understood. The authors studied p53 expression and gene mutation in PEPs by immunohistochemistry, single-strand conformation polymorphism, and direct sequencing in paraffin material from 8 PEPs. A group of classic angiomyolipomas (AMLs) were also analyzed for comparison. Five PEPs were from kidneys and 1 each from the heart, the liver, and the uterus. PEPs showed much stronger p53 nuclear staining (Allred score 6.4 ± 2.5) than the classic AML (2.3 ± 2.9) (P < .01). There was no p53 single-strand conformation polymorphism identified in either the PEPs or the 8 classic AMLs. p53 mutation analyses by direct sequencing of exons 5 to 9 showed 4 mutations in 3 of 8 PEPs but none in any of the 8 classic AMLs. The mutations included 2 missense mutations in a hepatic PEComa and 2 silent mutations in 2 renal PEPs. Both the missense mutations in the hepatic PEComa involved the exon 5, one involving codon 165, with change from CAG to CAC (coding amino acid changed from glutamine to histidine), and the other involving codon 182, with change from TGC to TAC (coding amino acid changed from cysteine to tyrosine). The finding of stronger p53 expression and mutations in epithelioid angiomyolipomas might have contributed to their less predictable behavior. However, the abnormal p53 expression cannot be entirely explained by p53 mutations in the exons examined in the PEPs.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska

NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor,more » and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity.« less
Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

PubMed

Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

2017-08-01

The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.
Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Pengfei; Zhang, Yingjie; Liu, Yunye

2016-01-01

Fibroblast growth factor 21 (FGF-21) is a secreted protein, which has anti-diabetic and lipocaic effects, but its ability to protect against hepatic fibrosis has not been studied. In this study, we investigated the ability of FGF-21 to attenuate dimethylnitrosamine (DMN)-induced hepatic fibrogenesis in mice and the mechanism of its action. Hepatic fibrosis was induced by injection of DMN, FGF-21 was administered to the mice once daily in association with DMN injection till the end of the experiment. Histopathological examination, tissue 4-hydroxyproline content and expressions of smooth muscle α-actin (α-SMA) and collagen I were measured to assess hepatic fibrosis. Ethanol/PDGF-BB-activated hepaticmore » stellate cells (HSCs) were used to understand the mechanisms of FGF-21 inhibited hepatic fibrogenesis. Results showed that FGF-21 treatment attenuated hepatic fibrogenesis and was associated with a significant decrease in intrahepatic fibrogenesis, 4-hydroxyproline accumulation, α-SMA expression and collagen I deposition. FGF-21 treatment inhibited the activation of HSCs via down-regulating the expression of TGF-β, NF-κB nuclear translocation, phosphorylation levels of smad2/3 and IκBα. Besides, FGF-21 treatment caused activated HSC apoptosis with increasing expression of Caspase-3, and decreased the ratio of Bcl-2 to Bax. In conclusion, FGF-21 attenuates hepatic fibrogenesis and inhibits the activation of HSC warranting the use of FGF-21 as a potential therapeutic agent in the treatment of hepatic fibrosis. - Highlights: • Fibroblast growth factor 21 attenuates hepatic fibrogenesis. • Fibroblast growth factor 21 attenuates hepatic fibrogenesis via TGF-β/smad2/3 signaling pathways. • Fibroblast growth factor 21 attenuates hepatic fibrogenesis via NF-κB signaling pathways.« less
Impairment of GH/IGF-1 Axis in the Liver of Patients with HCV-Related Chronic Hepatitis.

PubMed

Carotti, Simone; Guarino, Michele Pier Luca; Valentini, Francesco; Porzio, Silvio; Vespasiani-Gentilucci, Umberto; Perrone, Giuseppe; Zingariello, Maria; Gallo, Paolo; Cicala, Michele; Picardi, Antonio; Morini, Sergio

2018-02-01

Resistance to the action of growth hormone (GH) frequently complicates liver cirrhosis, while, physiologically, the activation of GH receptor (GHR) determines phosphorylation of signal transducer and activator of transcription (STAT)-5 and the consequent induction of insulin-like growth factor-1 (IGF-1) expression. The suppressor of cytokine signaling (SOCS)-3 negatively regulates this intracellular cascade. We aimed to evaluate the hepatic expression of the GH/IGF-1 axis components in the liver of patients with HCV-related chronic hepatitis at different fibrosis stages. The expression of GH/IGF-1 axis components, such as GHR, IGF-1, STAT5-p, and SOCS-3, was assessed by immunohistochemistry at the lobular level in 61 patients with HCV-related hepatitis. At the hepatocyte level, IGF-1 and nuclear STAT5-p positivity scores showed negative correlations with fibrosis stage, while SOCS-3 score a positive one (p<0.05 for all). Furthermore, the reduction of hepatocyte score of IGF-1 expression was associated with the serological parameters of liver damage (p<0.05) and with the increase of the score of IGF-1 expression by hepatic stellate cells (p<0.05). IGF-1 expression by hepatocytes was reduced with fibrosis progression, probably due to the impairment of GHR intracellular cascade by the SOCS-3 activation already in pre-cirrhotic stages. The inverse correlation between IGF-1 expressed by hepatocytes and by hepatic stellate cells suggests that IGF-1 may exert specific functions in different hepatic cells. © Georg Thieme Verlag KG Stuttgart · New York.
A Recombinant HAV Expressing a Neutralization Epitope of HEV Induces Immune Response against HAV and HEV in Mice.

PubMed

Xiang, Kui; Kusov, Yuri; Ying, Guan; Yan, Wang; Shan, Yi; Jinyuan, Wu; Na, Yin; Yan, Zhou; Hongjun, Li; Maosheng, Sun

2017-09-15

Hepatitis A virus (HAV) and hepatitis E virus (HEV) are causative agents of acute viral hepatitis transmitted via the fecal-oral route. Both viruses place a heavy burden on the public health and economy of developing countries. To test the possibility that HAV could be used as an expression vector for the development of a combination vaccine against hepatitis A and E infections, recombinant HAV-HEp148 was created as a vector to express an HEV neutralization epitope (HEp148) located at aa 459-606 of the HEV capsid protein. The recombinant virus expressed the HEp148 protein in a partially dimerized state in HAV-susceptible cells. Immunization with the HAV-HEp148 virus induced a strong HAV- and HEV-specific immune response in mice. Thus, the present study demonstrates a novel approach to the development of a combined hepatitis A and E vaccine.
A Recombinant HAV Expressing a Neutralization Epitope of HEV Induces Immune Response against HAV and HEV in Mice

PubMed Central

Kui, Xiang; Yuri, Kusov; Guan, Ying; Wang, Yan; Yi, Shan; Wu, Jinyuan; Yin, Na; Zhou, Yan; Li, Hongjun; Sun, Maosheng

2017-01-01

Hepatitis A virus (HAV) and hepatitis E virus (HEV) are causative agents of acute viral hepatitis transmitted via the fecal–oral route. Both viruses place a heavy burden on the public health and economy of developing countries. To test the possibility that HAV could be used as an expression vector for the development of a combination vaccine against hepatitis A and E infections, recombinant HAV-HEp148 was created as a vector to express an HEV neutralization epitope (HEp148) located at aa 459–606 of the HEV capsid protein. The recombinant virus expressed the HEp148 protein in a partially dimerized state in HAV-susceptible cells. Immunization with the HAV-HEp148 virus induced a strong HAV- and HEV-specific immune response in mice. Thus, the present study demonstrates a novel approach to the development of a combined hepatitis A and E vaccine. PMID:28914805
Regulation of hepatic 7 alpha-hydroxylase expression by dietary psyllium in the hamster.

PubMed Central

Horton, J D; Cuthbert, J A; Spady, D K

1994-01-01

Soluble fiber consistently lowers plasma total and low density lipoprotein (LDL)-cholesterol concentrations in humans and various animal models including the hamster; however, the mechanism of this effect remains incompletely defined. We performed studies to determine the activity of dietary psyllium on hepatic 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and LDL receptor expression in the hamster. In animals fed a cholesterol-free semisynthetic diet containing 7.5% cellulose (avicel) as a fiber source, substitution of psyllium for avicel increased hepatic 7 alpha-hydroxylase activity and mRNA levels by 3-4-fold. Comparable effects on 7 alpha-hydroxylase expression were observed with 1% cholestyramine. Psyllium also increased hepatic 7 alpha-hydroxylase activity and mRNA in animals fed a diet enriched with cholesterol and triglyceride. Activation of 7 alpha-hydroxylase was associated with an increase in hepatic cholesterol synthesis that was apparently not fully compensatory since the cholesterol content of the liver declined. Although dietary psyllium did not increase hepatic LDL receptor expression in animals fed the cholesterol-free, very-low-fat diet, it did increase (or at least restore) receptor expression that had been downregulated by dietary cholesterol and triglyceride. Thus, 7.5% dietary psyllium produced effects on hepatic 7 alpha-hydroxylase and LDL metabolism that were similar to those of 1% cholestyramine. Induction of hepatic 7 alpha-hydroxylase activity by dietary psyllium may account, in large part, for the hypocholesterolemic effect of this soluble fiber. Images PMID:8182140
Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

PubMed

Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

2016-01-15

Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.
Platelet-derived growth factor A mRNA in platelets is associated with the degree of hepatic fibrosis in chronic hepatitis C.

PubMed

Tanikawa, Aline Aki; Grotto, Rejane Maria Tommasini; Silva, Giovanni Faria; Ferrasi, Adriana Camargo; Sarnighausen, Valéria Cristina Rodrigues; Pardini, Maria Inês de Moura Campos

2017-01-01

Transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor (PDGF) are the main cytokines related to hepatic fibrogenesis. RNA isolated from the platelets and hepatic tissue of 43 HCV carriers was used for quantitative polymerase chain reaction to determine TGFB1, PDGFA, and PDGFB RNA expression. The mRNA expression of PDGFA in platelets was significantly lower in the group with advanced fibrosis than in the group with early-stage fibrosis. TGFB1 was more frequently expressed in platelets than in hepatic tissue, which was different from PDGFB. A pathway mediated by overexpression of TGFB1 via PDGFA in megakaryocytes could be involved in the development of fibrosis.
Hepatoblastoma and Abernethy Malformation Type I: Case Report.

PubMed

Correa, Catalina; Luengas, Juan P; Howard, Scott C; Veintemilla, Galo

2017-03-01

A 2-year-old boy presented with pneumonia and an abdominal mass was noted incidentally. A right lobe hepatic mass classified as PRETEXT III and congenital absence of the portal vein with drainage of the superior mesenteric vein to the inferior vena cava (Abernethy malformation type I) were confirmed by computed tomography and angiography. After a clinical diagnosis of hepatoblastoma had been made, he was treated with 4 cycles of doxorubicin and cisplatin and hepatic arterial chemoembolization with doxorubicin, after which the tumor was classified as POSTEXT III. He underwent a right extended hepatic lobectomy with resection of the caudate lobe but died on postoperative day 4 due to hepatic failure. The Abernethy malformation type I is associated with the development of hepatic tumors, and the abnormal blood flow might predispose to hepatic failure after liver resection. Extensive study of the hepatic vasculature is warranted in patients with suspected malformations. Liver transplant could be considered in patients with congenital portosystemic shunt and malignant liver tumors.
Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

PubMed

Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

2017-01-01

Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.
Morphology of congenital portosystemic shunts involving the right gastric vein in dogs.

PubMed

White, R N; Parry, A T

2015-07-01

To describe the anatomy of congenital portosystemic shunts involving the right gastric vein in dogs. Retrospective review of a consecutive series of dogs managed for congenital portosystemic shunt. Twenty-two dogs met the inclusion criteria of a congenital portosystemic shunt involving the right gastric vein with recorded intraoperative mesenteric portovenography or computed tomography angiography and gross observations at the time of surgery. Of these, 20 (91%) had a shunt that entered the pre-hepatic caudal vena cava at the level of the epiploic foramen and two (9%) had a shunt that entered the post-hepatic caudal vena cava at the level of the diaphragm. Shunts entering the pre-hepatic caudal vena cava could be further classified into three consistent subdivisions. The morphology of each shunt type described appeared to be a result of an abnormal communication between the left gastric vein and the caudal vena cava, the presence or absence of an abnormal communication between the splenic, left gastric and portal veins and the subsequent development of preferential blood flow through essentially normal portal vessels within the portal venous system. The abnormal communication (shunt) was through the left gastric vein and not the right gastric vein, as might have been expected. This information may help with surgical planning in cases undergoing shunt closure surgery. © 2015 British Small Animal Veterinary Association.
Prospective Evaluation of Transcatheter Arterial Chemoembolization (TACE) with Multiple Anti-Cancer Drugs (Epirubicin, Cisplatin, Mitomycin C, 5-Fluorouracil) Compared with TACE with Epirubicin for Treatment of Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahara, Shinya; Kawai, Nobuyuki; Sato, Morio, E-mail: morisato@mail.wakayama-med.ac.jp

Purpose: To compare the efficacy of transcatheter arterial chemoembolization (TACE) using multiple anticancer drugs (epirubicin, cisplatin, mitomycin C, and 5-furuorouracil: Multi group) with TACE using epirubicin (EP group) for hepatocellular carcinoma (HCC). Materials and Methods: The study design was a single-center, prospective, randomized controlled trial. Patients with unrespectable HCC confined to the liver, unsuitable for radiofrequency ablation, were assigned to the Multi group or the EP group. We assessed radiographic response as the primary endpoint; secondary endpoints were progression-free survival (PFS), safety, and hepatic branch artery abnormality (Grade I, no damage or mild vessel wall irregularity; Grade II, overt stenosis;more » Grade III, occlusion; Grades II and III indicated significant hepatic artery damage). A total of 51 patients were enrolled: 24 in the Multi group vs. 27 in the EP group. Results: No significant difference in HCC patient background was found between the groups. Radiographic response, PFS, and 1- and 2-year overall survival of the Multi vs. EP group were 54% vs. 48%, 6.1 months vs. 8.7 months, and 95% and 65% vs. 85% and 76%, respectively, with no significant difference. Significantly greater Grade 3 transaminase elevation was found in the Multi group (p = 0.023). Hepatic artery abnormality was observed in 34% of the Multi group and in 17.1% of the EP group (p = 0.019). Conclusion: TACE with multiple anti-cancer drugs was tolerable but appeared not to contribute to an increase in radiographic response or PFS, and caused significantly more hepatic arterial abnormalities compared with TACE with epirubicin alone.« less
Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients.

PubMed

Londoño, María-Carlota; Souza, Lara Neves; Lozano, Juan-José; Miquel, Rosa; Abraldes, Juan G; Llovet, Laura-Patricia; Quaglia, Alberto; Rimola, Antoni; Navasa, Miquel; Sánchez-Fueyo, Alberto

2018-04-28

Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Molindone and hepatotoxicity.

PubMed

Bhatia, S C; Banta, L E; Ehrlich, D W

1985-10-01

An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.
Imaging of the transplant liver.

PubMed

Babyn, Paul Sheppard

2010-04-01

As the number of patients with liver transplants continues to increase, radiologists need to be aware of the normal post-operative appearance of the different liver transplants currently performed along with the wide variety of complications encountered. The complications commonly affect the biliar and vascular systems and can include anastomotic bile leakage and biliary stenosis along with stenosis or obstruction of the hepatic artery, portal or hepatic veins and IVC. Other complications include parenchymal abnormalities such as hepatic infarction, organ rejection, localized collections and post transplant lymphoproliferative disorder. This article reviews and illustrates the role of imaging for pediatric transplantation including the role of interventional radiology.
Azathioprine Intolerance in Japanese Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis

PubMed Central

Morishita, Michiko; Watanabe, Haruki; Yan, Minglu; Zeggar, Sonia; Hiramatsu, Sumie; Ohashi, Keiji; Miyawaki, Yoshia; Katsuyama, Eri; Katsuyama, Takayuki; Takano Narazaki, Mariko; Toyota Tatebe, Noriko; Sunahori Watanabe, Katsue; Kawabata, Tomoko; Sada, Ken-Ei; Wada, Jun

2017-01-01

Objective To assess the safety of azathioprine (AZA) in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods We retrospectively enrolled 67 consecutive AAV patients who had initiated AZA treatment from January 2006 to August 2014 at Okayama University Hospital. We evaluated the development of severe adverse events (AEs), AZA discontinuation due to total AEs (severe AEs included) within 1 year, and AZA-associated risk factors. Results The patients' median age was 70 years old. Forty-nine women and 18 men participated at the initiation of the study. Fifty-eight (87%) patients experienced AEs, and 36 experienced severe AEs (21 hepatic and 11 cytopenic severe AEs). Thirty-one (46%) patients discontinued treatment because of AEs. Abnormal hepatic laboratory test results at the treatment initiation were more frequent in patients with hepatic severe AEs and were associated with treatment discontinuation. The leukocyte and neutrophil counts at the treatment initiation were lower in the patients who discontinued treatment because of cytopenic AEs than in those who continued treatment. Only two patients experienced flare-ups during treatment. Conclusion The AE-associated AZA discontinuation rate in Japanese AAV patients was relatively high. AZA use warrants caution in patients with abnormal hepatic laboratory test results or low leukocyte or neutrophil counts. PMID:28674351
Inhibition of Pyruvate Dehydrogenase Kinase 2 Protects Against Hepatic Steatosis Through Modulation of Tricarboxylic Acid Cycle Anaplerosis and Ketogenesis.

PubMed

Go, Younghoon; Jeong, Ji Yun; Jeoung, Nam Ho; Jeon, Jae-Han; Park, Bo-Yoon; Kang, Hyeon-Ji; Ha, Chae-Myeong; Choi, Young-Keun; Lee, Sun Joo; Ham, Hye Jin; Kim, Byung-Gyu; Park, Keun-Gyu; Park, So Young; Lee, Chul-Ho; Choi, Cheol Soo; Park, Tae-Sik; Lee, W N Paul; Harris, Robert A; Lee, In-Kyu

2016-10-01

Hepatic steatosis is associated with increased insulin resistance and tricarboxylic acid (TCA) cycle flux, but decreased ketogenesis and pyruvate dehydrogenase complex (PDC) flux. This study examined whether hepatic PDC activation by inhibition of pyruvate dehydrogenase kinase 2 (PDK2) ameliorates these metabolic abnormalities. Wild-type mice fed a high-fat diet exhibited hepatic steatosis, insulin resistance, and increased levels of pyruvate, TCA cycle intermediates, and malonyl-CoA but reduced ketogenesis and PDC activity due to PDK2 induction. Hepatic PDC activation by PDK2 inhibition attenuated hepatic steatosis, improved hepatic insulin sensitivity, reduced hepatic glucose production, increased capacity for β-oxidation and ketogenesis, and decreased the capacity for lipogenesis. These results were attributed to altered enzymatic capacities and a reduction in TCA anaplerosis that limited the availability of oxaloacetate for the TCA cycle, which promoted ketogenesis. The current study reports that increasing hepatic PDC activity by inhibition of PDK2 ameliorates hepatic steatosis and insulin sensitivity by regulating TCA cycle anaplerosis and ketogenesis. The findings suggest PDK2 is a potential therapeutic target for nonalcoholic fatty liver disease. © 2016 by the American Diabetes Association.
Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats.

PubMed

Alkhedaide, Adel; Soliman, Mohamed Mohamed; Ibrahim, Zein Shaban

2016-11-01

The aim of the current study was to examine the effects of chronic consumption of soft drinks (SDs) on hepatic oxidative stress and cytochrome P450 enzymes (CYPs) expression in the livers of Wistar rats. For 3 consecutive months, the rats had free access to three different soft drinks, Coca-Cola, Pepsi-Cola and 7-UP. The rats were subsequently compared with control group rats that had consumed water. Blood and hepatic tissue samples were assayed for the changes in antioxidants, liver function biomarkers and hepatic gene expression for different isoforms of hepatic CYP. The results indicated that SD consumption (SDC) decreased serum antioxidant levels and increased malondialdehyde secretion, and increased liver biomarkers (glutamate pyruvate transaminase and glutamate oxaloacetate). SD induced alterations in mRNA expression of hepatic antioxidants and cytochrome isoforms. The expression of peroxidase, catalase, CYP1A2, CYP3A2 and CYP2C11 in the liver were upregulated following SDC. By contrast, CYP2B1 was downregulated after 3 months of SDC in liver tissue samples. Thus, the present findings indicate that SDs induced oxidative stress in the liver of Wistar rats and for the first time, to the best of our knowledge, indicate that SDC disrupts hepatic CYP enzymes that may affect drug metabolism. Therefore, drug-dosing programs should be carefully designed to take these novel findings into consideration for the treatment of diseases.
Hepatic differentiation capability of rat bone marrow-derived mesenchymal stem cells and hematopoietic stem cells.

PubMed

Shu, Sai-Nan; Wei, Lai; Wang, Jiang-Hua; Zhan, Yu-Tao; Chen, Hong-Song; Wang, Yu

2004-10-01

To investigate the different effects of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) on hepatic differentiation. MSCs from rat bone marrow were isolated and cultured by standard methods. HSCs from rat bone marrow were isolated and purified by magnetic activated cell sorting. Both cell subsets were induced. Morphology, RT-PCR and immunocytochemistry were used to identify the hepatic differentiation grade. MSCs exhibited round in shape after differentiation, instead of fibroblast-like morphology before differentiation. Albumin mRNA and protein were expressed positively in MSCs, without detection of alpha-fetoprotein (AFP). HSCs were polygonal in shape after differentiation. The expression of albumin signal decreased and AFP signal increased. The expression of CK18 was continuous in MSCs and HSCs both before and after induction. Both MSCs and HSCs have hepatic differentiation capabilities. However, their capabilities are not the same. MSCs can differentiate into mature hepatocyte-like cells, never expressing early hepatic specific genes, while Thy-1.1(+) cells are inclined to differentiate into hepatic stem cell-like cells, with an increasing AFP expression and a decreasing albumin signal. CK18 mRNA is positive in Thy-1.1(+) cells and MSCs, negative in Thy-1.1(-) cells. It seems that CK18 has some relationship with Thy-1.1 antigen, and CK18 may be a predictive marker of hepatic differentiation capability.

Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

PubMed

Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

2016-01-01

The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
The spleen in liver cirrhosis: revisiting an old enemy with novel targets.

PubMed

Li, Liang; Duan, Mubing; Chen, Weisan; Jiang, An; Li, Xiaoming; Yang, Jun; Li, Zongfang

2017-05-23

The spleen is a secondary lymphoid organ which can influence the progression of multiple diseases, notably liver cirrhosis. In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. In this review, we summarize the literature to highlight the mechanistic contributions of splenomegaly and hypersplenism to the development of liver cirrhosis, focusing on three key aspects: hepatic fibrogenesis, hepatic immune microenvironment dysregulation and liver regeneration. We conclude with a discussion of the possible therapeutic strategies for modulating splenic abnormalities, including the novel potential usage of nanomedicine in non-surgically targetting splenic disorders for the treatment of liver cirrhosis.
Activation of hepatic Nogo-B receptor expression—A new anti-liver steatosis mechanism of statins

PubMed Central

Zhang, Wenwen; Yang, Xiaoxiao; Chen, Yuanli; Hu, Wenquan; Liu, Lipei; Zhang, Xiaomeng; Liu, Mengyang; Sun, Lei; Liu, Ying; Yu, Miao; Li, Xiaoju; Li, Luyuan; Zhu, Yan; Miao, Qing Robert; Han, Jihong; Duan, Yajun

2017-01-01

Deficiency of hepatic Nogo-B receptor (NgBR) expression activates liver X receptor α (LXRα) in an adenosine monophosphate-activated protein kinase α (AMPKα)-dependent manner, thereby inducing severe hepatic lipid accumulation and hypertriglyceridemia. Statins have been demonstrated non-cholesterol lowering effects including anti-nonalcoholic fatty liver disease (NAFLD). Herein, we investigated if the anti-NAFLD function of statins depends on activation of NgBR expression. In vivo, atorvastatin protected apoE deficient or NgBR floxed, but not hepatic NgBR deficient mice, against Western diet (WD)-increased triglyceride levels in liver and serum. In vitro, statins reduced lipid accumulation in nonsilencing small hairpin RNA-transfected (shNSi), but not in NgBR small hairpin RNA-transfected (shNgBRi) HepG2 cells. Inhibition of cellular lipid accumulation by atorvastatin is related to activation of AMPKα, and inactivation of LXRα and lipogenic genes. Statin also inhibited expression of oxysterol producing enzymes. Associated with changes of hepatic lipid levels by WD or atorvastatin, NgBR expression was inversely regulated. At cellular levels, statins increased NgBR mRNA and protein expression, and NgBR protein stability. In contrast to reduced cellular cholesterol levels by statin or β-cyclodextrin, increased cellular cholesterol levels decreased NgBR expression suggesting cholesterol or its synthesis intermediates inhibit NgBR expression. Indeed, mevalonate, geranylgeraniol or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or farnesol, blocked atorvastatin-induced NgBR expression. Furthermore, we determined that induction of hepatic NgBR expression by atorvastatin mainly depended on inactivation of extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (Akt). Taken together, our study demonstrates that statins inhibit NAFLD mainly through activation of NgBR expression. PMID:29217477
Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice

PubMed Central

Ai, Ding; Baez, Juan M.; Jiang, Hongfeng; Conlon, Donna M.; Hernandez-Ono, Antonio; Frank-Kamenetsky, Maria; Milstein, Stuart; Fitzgerald, Kevin; Murphy, Andrew J.; Woo, Connie W.; Strong, Alanna; Ginsberg, Henry N.; Tabas, Ira; Rader, Daniel J.; Tall, Alan R.

2012-01-01

Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease. PMID:22466652
Betaine alleviates hepatic lipid accumulation via enhancing hepatic lipid export and fatty acid oxidation in rats fed with a high-fat diet.

PubMed

Xu, Li; Huang, Danping; Hu, Qiaolin; Wu, Jing; Wang, Yizhen; Feng, Jie

2015-06-28

To assess the effects of betaine on hepatic lipid accumulation and investigate the underlying mechanism, thirty-two male Sprague-Dawley rats weighing 100 (sd 2·50) g were divided into four groups, and started on one of four treatments: basal diet, basal diet with betaine administration, high-fat diet and high-fat diet with betaine administration. The results showed that no significant difference of body weight was found among experimental groups. Compared with high-fat diet-fed rats, a betaine supplementation decreased (P< 0·05) hepatic TAG accumulation induced by high-fat diet, which was also supported by hepatic histology results. Additionally, hepatic betaine-homocysteine methyltransferase concentration [corrected] as well as its mRNA abundance and lecithin level were found increased (P< 0·05) by betaine supplementation in both basal diet-fed rats and high-fat diet-fed rats. Betaine administration in high-fat diet-fed rats exhibited a higher (P< 0·05) concentration [corrected] of hepatic carnitine palmitoyltransferase 1 (CPT1) compared with high-fat diet-fed rats. High-fat diet inhibited (P< 0·05) the gene expression of hepatic PPARα and CPT1. However, betaine administration in high-fat diet-fed rats elevated (P< 0·05) the gene expression of PPARα and CPT1. Moreover, concentration, gene and protein expressions of hepatic fibroblast growth factor 21 (FGF21) were increased (P< 0·05) in response to betaine administration in high-fat diet group; meanwhile the gene expression of hepatic AMP-activated protein kinase was increased (P< 0·05) as well. The results suggest that betaine administration enhanced hepatic lipid export and fatty acid oxidation in high-fat diet-fed rats, thus effectively alleviating fat accumulation in the liver.
Clinical Characteristics and Outcome of Hepatic Sarcoidosis: A Population-Based Study 1976-2013.

PubMed

Ungprasert, Patompong; Crowson, Cynthia S; Simonetto, Douglas A; Matteson, Eric L

2017-10-01

Data on clinical manifestations and outcome of hepatic sarcoidosis are scarce. This study aimed to use a population-based cohort of patients with incident sarcoidosis to better describe the characteristics of hepatic sarcoidosis. A cohort of incident cases of sarcoidosis in Olmsted County, MN, USA, from 1976 to 2013 was identified from the database. Diagnosis was verified by individual medical record review. Confirmed cases of sarcoidosis were then reviewed for liver involvement. Data on clinical manifestations, imaging study, liver biochemical tests, treatment, and outcome were collected. Cumulative incidence of cirrhosis adjusted for the competing risk of death was estimated. A total of 345 cases of incident sarcoidosis were identified. Of these, 19 cases (6%) had liver involvement (mean age 46.1 years, 53% female and 79% Caucasian). Most patients had asymptomatic liver disease and were discovered in pursuit of abnormal biochemical tests and imaging studies. Alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were elevated in the majority of patients (88 and 90%, respectively). Elevated transaminases were less common and less severe. About half of patients had abnormal imaging study with hypodense nodular lesions being the most common abnormality (six patients) followed by hepatomegaly (three patients). Liver biopsy revealed non-caseating granuloma in 88% (14 of 16 patients). A total of four patients developed cirrhosis. Involvement of the liver by sarcoidosis was seen in 6% of patients with sarcoidosis. The majority of patients were asymptomatic. Elevated ALP and GGT were the most common abnormal biochemical tests. Liver biopsy revealed non-caseating granuloma in almost all cases. Cirrhosis was seen in a significant number of patients. Generalizability of the observations to other populations may be limited, as the studied population was predominantly Caucasian. The prevalence of liver disease may be higher in more diverse populations.
Severe hypertriglyceridaemia in horses and ponies with endocrine disorders.

PubMed

Dunkel, B; Wilford, S A; Parkinson, N J; Ward, C; Smith, P; Grahame, L; Brazil, T; Schott, H C

2014-01-01

Severe hypertriglyceridaemia in horses and ponies with endocrine disorders has been reported anecdotally but has not been documented in the literature. To describe historical and clinicopathological findings as well as progression and outcome in horses and ponies with severe hypertriglyceridaemia (serum triglyceride concentration >5.65 mmol/l) secondary to an endocrine disorder that were otherwise apparently healthy. Cases from 6 participating institutions were identified and case details extracted from the medical records. Case details of 3 horses and 4 ponies were available. Presenting complaints included weight loss despite good appetite in 4 animals, while in 3 hypertriglyceridaemia was identified incidentally. All animals were bright and alert and showed a normal or increased appetite. Serum triglyceride concentrations ranged from 10.5 to 60.3 mmol/l. Other abnormalities included hyperglycaemia in 6 animals, suspected insulin resistance and mild to severe increases in hepatic enzyme activities. In 2 animals, moderate hepatic lipidosis was confirmed histologically. Three horses and 3 ponies were diagnosed with pituitary pars intermedia dysfunction based on clinical signs and basal adrenocorticotropic hormone (ACTH) concentrations or dexamethasone suppression test results. In 5 of these, type 2 diabetes mellitus was also confirmed, while one pony suffered from type 2 diabetes mellitus without concurrent pituitary pars intermedia dysfunction. Laboratory abnormalities improved in 4 animals with treatment (pergolide and/or insulin), in one horse specific treatment was not attempted, and in 2 ponies treatment was impaired by the owner or only partly effective. In one of the latter cases, biochemical abnormalities persisted for 7 years without apparent ill effects. Horses and ponies may develop severe hypertriglyceridaemia secondary to endocrine disorders that are associated with insulin resistance. Hypertriglyceridaemia can resolve with treatment of the endocrinopathy. Although biochemical evidence of hepatic compromise was present, clinical abnormalities were not noted in these animals. © 2013 EVJ Ltd.
NFE2 Induces miR-423-5p to Promote Gluconeogenesis and Hyperglycemia by Repressing the Hepatic FAM3A-ATP-Akt Pathway.

PubMed

Yang, Weili; Wang, Junpei; Chen, Zhenzhen; Chen, Ji; Meng, Yuhong; Chen, Liming; Chang, Yongsheng; Geng, Bin; Sun, Libo; Dou, Lin; Li, Jian; Guan, Youfei; Cui, Qinghua; Yang, Jichun

2017-07-01

Hepatic FAM3A expression is repressed under obese conditions, but the underlying mechanism remains unknown. This study determined the role and mechanism of miR-423-5p in hepatic glucose and lipid metabolism by repressing FAM3A expression. miR-423-5p expression was increased in the livers of obese diabetic mice and in patients with nonalcoholic fatty liver disease (NAFLD) with decreased FAM3A expression. miR-423-5p directly targeted FAM3A mRNA to repress its expression and the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic miR-423-5p inhibition suppressed gluconeogenesis and improved insulin resistance, hyperglycemia, and fatty liver in obese diabetic mice. In contrast, hepatic miR-423-5p overexpression promoted gluconeogenesis and hyperglycemia and increased lipid deposition in normal mice. miR-423-5p inhibition activated the FAM3A-ATP-Akt pathway and repressed gluconeogenic and lipogenic gene expression in diabetic mouse livers. The miR-423 precursor gene was further shown to be a target gene of NFE2, which induced miR-423-5p expression to repress the FAM3A-ATP-Akt pathway in cultured hepatocytes. Hepatic NFE2 overexpression upregulated miR-423-5p to repress the FAM3A-ATP-Akt pathway, promoting gluconeogenesis and lipid deposition and causing hyperglycemia in normal mice. In conclusion, under the obese condition, activation of the hepatic NFE2/miR-423-5p axis plays important roles in the progression of type 2 diabetes and NAFLD by repressing the FAM3A-ATP-Akt signaling pathway. © 2017 by the American Diabetes Association.
Hepatic expression of proteasome subunit alpha type-6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin-like modifier, a proviral host gene in hepatitis C virus infection.

PubMed

Broering, R; Trippler, M; Werner, M; Real, C I; Megger, D A; Bracht, T; Schweinsberg, V; Sitek, B; Eisenacher, M; Meyer, H E; Baba, H A; Weber, F; Hoffmann, A-C; Gerken, G; Schlaak, J F

2016-05-01

The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV. © 2016 John Wiley & Sons Ltd.
Dysregulated hepatic expression of glucose transporters in chronic disease: contribution of semicarbazide-sensitive amine oxidase to hepatic glucose uptake.

PubMed

Karim, Sumera; Liaskou, Evaggelia; Fear, Janine; Garg, Abhilok; Reynolds, Gary; Claridge, Lee; Adams, David H; Newsome, Philip N; Lalor, Patricia F

2014-12-15

Insulin resistance is common in patients with chronic liver disease (CLD). Serum levels of soluble vascular adhesion protein-1 (VAP-1) are also increased in these patients. The amine oxidase activity of VAP-1 stimulates glucose uptake via translocation of transporters to the cell membrane in adipocytes and smooth muscle cells. We aimed to document human hepatocellular expression of glucose transporters (GLUTs) and to determine if VAP-1 activity influences receptor expression and hepatic glucose uptake. Quantitative PCR and immunocytochemistry were used to study human liver tissue and cultured cells. We also used tissue slices from humans and VAP-1-deficient mice to assay glucose uptake and measure hepatocellular responses to stimulation. We report upregulation of GLUT1, -3, -5, -6, -7, -8, -9, -10, -11, -12, and -13 in CLD. VAP-1 expression and enzyme activity increased in disease, and provision of substrate to hepatic VAP-1 drives hepatic glucose uptake. This effect was sensitive to inhibition of VAP-1 and could be recapitulated by H2O2. VAP-1 activity also altered expression and subcellular localization of GLUT2, -4, -9, -10, and -13. Therefore, we show, for the first time, alterations in hepatocellular expression of glucose and fructose transporters in CLD and provide evidence that the semicarbazide-sensitive amine oxidase activity of VAP-1 modifies hepatic glucose homeostasis and may contribute to patterns of GLUT expression in chronic disease. Copyright © 2014 the American Physiological Society.
BMP type II receptors have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism.

PubMed

Mayeur, Claire; Leyton, Patricio A; Kolodziej, Starsha A; Yu, Binglan; Bloch, Kenneth D

2014-09-25

Expression of hepcidin, the hepatic hormone controlling iron homeostasis, is regulated by bone morphogenetic protein (BMP) signaling. We sought to identify which BMP type II receptor expressed in hepatocytes, ActR2a or BMPR2, is responsible for regulating hepcidin gene expression. We studied Bmpr2 heterozygous mice (Bmpr2(+/-)), mice with hepatocyte-specific deficiency of BMPR2, mice with global deficiency of ActR2a, and mice in which hepatocytes lacked both BMPR2 and ActR2a. Hepatic hepcidin messenger RNA (mRNA) levels, serum hepcidin and iron levels, and tissue iron levels did not differ in wild-type mice, Bmpr2(+/-) mice, and mice in which either BMPR2 or ActR2a was deficient. Deficiency of both BMP type II receptors markedly reduced hepatic hepcidin gene expression and serum hepcidin levels leading to severe iron overload. Iron injection increased hepatic hepcidin mRNA levels in mice deficient in either BMPR2 or ActR2a, but not in mice deficient in both BMP type II receptors. In addition, in mouse and human primary hepatocytes, deficiency of both BMPR2 and ActR2a profoundly decreased basal and BMP6-induced hepcidin gene expression. These results suggest that BMP type II receptors, BMPR2 and ActR2a, have redundant roles in the regulation of hepatic hepcidin gene expression and iron metabolism. © 2014 by The American Society of Hematology.
Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice

PubMed Central

Yiu, Wai Han; Pan, Chi-Jiunn; Allamarvdasht, Mohammad; Kim, So Youn; Chou, Janice Y.

2008-01-01

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), an endoplasmic reticulum-associated transmembrane protein that is ubiquitously expressed. GSD-Ib patients suffer from disturbed glucose homeostasis and myeloid dysfunctions. To evaluate the feasibility of gene replacement therapy for GSD-Ib, we have infused adenoviral (Ad) vector containing human G6PT (Ad-hG6PT) into G6PT-deficient (G6PT-/-) mice that manifest symptoms characteristics of the human disorder. Ad-hG6PT-infusion restores significant levels of G6PT mRNA expression in the liver, bone marrow, and spleen and corrects metabolic as well as myeloid abnormalities in G6PT-/- mice. The G6PT-/- mice receiving gene therapy exhibit improved growth; normalized serum profiles for glucose, cholesterol, triglyceride, uric acid, and lactic acid; and reduced hepatic glycogen deposition. The therapy also corrects neutropenia and lowers the elevated serum levels of granulocyte colony stimulating factor. The development of bone and spleen in the infused G6PT-/- mice is improved and accompanied by increased cellularity and normalized myeloid progenitor cell frequencies in both tissues. This effective use of gene therapy to correct metabolic imbalances and myeloid dysfunctions in GSD-Ib mice holds promise for the future of gene therapy in humans. PMID:17006547
Intake of phytic acid and myo-inositol lowers hepatic lipogenic gene expression and modulates gut microbiota in rats fed a high-sucrose diet.

PubMed

Okazaki, Yukako; Sekita, Ayaka; Katayama, Tetsuyuki

2018-05-01

Dietary phytic acid (PA) was recently reported by our group to suppress hepatic lipogenic gene expression and modulate gut microbiota in rats fed a high-sucrose (HSC) diet. The present study aimed to investigate whether the modulatory effects of PA depend on the dietary carbohydrate source and are attributed to the myo-inositol (MI) ring of PA. Male Sprague-Dawley rats were fed an HSC or a high-starch (HSR) diet with or without 1.02% sodium PA for 12 days. Subsequently, the rats were fed the HSC diet, the HSC diet containing 1.02% sodium PA or an HSC diet containing 0.2% MI for 12 days. The HSC diet significantly increased the hepatic triglyceride (TG) concentration as well as the activity and expression of hepatic lipogenic enzymes compared with the HSR diet. The increases were generally suppressed by dietary PA with a concomitant increase in the fecal and cecal ratios of Lactobacillus spp. In rats fed the HSR diet, PA intake did not substantially affect the factors associated with hepatic lipid metabolism or gut microbiota composition. The effects of MI intake were similar to that of PA intake on hepatic lipogenesis and gut microbiota in rats fed the HSC diet. These results suggest that dietary PA downregulates hepatic lipogenic gene expression and modulates gut microbiota composition in rats fed an HSC diet but not in rats fed an HSR diet. The MI ring of PA may be responsible for the effects of PA intake on hepatic lipogenic gene expression and gut microbiota.
Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease.

PubMed

Softic, Samir; Cohen, David E; Kahn, C Ronald

2016-05-01

Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.
Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease

PubMed Central

Softic, Samir; Cohen, David E.; Kahn, C. Ronald

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar sweetened beverages are major risk-factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced de novo lipogenesis. Hepatic de novo lipogenesis is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation resulting in increased production of reactive oxygen species. Furthermore fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD. PMID:26856717
Inflammation Stimulates the Expression of PCSK9

PubMed Central

Feingold, Kenneth R.; Moser, Arthur H.; Shigenaga, Judy K.; Patzek, Sophie M.; Grunfeld, Carl

2008-01-01

Inflammation induces marked changes in lipid and lipoprotein metabolism. Proprotein convertase subtilisin kexin 9 (PCSK9) plays an important role in regulating LDL receptor degradation. Here we demonstrate that LPS decreases hepatic LDL receptor protein but at the same time hepatic LDL receptor mRNA levels are not decreased. We therefore explored the effect of LPS on PCSK9 expression. LPS results in a marked increase in hepatic PCSK9 mRNA levels (4 hours-2.5 fold increase; 38 hours-12.5 fold increase). The increase in PCSK9 is a sensitive response with 1 ug LPS inducing a ½ maximal response. LPS also increased PCSK9 expression in the kidney. Finally, zymosan and turpentine, other treatments that induce inflammation, also stimulated hepatic expression of PCSK9. Thus, inflammation stimulates PCSK9 expression leading to increased LDL receptor degradation and decreasing LDL receptors thereby increasing serum LDL, which could have beneficial effects on host defense. PMID:18638454
Overexpression of insulin-like growth factor-I receptor as a pertinent biomarker for hepatocytes malignant transformation

PubMed Central

Yan, Xiao-Di; Yao, Min; Wang, Li; Zhang, Hai-Jian; Yan, Mei-Juan; Gu, Xing; Shi, Yun; Chen, Jie; Dong, Zhi-Zhen; Yao, Deng-Fu

2013-01-01

AIM: To investigate the dynamic features of insulin-like growth factor-I receptor (IGF-IR) expression in rat hepatocarcinogenesis, and the relationship between IGF-IR and hepatocytes malignant transformation at mRNA or protein level. METHODS: Hepatoma models were made by inducing with 2-fluorenylacetamide (2-FAA) on male Sprague-Dawley rats. Morphological changes of hepatocytes were observed by pathological Hematoxylin and eosin staining, the dynamic expressions of liver and serum IGF-IR were quantitatively analyzed by an enzyme-linked immunosorbent assay. The distribution of hepatic IGF-IR was located by immunohistochemistry. The fragments of IGF-IR gene were amplified by reverse transcription-polymerase chain reaction, and confirmed by sequencing. RESULTS: Rat hepatocytes after induced by 2-FAA were changed dynamically from granule-like degeneration, precancerous to hepatoma formation with the progressing increasing of hepatic mRNA or IGF-IR expression. The incidences of liver IGF-IR, IGF-IR mRNA, specific IGF-IR concentration (ng/mg wet liver), and serum IGF-IR level (ng/mL) were 0.0%, 0.0%, 0.63 ± 0.17, and 1.33 ± 0.47 in the control; 50.0%, 61.1%, 0.65 ± 0.2, and 1.51 ± 0.46 in the degeneration; 88.9%, 100%, 0.66 ± 0.14, and 1.92 ± 0.29 in the precancerosis; and 100%, 100%, 0.96 ± 0.09, and 2.43 ± 0.57 in the cancerous group, respectively. IGF-IR expression in the cancerous group was significantly higher (P < 0.01) than that in any of other groups at mRNA or protein level. The closely positive IGF-IR relationship was found between livers and sera (r = 0.91, t = 14.222, P < 0.01), respectively. CONCLUSION: IGF-IR expression may participate in rat hepatocarcinogenesis and its abnormality should be an early marker for hepatocytes malignant transformation. PMID:24106410
Effect of L-arginine supplementation on the hepatic phosphatidylinositol 3-kinase signaling pathway and gluconeogenic enzymes in early intrauterine growth-restricted rats

PubMed Central

Luo, Kaiju; Chen, Pingyang; Li, Suping; Li, Wen; He, Mingfeng; Wang, Tao; Chen, Juncao

2017-01-01

The present study aimed to investigate the response of the phosphatidylinositol 3-kinase (PI3K) signaling pathway and gluconeogenic enzymes in intrauterine growth-restricted rats to dietary L-arginine (L-Arg) supplementation during the lactation period early in life. Pregnant Sprague-Dawley rats were randomly divided into a control group (CON), an intrauterine growth restriction group (IUGR) and an L-Arg group (LA). The pregnant rats in the CON group were fed a 21% protein diet, and those in the IUGR and LA groups were fed a 10% low protein diet, and all rats were fed a 21% protein diet after delivery. Water was available ad libitum to the pregnant rats during the 21-day lactation period, and the water provided to the LA group included 200 mg/kg/day L-Arg. Blood glucose, serum insulin, homeostasis model of assessment for insulin resistance (HOMA-IR), PI3K and protein kinase B (PKB) protein expression, and phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) mRNA expression in the offspring rats were measured postnatally at 1, 3 and 8 weeks. No significant difference in blood glucose, serum insulin and HOMA-IR were identified at any time point among the three groups. PI3K and PKB expression was lower in the IUGR group offspring compared with that in the CON group offspring, but both were increased by dietary L-Arg supplementation. PEPCK mRNA and G-6-Pase mRNA expression levels in the offspring of the IUGR group were higher compared with those in the CON group but were downregulated following L-Arg supplementation. These results suggest that dietary L-Arg supplementation during the early lactation period promoted catch-up growth and reversed abnormalities in hepatic insulin signaling and gene expression of gluconeogenic enzymes in IUGR offspring rats. PMID:28962167
Association of the Interleukin-27 Gene Expression and Hepatitis B Virus Infection in Liver Transplanted Patients.

PubMed

Zare, Abdolhossein; Karimi, Mohammad Hossein; Rashki, Ahmad; Geramizadeh, Bita; Afshari, Afsoon; Miri, Hamid Reza; Yaghobi, Ramin

2017-10-01

Hepatitis B viral infection is among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent viral indication for liver transplant. Cytokine-mediated immunity plays a critical role in introducing and promoting hepatitis B virus outcomes and in graft microenvironment. Interleukin 27 is a heterodimeric cytokine and a member of interleukin-6/interleukin-12 family. Interleukin-27 shows a broad range of pro- and antiinflammatory properties and plays a determining role during immune responses in combating hepatitis B virus. Therefore, in this study, the possible association between expressions of interleukin-27 gene with hepatitis B virus infection was evaluated in liver transplant patients. In a cross-sectional study from liver transplant patients with the risk of hepatitis B virus infection who admitted to Namazi Hospital affiliated to Shiraz University of Medical Sciences, 50 patients were selected and subgrouped to 25 hepatitis B virus-infected and 25 noninfected ones between years 2011 and 2013. The 25 healthy controls also were enrolled in this study. The presence of hepatitis B virus infection was assessed using polymerase chain reaction and enzyme-linked immunosorbent assay protocols in liver transplant patients. In addition, the interleukin-27 gene expression level was analyzed using an in-house-SYBER Green real time polymerase chain reaction method. The rate of interleukin-27 gene expression level was statistically analyzed in studied patient groups and controls using the Livak (2-▵▵CT) method. The expression level of interleukin-27 gene was increased 10.27- and 2.36-fold in hepatitis B virus-infected and uninfected liver transplanted patients compared with healthy controls. Hepatitis B virus infection can lead to overexpression of interleukin-27 gene in liver transplant patients compared with uninfected ones and controls. However, further studies are needed to characterize the effective antihepatitis B virus effects of interleukin-27 in liver transplant patients.
Telesonography Adaptation and Use to Improve the Standard of Patient Care Within a Dominican Community

ClinicalTrials.gov

2009-05-06

Ascites; Blunt Abdominal Trauma; Cholelithiasis; Cholecystitis; Cholangitis; Pancreatitis; Hydronephrosis; Abdominal Aortic Aneurysm; Hepatitis; Portal Hypertension; Urolithiasis; Abnormal Uterine Bleeding; Ovarian Mass; Ovarian Torsion

Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report

PubMed Central

Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

2008-01-01

Introduction Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. Case presentation We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Conclusion Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis. PMID:18226219
Hormonal and metabolic defects in a prader-willi syndrome mouse model with neonatal failure to thrive.

PubMed

Stefan, M; Ji, H; Simmons, R A; Cummings, D E; Ahima, R S; Friedman, M I; Nicholls, R D

2005-10-01

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.
The regulatory effects of fish oil and chitosan on hepatic lipogenic signals in high-fat diet-induced obese rats.

PubMed

Chiu, Chen-Yuan; Chang, Tien-Chia; Liu, Shing-Hwa; Chiang, Meng-Tsan

2017-10-01

The present study investigated the regulatory effects of fish oil and chitosan on the signals of hepatic lipid metabolism and the postulated mechanism in high-fat diet-induced obese rats. Diet supplementation of chitosan and fish oil efficiently suppressed the increased weights in body and livers of high-fat diet-fed rats. Supplementation of chitosan and fish oil significantly decreased the activities of hepatic lipid biosynthesis-related enzymes and efficiently regulated plasma lipoprotein homeostasis. Both chitosan and fish oil significantly ameliorated the alterations in the protein expressions of hepatic lipogenic transcription factors (LXRα and PPARα), and could also significantly regulate the downstream hepatic lipogenic genes (FAS, HMGCR, CYP7A1, FATP, FABP, AOX, and ABCA) expressions in high-fat diet-fed rats. These results suggest that both fish oil and chitosan exerts downregulative effects on hepatic lipid metabolism in high-fat diet-induced obese rats via the LXRα inhibition and PPARα activation, which further affect the expressions of hepatic lipogenesis-associated genes. Copyright © 2017. Published by Elsevier B.V.
Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression

PubMed Central

Estall, Jennifer L.; Kahn, Mario; Cooper, Marcus P.; Fisher, ffolliott Martin; Wu, Michele K.; Laznik, Dina; Qu, Lishu; Cohen, David E.; Shulman, Gerald I.; Spiegelman, Bruce M.

2009-01-01

OBJECTIVE The peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1α activity affect metabolism and energy homeostasis has yet to be determined. RESEARCH DESIGN AND METHODS To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we used the Cre/Lox system to create mice heterozygous for PGC-1α specifically within the liver (LH mice). RESULTS These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial β-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. CONCLUSIONS These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels, underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism. PMID:19366863
Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

PubMed Central

Alkhedaide, Adel; Soliman, Mohamed Mohamed; Ibrahim, Zein Shaban

2016-01-01

The aim of the current study was to examine the effects of chronic consumption of soft drinks (SDs) on hepatic oxidative stress and cytochrome P450 enzymes (CYPs) expression in the livers of Wistar rats. For 3 consecutive months, the rats had free access to three different soft drinks, Coca-Cola, Pepsi-Cola and 7-UP. The rats were subsequently compared with control group rats that had consumed water. Blood and hepatic tissue samples were assayed for the changes in antioxidants, liver function biomarkers and hepatic gene expression for different isoforms of hepatic CYP. The results indicated that SD consumption (SDC) decreased serum antioxidant levels and increased malondialdehyde secretion, and increased liver biomarkers (glutamate pyruvate transaminase and glutamate oxaloacetate). SD induced alterations in mRNA expression of hepatic antioxidants and cytochrome isoforms. The expression of peroxidase, catalase, CYP1A2, CYP3A2 and CYP2C11 in the liver were upregulated following SDC. By contrast, CYP2B1 was downregulated after 3 months of SDC in liver tissue samples. Thus, the present findings indicate that SDs induced oxidative stress in the liver of Wistar rats and for the first time, to the best of our knowledge, indicate that SDC disrupts hepatic CYP enzymes that may affect drug metabolism. Therefore, drug-dosing programs should be carefully designed to take these novel findings into consideration for the treatment of diseases. PMID:27882225
Effects of castration on expression of lipid metabolism genes in the liver of korean cattle.

PubMed

Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001) hepatic lipids contents and higher (p<0.01) mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.
Non-Alcoholic Fatty Liver Disease in HIV Infection.

PubMed

Macías, Juan; Pineda, Juan A; Real, Luis M

2017-01-01

Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.
α-Antitrypsin Deficiency and Neonatal Hepatitis

PubMed Central

Porter, C. A.; Mowat, Alex P.; Cook, P. J. L.; Haynes, D. W. G.; Shilkin, K. B.; Williams, Roger

1972-01-01

Five out of 28 infants investigated in a regional survey of neonatal hepatitis were found to have genetically-determined deficiency of α1-antitrypsin (ZZ phenotype). The clinical course and pathological changes varied considerably. All five infants had an acute hepatitis-like illness, and although this subsided cirrhosis later developed in three cases. The remaining two infants had minimal abnormalities of the liver function tests at 12 and 18 months of age, and one had increased hepatic fibrosis. Australia antigen was found in the serum of three infants, and Australia antigen or antibody in one or both parents of these and of one further case whose serum was negative. It is suggested that the association of neonatal hepatitis with α1-antitrypsin deficiency may be commoner than previously realized and that Australia antigen acts as a trigger factor in these cases. ImagesFIG. 3FIG. 4FIG. 5FIG. 6 PMID:5069219
Derivation and characterization of hepatic progenitor cells from human embryonic stem cells.

PubMed

Zhao, Dongxin; Chen, Song; Cai, Jun; Guo, Yushan; Song, Zhihua; Che, Jie; Liu, Chun; Wu, Chen; Ding, Mingxiao; Deng, Hongkui

2009-07-31

The derivation of hepatic progenitor cells from human embryonic stem (hES) cells is of value both in the study of early human liver organogenesis and in the creation of an unlimited source of donor cells for hepatocyte transplantation therapy. Here, we report for the first time the generation of hepatic progenitor cells derived from hES cells. Hepatic endoderm cells were generated by activating FGF and BMP pathways and were then purified by fluorescence activated cell sorting using a newly identified surface marker, N-cadherin. After co-culture with STO feeder cells, these purified hepatic endoderm cells yielded hepatic progenitor colonies, which possessed the proliferation potential to be cultured for an extended period of more than 100 days. With extensive expansion, they co-expressed the hepatic marker AFP and the biliary lineage marker KRT7 and maintained bipotential differentiation capacity. They were able to differentiate into hepatocyte-like cells, which expressed ALB and AAT, and into cholangiocyte-like cells, which formed duct-like cyst structures, expressed KRT19 and KRT7, and acquired epithelial polarity. In conclusion, this is the first report of the generation of proliferative and bipotential hepatic progenitor cells from hES cells. These hES cell-derived hepatic progenitor cells could be effectively used as an in vitro model for studying the mechanisms of hepatic stem/progenitor cell origin, self-renewal and differentiation.
Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis.

PubMed

Wehr, Alexander; Baeck, Christer; Heymann, Felix; Niemietz, Patricia Maria; Hammerich, Linda; Martin, Christian; Zimmermann, Henning W; Pack, Oliver; Gassler, Nikolaus; Hittatiya, Kanishka; Ludwig, Andreas; Luedde, Tom; Trautwein, Christian; Tacke, Frank

2013-05-15

Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6(+/gfp) and Cxcr6(gfp/gfp) mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6(-/-) mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6(-/-) mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.
Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats.

PubMed

Chang, Ching-Chih; Lee, Wen-Shin; Chuang, Chiao-Lin; Hsin, I-Fang; Hsu, Shao-Jung; Chang, Ting; Huang, Hui-Chun; Lee, Fa-Yauh; Lee, Shou-Dong

2017-05-05

Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism. Copyright © 2017 Elsevier B.V. All rights reserved.
Specific Macronutrients Exert Unique Influences on the Adipose-Liver Axis to Promote Hepatic Steatosis in Mice.

PubMed

Duwaerts, Caroline C; Amin, Amin M; Siao, Kevin; Her, Chris; Fitch, Mark; Beysen, Carine; Turner, Scott M; Goodsell, Amanda; Baron, Jody L; Grenert, James P; Cho, Soo-Jin; Maher, Jacquelyn J

2017-09-01

The factors that distinguish metabolically healthy obesity from metabolically unhealthy obesity are not well understood. Diet has been implicated as a determinant of the unhealthy obesity phenotype, but which aspects of the diet induce dysmetabolism are unknown. The goal of this study was to investigate whether specific macronutrients or macronutrient combinations provoke dysmetabolism in the context of isocaloric, high-energy diets. Mice were fed 4 high-energy diets identical in calorie and nutrient content but different in nutrient composition for 3 weeks to 6 months. The test diets contained 42% carbohydrate (sucrose or starch) and 42% fat (oleate or palmitate). Weight and glucose tolerance were monitored; blood and tissues were collected for histology, gene expression, and immunophenotyping. Mice gained weight on all 4 test diets but differed significantly in other metabolic outcomes. Animals fed the starch-oleate diet developed more severe hepatic steatosis than those on other formulas. Stable isotope incorporation showed that the excess hepatic steatosis in starch-oleate-fed mice derived from exaggerated adipose tissue lipolysis. In these mice, adipose tissue lipolysis coincided with adipocyte necrosis and inflammation. Notably, the liver and adipose tissue abnormalities provoked by starch-oleate feeding were reproduced when mice were fed a mixed-nutrient Western diet with 42% carbohydrate and 42% fat. The macronutrient composition of the diet exerts a significant influence on metabolic outcome, independent of calories and nutrient proportions. Starch-oleate appears to cause hepatic steatosis by inducing progressive adipose tissue injury. Starch-oleate phenocopies the effect of a Western diet; consequently, it may provide clues to the mechanism whereby specific nutrients cause metabolically unhealthy obesity.
Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.

PubMed

Monetti, Mara; Levin, Malin C; Watt, Matthew J; Sajan, Mini P; Marmor, Stephen; Hubbard, Brian K; Stevens, Robert D; Bain, James R; Newgard, Christopher B; Farese, Robert V; Hevener, Andrea L; Farese, Robert V

2007-07-01

Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triacylglycerol (TG) biosynthesis, in the liver (Liv-DGAT2 mice). Liv-DGAT2 mice developed hepatic steatosis, with increased amounts of TG, diacylglycerol, ceramides, and unsaturated long-chain fatty acyl-CoAs in the liver. However, they had no abnormalities in plasma glucose and insulin levels, glucose and insulin tolerance, rates of glucose infusion and hepatic glucose production during hyperinsulinemic-euglycemic clamp studies, or activities of insulin-stimulated signaling proteins in the liver. DGAT1 overexpression in the liver also failed to induce glucose or insulin intolerance. Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance.
Vascular Complications After Liver Transplantation

PubMed Central

Wozney, Paul; Bron, Klaus M.; Point, Stuart; Starzl, Thomas E.

2011-01-01

During the past 5 years, 104 angiographic studies were performed in 87 patients (45 children and 42 adults) with 92 transplanted livers for evaluation of possible vascular complications. Seventy percent of the studies were abnormal. Hepatic artery thrombosis was the most common complication (seen in 42% of children studied, compared with only 12% of adults) and was a major complication that frequently resulted in graft failure, usually necessitating retransplantation. In six children, reconstitution of the intrahepatic arteries by collaterals was seen. Three survived without retransplant. Arterial stenosis at the anastomosis or in the donor hepatic artery was observed in 11% of patients. Portal vein thrombosis or stenosis occurred in 13% of patients. Two children and one adult with portal vein thrombosis demonstrated hepatopetal collaterals that reconstituted the intrahepatic portal vessels. Uncommon complications included anastomotic and donor hepatic artery pseudoaneurysms, a hepatic artery–dissecting aneurysm, pancreaticoduodenal mycotic aneurysms, hepatic artery–portal vein fistula, biliary–portal vein fistula, hepatic vein occlusion, and inferior vena cava thrombosis. PMID:3529892
Prehepatocholedochal proper hepatic artery. Rare anatomical variant. Surgical considerations. Case report.

PubMed

Ardeleanu, V; Chicoş, S; Tutunaru, D; Georgescu, C

2014-01-01

In classical anatomic variants, the proper hepatic artery (PHA)continues the common hepatic artery (CHA) after the gastroduodenal artery (GDA) detaches itself and divides into the right hepatic artery (RHA) and left hepatic artery (LHA), the proper hepatic artery being located to the left of the hepatocholedochal duct (HCD). This paper presents an abnormal positioning of the PHA placed before the HCD with an increased diameter of about 5-7 mm, which could be confused with the HCD. We present the case of a 57 year-old woman diagnosed with acute lithiasic cholecystitis, associated with hypersplenism and hypertension. The literature mentions manifold anatomical variants of arterial liver vascularization,including PHA. For this reason, this paper presents an overview of similar cases that can be found in medical literature. The aforementioned case is a rare topographic anatomy for the PHA that can easily pass for HCD especially during celioscopy, therefore it is crucial for this to be acknowledged by all surgeons. Celsius.
In type 1 diabetics, high-dose biotin may compensate for low hepatic insulin exposure, promoting a more normal expression of glycolytic and gluconeogenic enyzymes and thereby aiding glycemic control.

PubMed

McCarty, Mark F

2016-10-01

In type 1 diabetics, hepatic exposure to insulin is chronically subnormal even in the context of insulin therapy; as a result, expression of glycolytic enzymes is decreased, and that of gluconeogenic enzymes is enhanced, resulting in a physiologically inappropriate elevation of hepatic glucose output. Subnormal expression of glucokinase (GK) is of particular importance in this regard. Possible strategies for correcting this perturbation of hepatic enzyme expression include administration of small molecule allosteric activators of GK, as well as a procedure known as chronic intermittent intravenous insulin therapy (CIIIT); however, side effects accompany the use of GK activators, and CIIIT is time and labor intensive. Alternatively, administration of high-dose biotin has potential for modulating hepatic enzyme expression in a favorable way. Studies in rodents and in cultured hepatocytes demonstrate that, in the context of low insulin exposure, supra-physiological levels of biotin induce increased expression of GK while suppressing that of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects may be a downstream consequence of the fact that biotin down-regulates mRNA expression of FOXO1; insulin's antagonism of the activity of this transcription factor is largely responsible for its modulatory impact on hepatic glycolysis and gluconeogenesis. Hence, high-dose biotin may compensate for subnormal insulin exposure by suppressing FOXO1 levels. High-dose biotin also has the potential to oppose hepatic steatosis by down-regulating SREBP-1 expression. Two pilot trials of high-dose biotin (16 or 2mg per day) in type 1 diabetics have yielded promising results. There is also some reason to suspect that high-dose biotin could aid control of diabetic neuropathy and nephropathy via its stimulatory effect on cGMP production. Owing to the safety, good tolerance, moderate expense, and current availability of high-dose biotin, this strategy merits more extensive evaluation in type 1 diabetes. Copyright © 2016 Elsevier Ltd. All rights reserved.
Gene-specific alterations of hepatic nuclear receptor regulated gene expression by ligand activation or hepatocyte-selective knockout inhibition of RXRα signaling during inflammation

PubMed Central

Kosters, Astrid; Tian, Feng; Wan, Yvonne Yu-Jie; Karpen, Saul J.

2013-01-01

Background Inflammation leads to transcriptional downregulation of many hepatic genes, particulary those activated by RXRα-heterodimers. Inflammation-mediated reduction of nuclear RXRα levels is a main factor in reduced nuclear receptor (NR)–regulated hepatic gene expression, eventually leading to cholestasis and liver damage. Aim To investigate roles for RXRα in hepatic gene expression during inflammation, using two complementary mouse models: ligand–activation of RXRα, and in mice expressing hepatocyte-specific expression of RXRα missing its DNA-binding-domain (DBD; hs-RxrαΔex4−/−) Methods To activate RXRα, mice were gavage-fed with LG268 or vehicle for 5 days. To inhibit RXRα function, hs-RxrαΔex4−/− were used. All mice were IP-injected with LPS or saline for 16 hrs prior to analysis of hepatic RNA, protein and NR-DNA binding. Results LG268-treatment attenuated the LPS-mediated reductions of several RXRα-regulated genes, coinciding with maintained RXRα occupancy in both Bsep and Ostβ promoters. Lacking full hepatocyte-RXRα function (hs-RxrαΔex4−/− mice) led to enhancement of LPS-mediated changes in gene expression, but surprisingly, maintenance of RNA levels of some RXRα-regulated genes. Investigations revealed that Hs-Rxrα−/− hepatocytes expressed an internally-truncated, ~44 kDa, RXRα-form. DNA-binding capacity of NR-heterodimers was equivalent in wt and hs-RxrαΔex4−/− livers, but reduced by LPS in both. ChIP-QPCR revealed reduced RXRα occupancy to the Bsep RXRα:FXR site was reduced, but not absent, in hs-RxrαΔex4−/− livers. Conclusions There are differential regulatory roles for hepatic RXRα, both in basal and inflammatory states, suggesting new and complex multi-domain roles for RXRα in regulating hepatic gene expression. Moreover, there is an unexpected non-obligate role for the DBD of RXRα. PMID:22098603
Quantitative analysis of brain magnetic resonance imaging for hepatic encephalopathy

NASA Astrophysics Data System (ADS)

Syh, Hon-Wei; Chu, Wei-Kom; Ong, Chin-Sing

1992-06-01

High intensity lesions around ventricles have recently been observed in T1-weighted brain magnetic resonance images for patients suffering hepatic encephalopathy. The exact etiology that causes magnetic resonance imaging (MRI) gray scale changes has not been totally understood. The objective of our study was to investigate, through quantitative means, (1) the amount of changes to brain white matter due to the disease process, and (2) the extent and distribution of these high intensity lesions, since it is believed that the abnormality may not be entirely limited to the white matter only. Eleven patients with proven haptic encephalopathy and three normal persons without any evidence of liver abnormality constituted our current data base. Trans-axial, sagittal, and coronal brain MRI were obtained on a 1.5 Tesla scanner. All processing was carried out on a microcomputer-based image analysis system in an off-line manner. Histograms were decomposed into regular brain tissues and lesions. Gray scale ranges coded as lesion were then brought back to original images to identify distribution of abnormality. Our results indicated the disease process involved pallidus, mesencephalon, and subthalamic regions.
Native fluorescence characterization of human liver abnormalities

NASA Astrophysics Data System (ADS)

Ganesan, Singaravelu; Madhuri, S.; Aruna, Prakasa R.; Suchitra, S.; Srinivasan, T. G.

1999-05-01

Fluorescence spectroscopy of intrinsic biomolecules has been extensively used in biology and medicine for the past several decades. In the present study, we report the native fluorescence characteristics of blood plasma from normal human subjects and patients with different liver abnormalities such as hepatitis, leptospirosis, jaundice, cirrhosis and liver cell failure. Native fluorescence spectra of blood plasma -- acetone extract were measured at 405 nm excitation. The average spectrum of normal blood plasma has a prominent emission peak around 464 nm whereas in the case of liver diseased subjects, the primary peak is red shifted with respect to normal. In addition, liver diseased cases show distinct secondary emission peak around 615 nm, which may be attributed to the presence of endogenous porphyrins. The red shift of the prominent emission peak with respect to normal is found to be maximum for hepatitis and minimum for cirrhosis whereas the secondary emission peak around 615 nm was found to be more prominent in the case of cirrhosis than the rest. The ratio parameter I465/I615 is found to be statistically significant (p less than 0.001) in discriminating liver abnormalities from normal.
[Related factors for severe liver fibrosis in chronic hepatitis C patients with remunerated blood donation history in Jurong of Jiangsu province].

PubMed

Yao, Y N; Huang, P; Chen, H B; Zhang, L; Chen, M Z; Yu, R B

2017-01-10

Objective: The incidence of liver fibrosis in patients with chronic hepatitis C is high. Without effective treatment, it would lead to liver cirrhosis. This study is to identify the related factors for the incidence of liver fibrosis in patients with chronic hepatitis C in order to make early intervention treatment and reduce the case fatality rate. Methods: This cross-sectional survey was conducted in adults aged ≥50 years with local residence for more than 5 years in Jurong of Jiangsu province from March to May in 2015, the patients infected with hepatitis C virus through remunerated blood donation were screened and included in the analysis. Descriptive statistical analysis was done to compare the differences in the incidence of liver fibrosis among the patients with different age, sex and education level or co-infected with hepatitis B virus or not. The risk factors for severe liver fibrosis were identified with univariate and multivariate logistic regression analysis. Liver fibrosis was diagnosed by using FIB-4 index method. Results: A total of 719 patients with chronic hepatitis C were surveyed. Severe liver fibrosis developed in 285 of the 719 patients, in whom 21.84 % was males. Multivariate logistic regression analysis showed that the patients with higher education level ( OR =0.65, 95 %CI : 0.47-0.90) and with access of antiviral therapy ( OR =0.33, 95 %CI : 0.22-0.49) had lower risk for severe liver fibrosis, the patients with high fasting blood glucose level ( OR =1.80, 95 % CI : 1.19-2.77) and abnormal white blood cell count ( OR =2.77, 95 % CI : 1.95-3.90) had higher risk for severe liver fibrosis. Conclusions: The incidence of severe liver fibrosis in patients with hepatitis C was affected by many factors. Higher education level and antiviral therapy were the protective factors, but high fasting blood glucose level and abnormal white blood cell count were the risk factors.

Obesity Increases Sensitivity to Endotoxin Liver Injury: Implications for the Pathogenesis of Steatohepatitis

NASA Astrophysics Data System (ADS)

Yang, Shi Qi; Zhi Lin, Hui; Lane, M. Daniel; Clemens, Mark; Diehl, Anna Mae

1997-03-01

Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor α (TNFα ), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon γ , which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.
Effect of hepatitis B virus infection on sperm quality and oxidative stress state of the semen of infertile males.

PubMed

Qian, Li; Li, Qiong; Li, Haibo

2016-09-01

The effects of hepatitis B virus (HBV) infection on sperm quality and oxidative stress state of the semen of infertile males remain undetermined. Normal males and 60 semen samples from infertile males (with or without HBV infection) were subjected to semen analysis. Semen volume, semen pH, sperm density, percentage of forward, movement of sperm, sperm activation rate, sperm survival rate, rate of normal sperm morphology of infertile males with HBV infection were significantly lower than those of infertile males without genital infection and of normal males (P<.05), while interleukin (IL)-17, IL-18, and malondialdehyde (MDA) levels in subjects with HBV infection were significantly higher than those of infertile males without genital infection and of normal males (P<.05). In patients with HBV infection, MDA level was found to be negatively correlated with semen quality, but positively correlated with semen IL-17 and IL-18 concentrations. HBV infection increased MDA level, induced abnormal expression of IL-17 and IL-18, and negatively affected male reproductive capacity, resulting in male infertility. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
An update on the pathophysiology and management of polycystic liver disease.

PubMed

Wong, May Yw; McCaughan, Geoffrey W; Strasser, Simone I

2017-06-01

Polycystic liver disease (PLD) is characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. They are classified as an inherited ciliopathy /cholangiopathy as pathology exists at the level of the primary cilia of cholangiocytes. Aberrant expression of the proteins in primary cilia can impair their structures and functions, thereby promoting cystogenesis. Areas covered: This review begins by looking at the epidemiology of PLD and its natural history. It then describes the pathophysiology and corresponding potential treatment strategies for PLD. Expert commentary: Traditionally, therapies for symptomatic PLD have been limited to symptomatic management and surgical interventions. Such techniques are not completely effective, do not alter the natural history of the disease, and are linked with high rate of re-accumulation of cysts. As a result, there has been a push for drugs targeted at abnormal cellular signaling cascades to address deregulated proliferation, cell dedifferentiation, apoptosis and fluid secretion. Currently, the only available drug treatments that halt disease progression and improve quality of life in PLD patients are somatostatin analogues. Numerous preclinical studies suggest that targeting components of the signaling pathways that influence cyst development can ameliorate growth of hepatic cysts.
Dietary phytic acid prevents fatty liver by reducing expression of hepatic lipogenic enzymes and modulates gut microflora in rats fed a high-sucrose diet.

PubMed

Sekita, Ayaka; Okazaki, Yukako; Katayama, Tetsuyuki

2016-06-01

The aim of this study was to investigate the effect of phytic acid (PA) on fatty liver and gut microflora in rats fed a high-sucrose (HSC) diet. Three groups of rats were fed a high-starch (HSR) diet or an HSC diet with or without 1.02% sodium PA for 12 d. We evaluated hepatic weight, total lipids, and triacylglycerol (TG) levels, the activities and expression of hepatic lipogenic enzymes (glucose-6-phosphate dehydrogenase, malic enzyme 1, and fatty acid synthetase), and fecal microflora. The HSC diet significantly increased hepatic total lipids and TG levels, and the activities and expression of the hepatic lipogenic enzymes compared with the HSR diet. These upregulations were clearly suppressed by dietary PA. Consumption of PA elevated the fecal ratio of Lactobacillus spp. and depressed the ratio of Clostridium cocoides, and suppressed the elevation in the ratio of C. leptum induced by the HSC diet. This work showed that dietary PA ameliorates sucrose-induced fatty liver through reducing the expression of hepatic lipogenesis genes and modulates gut microflora in rats. Copyright © 2016 Elsevier Inc. All rights reserved.
Collapsed Reticular Network and its Possible Mechanism during the Initiation and/or Progression of Hepatic Fibrosis

PubMed Central

Wen, Shi-Lei; Feng, Shi; Tang, Shi-Hang; Gao, Jin-Hang; Zhang, Lin-hao; Tong, Huan; Yan, Zhao-Ping; Fang, Ding Zhi

2016-01-01

Among the researches on hepatic fibrosis, great attention was paid to both hepatocytes and extracellular matrix (ECM). However, little focus was drawn on reticular fibrous network, which is important for demarcation and support of hepatocytes. The aim of this study was to investigate the change pattern of reticular fibers in hepatic fibrosis/cirrhosis and its underlying mechanism. In this study, thioacetamide (TAA) and bile duct ligation (BDL) were utilized to induce rat hepatic fibrosis respectively, and Human liver cirrhotic microassay was analyzed with IHC to confirm the results in animal experiment and to detect the metalloproteinases (MMPs) expressions. As a result, the reticular fibers decreased markedly after 1 week in TAA and 1 day in BDL treated rats. Multiple representative regulators of MMPs and MMPs increased significantly in their expressions and activities. Further more, in human liver cirrhotic microassay, MMPs expressions also showed similar patterns as that of animal experiment. In Conclusions: Degradation or collapse of reticular fibers in hepatic sinusoid can be considered as a pathological feature during the initiation and/or progression of hepatic fibrosis. Moreover, such degradation is associated with and probably caused by the over/dysregulated expression of MMPs. PMID:27739503
DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying

Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able tomore » elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.« less
Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77.

PubMed

Zhou, Feiye; Bai, Mengyao; Zhang, Yuqing; Zhu, Qin; Zhang, Linlin; Zhang, Qi; Wang, Shushu; Zhu, Kecheng; Liu, Yun; Wang, Xiao; Zhou, Libin

2018-01-08

Fibroblast growth factor 21 (FGF21), a hormone-like protein mainly derived from liver, exhibits multiple beneficial effect on energy metabolism. Similar to FGF21, berberine exerts anti-hyperglycemic and anti-dyslipidemic properties. Previous studies revealed that the beneficial metabolic effect of berberine was attributed to the activation of AMP-activated protein kinase (AMPK). Here we investigated the effect of berberine on FGF21 expression in primary mouse hepatocytes. As expected, berberine induced hepatic FGF21 expression in a dose-dependent and time-dependent manner, along with the increased expression of NUR77, a proved transcription factor of FGF21. Berberine stimulated the phosphorylations of AMPK and acetyl-CoA carboxylase in primary mouse hepatocytes. Adenovirus-mediated overexpression of constitutively active AMPK triggered hepatic FGF21 and NUR77 expressions. The inhibition of AMPK by compound C abolished berberine-stimulated FGF21 and NUR77 expressions. These results suggest that berberine-induced activation of AMPK may contribute to hepatic FGF21 expression via NUR77. Copyright © 2017 Elsevier Inc. All rights reserved.
Fetal scalp pH testing

MedlinePlus

... such as HIV/AIDS or hepatitis C. Normal Results Normal fetal blood sample results are: Normal pH: ... meaning of your specific test results. What Abnormal Results Mean A fetal scalp blood pH level of ...
Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

PubMed

Wang, Feng; Liu, Jin-Cheng; Zhou, Rui-Jun; Zhao, Xi; Liu, Mei; Ye, Hua; Xie, Mei-Lin

2017-09-25

Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol-induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150-300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.
Hepatic alveolar echinococcosis: correlative US and CT study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Didier, D.; Weiler, S.; Rohmer, P.

1985-01-01

A total of 24 cases of hepatic alveolar echinococcosis (HAE) due to Echinococcus multilocularis was assessed by US and CT. The diagnosis was confirmed in all cases by immunologic and histologic study. Both US and CT patterns of HAE showed changes of liver morphology in both contour and size. Abnormal areas of parenchyma were nodular or in fields, irregular, heterogeneous, and basically echogenic. Clustered microcalcifications were encountered within the abnormal parenchymal fields in 50% of cases, and necrotized zones occurred in 40% of cases. Dilatation of intrahepatic bile ducts was commonly seen, especially on US; hilar involvement was frequent. Follow-upmore » by both techniques can display increases of primary lesions, occurrence of new foci, and local or regional extensions. Precise evaluations of the lesions arising from correlative use of US and CT permits adequate therapeutic management.« less
Identification of differentially expressed genes induced by energy restriction using annealing control primer system from the liver and adipose tissues of broilers.

PubMed

Wang, J W; Chen, W; Kang, X T; Huang, Y Q; Tian, Y D; Wang, Y B

2012-04-01

Female Arbor Acre broilers were divided into 2 groups at 18 d of age. One group of chickens had free access to feed (AL), and the other group of chickens had 30% energy restriction (ER). Adipose and hepatic RNA samples were collected at 48 d of age. We employed an accurate reverse-transcription (RT) PCR method that involves annealing control primers to identify the differentially expressed genes (DEG) between ER and AL groups. Using 20 annealing control primers, 43 differentially expressed bands (40 downregulated and 3 upregulated in the ER group) were detected from the hepatic tissue, whereas no differentially expressed bands were detected from the adipose tissue. It seems that energy restriction could induce more DEG in hepatic tissue than that in adipose tissue and could result in more gene-expression downregulation in hepatic tissue. Eight DEG (6 known and 2 unknown genes) were gained from hepatic tissue and confirmed by RT-PCR, which were all supported by released expressed sequence tag sequences. Their expressions were all downregulated by energy restriction in hepatic tissues. Six known genes are RPL7, RPLP1, FBXL12, ND1, ANTXR2, and SLC22A18, respectively, which seem to play essential roles in the protein translation, energy metabolism, and tumor inhibition. The alterations of gene expression in 3 selected genes, including ND1 (P < 0.01), FBXL12 (P < 0.01), and RPLP1 (P < 0.05), were supported by real-time quantitative RT-PCR reaction. Our data provide new insights on the metabolic state of broilers changed by energy restriction.
Regulation of Hepatic Cholesteryl Ester Transfer Protein Expression and Reverse Cholesterol Transport by Inhibition of DNA Topoisomerase II.

PubMed

Liu, Mengyang; Chen, Yuanli; Zhang, Ling; Wang, Qixue; Ma, Xingzhe; Li, Xiaoju; Xiang, Rong; Zhu, Yan; Qin, Shucun; Yu, Yang; Jiang, Xian-cheng; Duan, Yajun; Han, Jihong

2015-06-05

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoprotein to triglyceride-rich lipoproteins. CETP expression can be transcriptionally activated by liver X receptor (LXR). Etoposide and teniposide are DNA topoisomerase II (Topo II) inhibitors. Etoposide has been reported to inhibit atherosclerosis in rabbits with un-fully elucidated mechanisms. In this study we determined if Topo II activity can influence cholesterol metabolism by regulating hepatic CETP expression. Inhibition of Topo II by etoposide, teniposide, or Topo II siRNA increased CETP expression in human hepatic cell line, HepG2 cells, which was associated with increased CETP secretion and mRNA expression. Meanwhile, inhibition of LXR expression by LXR siRNA attenuated induction of CETP expression by etoposide and teniposide. Etoposide and teniposide induced LXRα expression and LXRα/β nuclear translocation while inhibiting expression of receptor interacting protein 140 (RIP140), an LXR co-repressor. In vivo, administration of teniposide moderately reduced serum lipid profiles, induced CETP expression in the liver, and activated reverse cholesterol transport in CETP transgenic mice. Our study demonstrates a novel function of Topo II inhibitors in cholesterol metabolism by activating hepatic CETP expression and reverse cholesterol transport. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

PubMed

Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

2017-06-01

Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP up-regulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepato-protective agent. © Author(s) 2017. This article is published with open access by China Medical University.
Light interference as a possible stressor altering HSP70 and its gene expression levels in brain and hepatic tissues of golden spiny mice.

PubMed

Ashkenazi, Lilach; Haim, Abraham

2012-11-15

Light at night and light interference (LI) disrupt the natural light:dark cycle, causing alterations at physiological and molecular levels, partly by suppressing melatonin (MLT) secretion at night. Heat shock proteins (HSPs) can be activated in response to environmental changes. We assessed changes in gene expression and protein level of HSP70 in brain and hepatic tissues of golden spiny mice (Acomys russatus) acclimated to LI for two (SLI), seven (MLI) and 21 nights (LLI). The effect of MLT treatment on LI-mice was also assessed. HSP70 levels increased in brain and hepatic tissues after SLI, whereas after MLI and LLI, HSP70 decreased to control levels. Changes in HSP70 levels as a response to MLT occurred after SLI only in hepatic tissue. However, hsp70 expression following SLI increased in brain tissue, but not in hepatic tissue. MLT treatment and SLI caused a decrease in hsp70 levels in brain tissue and an increase in hsp70 in hepatic tissue. SLI acclimation elicited a stress response in A. russatus, as expressed by increased HSP70 levels and gene expression. Longer acclimation decreases protein and gene expression to their control levels. We conclude that for brain and hepatic tissues of A. russatus, LI is a short-term stressor. Our results also revealed that A. russatus can acclimate to LI, possibly because of its circadian system plasticity, which allows it to behave both as a nocturnal and as a diurnal rodent. To the best of our knowledge, this is the first study showing the effect of LI as a stressor at the cellular level, by activating HSP70.
Tumor necrosis factor-alpha-independent downregulation of hepatic cholesterol 7alpha-hydroxylase gene in mice treated with lead nitrate.

PubMed

Kojima, Misaki; Sekikawa, Kenji; Nemoto, Kiyomitsu; Degawa, Masakuni

2005-10-01

We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-alpha (TNF-alpha), downregulated gene expression of cholesterol 7alpha-hydroxylase. Herein, to clarify the role of TNF-alpha in LN-induced downregulation of cholesterol 7alpha-hydroxylase, effects of LN on gene expression of hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) in TNF-alpha-knockout (KO) and TNF-alpha-wild-type (WT) mice were comparatively examined. Gene expression of hepatic Cyp7a1 in both WT and KO mice decreased to less than 5% of the corresponding controls at 6-12 h after treatment with LN (100 mumol/kg body weight, iv). Levels of hepatic TNF-alpha protein in either WT or KO mice were below the detection limit, although expression levels of the TNF-alpha gene markedly increased at 6 h in WT mice by LN treatment, but not in KO mice. In contrast, in both WT and KO mice, levels of hepatic IL-1beta protein, which is known to be a suppressor of the cholesterol 7alpha-hydroxylase gene in hamsters, were significantly increased 3-6 h after LN treatment. Furthermore, LN-induced downregulation of the Cyp7a1 gene did not necessarily result from altered gene expression of hepatic transcription factors, including positive regulators (liver X receptor alpha, retinoid X receptor alpha, fetoprotein transcription factor, and hepatocyte nuclear factor 4alpha) and a negative regulator small heterodimer partner responsible for expression of the Cyp7a1 gene. The present findings indicated that LN-induced downregulation of the Cyp7a1 gene in mice did not necessarily occur through a TNF-alpha-dependent pathway and might occur mainly through an IL-1beta-dependent pathway.
Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism

PubMed Central

Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

2015-01-01

Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in intestinal permeability. Together, we demonstrated that LF41 pre-feeding enabled the liver to alleviate LPS-induced hepatic TNF-α expression and injury via a PGE2-EP4- and IL-10-dependent mechanism. PMID:25978374
Chronic exposure to low doses of pharmaceuticals disturbs the hepatic expression of circadian genes in lean and obese mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anthérieu, Sébastien; Le Guillou, Dounia; Coulouarn, Cédric

Drinking water can be contaminated with pharmaceuticals. However, it is uncertain whether this contamination can be harmful for the liver, especially during obesity. Hence, the goal of our study was to determine whether chronic exposure to low doses of pharmaceuticals could have deleterious effects on livers of lean and obese mice. To this end, lean and ob/ob male mice were treated for 4 months with a mixture of 11 drugs provided in drinking water at concentrations ranging from 10 to 10{sup 6} ng/l. At the end of the treatment, some liver and plasma abnormalities were observed in ob/ob mice treatedmore » with the cocktail containing 10{sup 6} ng/l of each drug. For this dosage, a gene expression analysis by microarray showed altered expression of circadian genes (e.g. Bmal1, Dbp, Cry1) in lean and obese mice. RT-qPCR analyses carried out in all groups of animals confirmed that expression of 8 different circadian genes was modified in a dose-dependent manner. For some genes, a significant modification was observed for dosages as low as 10{sup 2}–10{sup 3} ng/l. Drug mixture and obesity presented an additive effect on circadian gene expression. These data were validated in an independent study performed in female mice. Thus, our study showed that chronic exposure to trace pharmaceuticals disturbed hepatic expression of circadian genes, particularly in obese mice. Because some of the 11 drugs can be found in drinking water at such concentrations (e.g. acetaminophen, carbamazepine, ibuprofen) our data could be relevant in environmental toxicology, especially for obese individuals exposed to these contaminants. - Highlights: • The contamination of drinking water with drugs may have harmful effects on health. • Some drugs can be more hepatotoxic in the context of obesity and fatty liver. • Effects of chronic exposure of trace drugs were studied in lean and obese mouse liver. Drugs and obesity present additive effects on circadian gene expression and toxicity. • Trace pharmaceuticals could be harmful for the liver, especially in obese individuals.« less
Molecular and cytogenomic profiling of hepatic adenocarcinoma expressing inhibinA, a mimicker of neuroendocrine tumors: proposal to reclassify as "cholangioblastic variant of intrahepatic cholangiocarcinoma".

PubMed

Braxton, David R; Saxe, Debra; Damjanov, Nevena; Stashek, Kristen; Shroff, Stuti; Morrissette, Jennifer D; Tondon, Rashmi; Furth, Emma E

2017-04-01

Only a single case report exists in the literature of hepatic adenocarcinoma expressing InhibinA in a young woman, in which the authors proposed it to be a rare variant of intrahepatic cholangiocarcinoma (iCCA). We present novel molecular and histologic findings in our series of three cases occurring in young women and show these tumors may mimic well-differentiated neuroendocrine tumors (NET). Immunohistochemical (IHC) profiling was performed along with a next-generation sequencing (NGS) 47-gene solid tumor panel, and cytogenomic profiling via single-nucleotide polypmorphism microarray. IHC for inhibinA, chromogranin A (ChrA), and synaptophysin (Syn) was surveyed in liver tumors and in fetal liver. Two of the three patients recurred with metastatic disease with two confirmed deaths. Histological patterns present in the tumors included solid, trabecular, organoid, microcystic, and blastemal-like. IHC was positive for cytokeratin 7 in 3/3, cytokeratin 19 in 3/3, inhibinA in 3/3, ChrA in 3/3, Syn in 3/3, Sox9 in 2/3 and HepPar1 in 0/3. NGS was negative for pathogenic mutations. Recurrent cytogenomic abnormalities included gain of 17q, and loss of 6q. InhibinA was strong and diffusely expressed in 0/10 (0%) iCCA, 0/15 (0%) hepatocellular carcinomas (HCC), in the biliary component of 1/4 (25%) combined HCC-iCCA, 0/4 hepatoblastomas, 1/8 (13%) metastatic NET, and in 1/8 fetal liver tissues. We propose a classification of "cholangioblastic variant of intrahepatic cholangiocarcinoma" and molecular pathogenesis for this rare malignancy. Accurate identification on core biopsy is crucial for clinical management as it may mimic neuroendocrine neoplasms. Copyright © 2017 Elsevier Inc. All rights reserved.
[Autoimmune hepatitis: Immunological diagnosis].

PubMed

Brahim, Imane; Brahim, Ikram; Hazime, Raja; Admou, Brahim

2017-11-01

Autoimmune hepatopathies (AIHT) including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AIC), represent an impressive entities in clinical practice. Their pathogenesis is not perfectly elucidated. Several factors are involved in the initiation of hepatic autoimmune and inflammatory phenomena such as genetic predisposition, molecular mimicry and/or abnormalities of T-regulatory lymphocytes. AIHT have a wide spectrum of presentation, ranging from asymptomatic forms to severe acute liver failure. The diagnosis of AIHT is based on the presence of hyperglobulinemia, cytolysis, cholestasis, typical even specific circulating auto-antibodies, distinctive of AIH or PBC, and histological abnormalities as well as necrosis and inflammation. Anti-F actin, anti-LKM1, anti-LC1 antibodies permit to distinguish between AIH type 1 and AIH type 2. Anti-SLA/LP antibodies are rather associated to more severe hepatitis, and particularly useful for the diagnosis of seronegative AIH for other the antibodies. Due to the relevant diagnostic value of anti-M2, anti-Sp100, and anti-gp210 antibodies, the diagnosis of PBC is more affordable than that of PSC and AIC. Based on clinical data, the immunological diagnosis of AIHT takes advantage of the various specialized laboratory techniques including immunofluorescence, immunodot or blot, and the Elisa systems, provided of a closer collaboration between the biologist and the physician. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Role of Patatin-Like Phospholipase Domain-Containing 3 on Lipid-Induced Hepatic Steatosis and Insulin Resistance in Rats

PubMed Central

Kumashiro, Naoki; Yoshimura, Toru; Cantley, Jennifer L; Majumdar, Sachin K; Guebre-Egziabher, Fitsum; Kursawe, Romy; Vatner, Daniel F; Fat, Ioana; Kahn, Mario; Erion, Derek M; Zhang, Xian-Man; Zhang, Dongyan; Manchem, Vara Prasad; Bhanot, Sanjay; Gerhard, Glenn S; Petersen, Kitt F; Cline, Gary W; Samuel, Varman T; Shulman, Gerald I

2013-01-01

Genome-wide array studies have associated the patatin-like phospholipase domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. While the precursors for phosphatidic acid (PA) (long-chain fatty acyl-CoAs and lysophosphatidic acid [LPA]) were not decreased, we did observe an ∼20% reduction in the hepatic PA content, ∼35% reduction in the PA/LPA ratio, and ∼60%-70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ∼50% reduction in hepatic diacylglycerol (DAG) content, an ∼80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a 2-fold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 messenger RNA (mRNA) expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans. Conclusion: PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of nonalcoholic fatty liver disease-associated hepatic insulin resistance. ((Hepatology 2013;57:1763-1772)) PMID:23175050

Expression Profile of Interferon Regulatory Factor 1 in Chronic Hepatitis B Virus-Infected Liver Transplant Patients.

PubMed

Janfeshan, Sahar; Yaghobi, Ramin; Eidi, Akram; Karimi, Mohammad Hossein; Geramizadeh, Bita; Malekhosseini, Seyed Ali; Kafilzadeh, Farshid

2017-12-01

Hepatitis B virus, which mainly affects normal liver function, leads to severe acute and chronic hepatitis, resulting in cirrhosis and hepatocellular carcinoma, but can be safely treated after liver transplant. Evaluation of determinative biomarkers may facilitate more effective treatment of posttransplant rejection. Therefore, we investigated interferon regulatory factor 1 expression in hepatitis B virus-infected liver transplant patients with and without previous rejection compared with controls. Hepatitis B virus-infected liver recipients were divided into those with (20 patients) and without a rejection (26 patients), confirmed by pathologic analyses in those who had a rejection. In addition, a healthy control group composed of 13 individuals was included. Expression levels of interferon regulatory factor 1 were evaluated during 3 follow-ups after transplant using an in-house comparative SYBR green real-time polymerase chain reaction method. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Modifications of interferon regulatory factor 1 gene expression levels in patient groups with and without rejection were not significant between days 1, 4, and 7 after liver transplant. Interferon regulatory factor 1 mRNA expression levels were down-regulated in patients without rejection versus patients with rejection, although not significantly at day 1 (P = .234) and day 4 (P = .302) but significantly at day 7 (P = .004) after liver transplant. Down-regulation of interferon regulatory factor 1 gene expression in hepatitis B virus patients without rejection emphasized counteraction between hepatitis B virus replication and interferon regulatory factor 1 production. On the other hand, interferon regulatory factor 1 gene overexpression in patients with rejection may result in inflammatory reactions and ischemic-reperfusion injury. Therefore, a better understanding of the association between interferon regulatory factor 1 and hepatitis B virus pathogenesis in a larger population with longer follow-up is needed.
Transcription factors YY1, Sp1 and Sp3 modulate dystrophin Dp71 gene expression in hepatic cells.

PubMed

Peñuelas-Urquides, Katia; Becerril-Esquivel, Carolina; Mendoza-de-León, Laura C; Silva-Ramírez, Beatriz; Dávila-Velderrain, José; Cisneros, Bulmaro; de León, Mario Bermúdez

2016-07-01

Dystrophin Dp71, the smallest product encoded by the Duchenne muscular dystrophy gene, is ubiquitously expressed in all non-muscle cells. Although Dp71 is involved in various cellular processes, the mechanisms underlying its expression have been little studied. In hepatic cells, Dp71 expression is down-regulated by the xenobiotic β-naphthoflavone. However, the effectors of this regulation remain unknown. In the present study we aimed at identifying DNA elements and transcription factors involved in Dp71 expression in hepatic cells. Relevant DNA elements on the Dp71 promoter were identified by comparing Dp71 5'-end flanking regions between species. The functionality of these elements was demonstrated by site-directed mutagenesis. Using EMSAs and ChIP, we showed that the Sp1 (specificity protein 1), Sp3 (specificity protein 3) and YY1 (Yin and Yang 1) transcription factors bind to the Dp71 promoter region. Knockdown of Sp1, Sp3 and YY1 in hepatic cells increased endogenous Dp71 expression, but reduced Dp71 promoter activity. In summary, Dp71 expression in hepatic cells is carried out, in part, by YY1-, Sp1- and Sp3-mediated transcription from the Dp71 promoter. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.
HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPAR{gamma}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Kook Hwan; Hong, Sung Pyo; Kim, KyeongJin

2007-04-20

Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPAR{gamma} (peroxisome proliferators-activated receptor {gamma}) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPAR{gamma}. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfectedmore » with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPAR{gamma} transcriptional activity. However, HCV core protein had no effect on PPAR{gamma} gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.« less
Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis

PubMed Central

Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

2015-01-01

Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469
Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery.

PubMed

Pardina, E; Ferrer, R; Rossell, J; Ricart-Jané, D; Méndez-Lara, K A; Baena-Fustegueras, J A; Lecube, A; Julve, J; Peinado-Onsurbe, J

2017-09-01

The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.
Characterization of hepatic progenitors from human fetal liver during second trimester.

PubMed

Rao, Mekala-Subba; Khan, Aleem-Ahmed; Parveen, Nyamath; Habeeb, Mohammed-Aejaz; Habibullah, Chittoor-Mohammed; Pande, Gopal

2008-10-07

To enrich hepatic progenitors using epithelial cell adhesion molecule (EpCAM) as a marker from human fetal liver and investigate the expression of human leukocyte antigen (HLA) and their markers associated with hepatic progenitor cells. EpCAM +ve cells were isolated using magnetic cell sorting (MACS) from human fetuses (n = 10) at 15-25 wk gestation. Expression of markers for hepatic progenitors such as albumin, alpha-fetoprotein (AFP), CD29 (integrin beta1), CD49f (integrin alpha6) and CD90 (Thy 1) was studied by using flow cytometry, immunocytochemistry and RT-PCR; HLA class I (A, B, C) and class II (DR) expression was studied by flow cytometry only. FACS analysis indicated that EpCAM +ve cells were positive for CD29, CD49f, CD90, CD34, HLA class I, albumin and AFP but negative for HLA class II (DR) and CD45. RT PCR showed that EpCAM +ve cells expressed liver epithelial markers (CK18), biliary specific marker (CK19) and hepatic markers (albumin, AFP). On immunocytochemical staining, EpCAM +ve cells were shown positive signals for CK18 and albumin. Our study suggests that these EpCAM +ve cells can be used as hepatic progenitors for cell transplantation with a minimum risk of alloreactivity and these cells may serve as a potential source for enrichment of hepatic progenitor.
Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

PubMed

Ben Ari, Ziv; Avlas, Orna; Pappo, Orit; Zilbermints, Veacheslav; Cheporko, Yelena; Bachmetov, Larissa; Zemel, Romy; Shainberg, Asher; Sharon, Eran; Grief, Franklin; Hochhauser, Edith

2012-01-01

Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF. Copyright © 2012 S. Karger AG, Basel.
miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice

PubMed Central

Goedeke, Leigh; Rotllan, Noemi; Ramírez, Cristina M.; Aranda, Juan F.; Canfrán-Duque, Alberto; Araldi, Elisa; Fernández-Hernando, Ana; Langhi, Cedric; de Cabo, Rafael; Baldán, Ángel; Suárez, Yajaira; Fernández-Hernando, Carlos

2015-01-01

Rationale Recently, there has been significant interest in the therapeutic administration of miRNA mimics and inhibitors to treat cardiovascular disease. In particular, miR-27b has emerged as a regulatory hub in cholesterol and lipid metabolism and potential therapeutic target for treating atherosclerosis. Despite this, the impact of miR-27b on lipid levels in vivo remains to be determined. As such, here we set out to further characterize the role of miR-27b in regulating cholesterol metabolism in vitro and to determine the effect of miR-27b overexpression and inhibition on circulating and hepatic lipids in mice. Methods and Results Our results identify miR-27b as an important regulator of LDLR activity in human and mouse hepatic cells through direct targeting of LDLR and LDLRAP1. In addition, we report that modulation of miR-27b expression affects ABCA1 protein levels and cellular cholesterol efflux to ApoA1 in human hepatic Huh7 cells. Overexpression of pre-miR-27b in the livers of wild-type mice using AAV8 vectors increased pre-miR-27b levels 50–fold and reduced hepatic ABCA1 and LDLR expression by 50% and 20%, respectively, without changing circulating and hepatic cholesterol and triglycerides. To determine the effect of endogenous miR-27b on circulating lipids, wild-type mice were fed a Western diet for one month and injected with 5 mg/kg of LNA control or LNA anti-miR-27b oligonucleotides. Following two weeks of treatment, the expression of ABCA1 and LDLR were increased by 10–20% in the liver, demonstrating effective inhibition of miR-27b function. Intriguingly, no differences in circulating and hepatic lipids were observed between treatment groups. Conclusions The results presented here provide evidence that short-term modulation of miR-27b expression in wild-type mice regulates hepatic LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels. PMID:26520906
The effect of maternal intake of sucrose or high-fructose corn syrup (HFCS)-55 during gestation and lactation on lipogenic gene expression in rat offspring at 3 and 12 weeks of age.

PubMed

Kaur, H; Toop, C R; Muhlhausler, B S; Gentili, S

2018-06-18

Perinatal exposure to sucrose or high-fructose corn syrup-55 (HFCS-55) in rats has previously been associated with altered hepatic fat content and composition post-weaning, although the effects on hepatic metabolism are unknown. The current study aimed to determine the sex-specific effects of maternal consumption of sucrose or HFCS-55 on the expression of hepatic lipogenic genes in the offspring. Liver samples were collected from offspring of albino Wistar rats provided with ad libitum access to either water (control), 10% sucrose or 10% HFCS-55 solution during pregnancy and lactation at 3 weeks (control n=16, sucrose n=22, HFCS-55 n=16) and 12 weeks (control n=16, sucrose n=10, HFCS-55 n=16) of age. Hepatic expression of the transcription factors such as carbohydrate response element-binding protein, sterol regulatory element-binding protein-1c and downstream genes was determined by quantitative real-time PCR. Sucrose-exposed offspring had higher hepatic SREBP-1c messenger RNA expression compared with control and HFCS-55 groups at both 3 weeks (P=0.01) and 12 weeks (P=0.03) of age. There were no differences in the expression of other hepatic lipogenic genes between groups at either 3 or 12 weeks. Thus, perinatal exposure to sucrose may be more detrimental to offspring hepatic metabolism compared with HFCS-55, independent of sex, and it will be important to evaluate the longer-term effects of perinatal sucrose exposure in future studies.
Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

PubMed Central

Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001) hepatic lipids contents and higher (p<0.01) mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration. PMID:25557684
Chardonnay Grape Seed Flour Ameliorates Hepatic Steatosis and Insulin Resistance via Altered Hepatic Gene Expression for Oxidative Stress, Inflammation, and Lipid and Ceramide Synthesis in Diet-Induced Obese Mice

PubMed Central

Seo, Kun-Ho; Bartley, Glenn E.; Tam, Christina; Kim, Hong-Seok; Kim, Dong-Hyeon; Chon, Jung-Whan; Yokoyama, Wallace

2016-01-01

To identify differentially expressed hepatic genes contributing to the improvement of high-fat (HF) diet-induced hepatic steatosis and insulin resistance following supplementation of partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd), diet-induced obese (DIO) mice were fed HF diets containing either ChrSd or microcrystalline cellulose (MCC, control) for 5 weeks. The 2-h insulin area under the curve was significantly lowered by ChrSd, indicating that ChrSd improved insulin sensitivity. ChrSd intake also significantly reduced body weight gain, liver and adipose tissue weight, hepatic lipid content, and plasma low-density lipoprotein (LDL)-cholesterol, despite a significant increase in food intake. Exon microarray analysis of hepatic gene expression revealed down-regulation of genes related to triglyceride and ceramide synthesis, immune response, oxidative stress, and inflammation and upregulation of genes related to fatty acid oxidation, cholesterol, and bile acid synthesis. In conclusion, the effects of ChrSd supplementation in a HF diet on weight gain, insulin resistance, and progression of hepatic steatosis in DIO mice were associated with modulation of hepatic genes related to oxidative stress, inflammation, ceramide synthesis, and lipid and cholesterol metabolism. PMID:27977712
Insulin resistance, adipokine profile and hepatic expression of SOCS-3 gene in chronic hepatitis C.

PubMed

Wójcik, Kamila; Jabłonowska, Elżbieta; Omulecka, Aleksandra; Piekarska, Anna

2014-08-14

To analyze adipokine concentrations, insulin resistance and hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C genotype 1 with normal body weight, glucose and lipid profile. The study group consisted of 31 patients with chronic hepatitis C and 9 healthy subjects. Total levels of adiponectin, leptin, resistin, visfatin, omentin, osteopontin and insulin were measured using an ELISA kit. The hepatic expression of SOCS-3 was determined by the use of the reverse transcription polymerase chain reaction method. Homeostasis model assessment for insulin resistance (HOMA-IR) values were significantly higher in hepatitis C virus (HCV) infected patients without metabolic disorders compared to healthy controls (2.24 vs 0.59, P = 0.0003). Hepatic steatosis was observed in 32.2% of patients with HCV infection and was found in patients with increased HOMA-IR index (2.81 vs 1.99, P = 0.05) and reduced adiponectin level (5.96 vs 8.37, P = 0.04). Inflammatory activity (G ≥ 2) was related to increased osteopontin concentration (34.04 vs 23.35, P = 0.03). Advanced liver fibrosis (S ≥ 2) was associated with increased levels of omentin and osteopontin (436.94 vs 360.09, P = 0.03 and 32.84 vs 20.29, P = 0.03) and reduced resistin concentration (1.40 vs 1.74, P = 0.047). No correlations were reported between adipokine profile, HOMA-IR values and hepatic expression of the SOCS-3 gene. We speculated that no relationship between adipokines and HOMA-IR values may indicate that HCV can induce insulin resistance itself. Some adipokines appear to be biochemical markers of steatosis, inflammation and fibrosis in patients with chronic HCV infection. © 2014 Baishideng Publishing Group Inc. All rights reserved.
Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21*

PubMed Central

Cyphert, Holly A.; Ge, Xuemei; Kohan, Alison B.; Salati, Lisa M.; Zhang, Yanqiao; Hillgartner, F. Bradley

2012-01-01

Previous studies have shown that starvation or consumption of a high fat, low carbohydrate (HF-LC) ketogenic diet induces hepatic fibroblast growth factor 21 (FGF21) gene expression in part by activating the peroxisome proliferator-activated receptor-α (PPARα). Using primary hepatocyte cultures to screen for endogenous signals that mediate the nutritional regulation of FGF21 expression, we identified two sources of PPARα activators (i.e. nonesterified unsaturated fatty acids and chylomicron remnants) that induced FGF21 gene expression. In addition, we discovered that natural (i.e. bile acids) and synthetic (i.e. GW4064) activators of the farnesoid X receptor (FXR) increased FGF21 gene expression and secretion. The effects of bile acids were additive with the effects of nonesterified unsaturated fatty acids in regulating FGF21 expression. FXR activation of FGF21 gene transcription was mediated by an FXR/retinoid X receptor binding site in the 5′-flanking region of the FGF21 gene. FGF19, a gut hormone whose expression and secretion is induced by intestinal bile acids, also increased hepatic FGF21 secretion. Deletion of FXR in mice suppressed the ability of an HF-LC ketogenic diet to induce hepatic FGF21 gene expression. The results of this study identify FXR as a new signaling pathway activating FGF21 expression and provide evidence that FXR activators work in combination with PPARα activators to mediate the stimulatory effect of an HF-LC ketogenic diet on FGF21 expression. We propose that the enhanced enterohepatic flux of bile acids during HF-LC consumption leads to activation of hepatic FXR and FGF19 signaling activity and an increase in FGF21 gene expression and secretion. PMID:22661717
Identification of the transcriptional regulators by expression profiling infected with hepatitis B virus.

PubMed

Chai, Xiaoqiang; Han, Yanan; Yang, Jian; Zhao, Xianxian; Liu, Yewang; Hou, Xugang; Tang, Yiheng; Zhao, Shirong; Li, Xiao

2016-02-01

The molecular pathogenesis of infection by hepatitis B virus with human is extremely complex and heterogeneous. To date the molecular information is not clearly defined despite intensive research efforts. Thus, studies aimed at transcription and regulation during virus infection or combined researches of those already known to be beneficial are needed. With the purpose of identifying the transcriptional regulators related to infection of hepatitis B virus in gene level, the gene expression profiles from some normal individuals and hepatitis B patients were analyzed in our study. In this work, the differential expressed genes were selected primarily. The several genes among those were validated in an independent set by qRT-PCR. Then the differentially co-expression analysis was conducted to identify differentially co-expressed links and differential co-expressed genes. Next, the analysis of the regulatory impact factors was performed through mapping the links and regulatory data. In order to give a further insight to these regulators, the co-expression gene modules were identified using a threshold-based hierarchical clustering method. Incidentally, the construction of the regulatory network was generated using the computer software. A total of 137,284 differentially co-expressed links and 780 differential co-expressed genes were identified. These co-expressed genes were significantly enriched inflammatory response. The results of regulatory impact factors revealed several crucial regulators related to hepatocellular carcinoma and other high-rank regulators. Meanwhile, more than one hundred co-expression gene modules were identified using clustering method. In our study, some important transcriptional regulators were identified using a computational method, which may enhance the understanding of disease mechanisms and lead to an improved treatment of hepatitis B. However, further experimental studies are required to confirm these findings. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
MiR-29b inhibits collagen maturation in hepatic stellate cells through down-regulating the expression of HSP47 and lysyl oxidase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yifei; Ghazwani, Mohammed; Li, Jiang

Highlights: • Enhanced HSP47 and LOX expression is associated with decreased miR-29b level in liver fibrosis. • miR-29b down-regulates HSP47 and LOX expression. • The suppression of HSP47 and LOX by miR-29b is mediated by putative sites at their 3′-UTRs. • miR-29b inhibits extracellular LOX activity and collagen maturation. - Abstract: Altered expression of miR-29b is implicated in the pathogenesis and progression of liver fibrosis. We and others previously demonstrated that miR-29b down-regulates the expression of several extracellular-matrix (ECM) genes including Col 1A1, Col 3A1 and Elastin via directly targeting their 3′-UTRs. However, whether or not miR-29b plays a rolemore » in the post-translational regulation of ECM biosynthesis has not been reported. Heat shock protein 47 (HSP47) and lysyl oxidase (LOX) are known to be essential for ECM maturation. In this study we have demonstrated that expression of HSP47 and LOX was significantly up-regulated in culture-activated primary rat hepatic stellate cells (HSCs), TGF-β stimulated LX-2 cells and liver tissue of CCl{sub 4}-treated mice, which was accompanied by a decrease of miR-29b level. In addition, over-expression of miR-29b in LX-2 cells resulted in significant inhibition on HSP47 and LOX expression. Mechanistically, miR-29b inhibited the expression of a reporter gene that contains the respective full-length 3′-UTR from HSP47 and LOX gene, and this inhibitory effect was abolished by the deletion of a putative miR-29b targeting sequence from the 3′-UTRs. Transfection of LX-2 cells with miR-29b led to abnormal collagen structure as shown by electron-microscopy, presumably through down-regulation of the expression of molecules involved in ECM maturation including HSP47 and LOX. These results demonstrated that miR-29b is involved in regulating the post-translational processing of ECM and fibril formation.« less
Cultured Mycelium Cordyceps sinensis allevi¬ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells.

PubMed

Peng, Yuan; Huang, Kai; Shen, Li; Tao, Yan-yan; Liu, Cheng-hai

2016-02-01

Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg·kg(-1)·d(-1), ig) during this period. In another part of experiments, the mice were also injected with an NK cell-deleting antibody ASGM-1 (20 μg, ip) 5 times in the first 3 weeks. After the mice were sacrificed, serum liver function, and liver inflammation, hydroxyproline content and collagen deposition were assessed. The numbers of hepatic NK cells and expression of NKG2D (activation receptor of NK cells) on isolated liver lymphocytes were analyzed using flow cytometry. Desmin expression and cell apoptosis in liver tissues were studied using desmin staining and TUNEL assay, respectively. The levels of α-SMA, TGF-β, RAE-1δ and RAE-1ε in liver tissues were determined by RT-qPCR. In CCl4-treated mice, CMCS administration significantly improved liver function, attenuated liver inflammation and fibrosis, and increased the numbers of hepatic NK cells and expression level of NKG2D on hepatic NK cells. Furthermore, CMCS administration significantly decreased desmin expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Injection with NK cell-deleting ASGM-1 not only diminished the numbers of hepatic NK cells, but also greatly accelerated liver inflammation and fibrosis in CCl4-treated mice. In CCl4-treated mice with NK cell depletion, CMCS administration decelerated the rate of liver fibrosis development, and mildly upregulated the numbers of hepatic NK cells but without changing NKG2D expression. CMCS alleviates CCl4-induced liver inflammation and fibrosis via promoting activation of hepatic NK cells. CMCS partially reverses ASGM-1-induced depletion of hepatic NK cells.
MiR-145 mediates zebrafish hepatic outgrowth through progranulin A signaling

PubMed Central

Li, Ya-Wen; Chiang, Keng-Yu; Li, Yen-Hsing; Wu, Sung-Yu; Liu, Wangta; Lin, Chia-Ray

2017-01-01

MicroRNAs (miRs) are mRNA-regulatory molecules that fine-tune gene expression and modulate both processes of development and tumorigenesis. Our previous studies identified progranulin A (GrnA) as a growth factor which induces zebrafish hepatic outgrowth through MET signaling. We also found that miR-145 is one of potential fine-tuning regulators of GrnA involved in embryonic hepatic outgrowth. The low level of miR-145 seen in hepatocarinogenesis has been shown to promote pathological liver growth. However, little is known about the regulatory mechanism of miR-145 in embryonic liver development. In this study, we demonstrate a significant decrease in miR-145 expression during hepatogenesis. We modulate miR-145 expression in zebrafish embryos by injection with a miR-145 mimic or a miR-145 hairpin inhibitor. Altered embryonic liver outgrowth is observed in response to miR-145 expression modulation. We also confirm a critical role of miR-145 in hepatic outgrowth by using whole-mount in situ hybridization. Loss of miR-145 expression in embryos results in hepatic cell proliferation, and vice versa. Furthermore, we demonstrate that GrnA is a target of miR-145 and GrnA-induced MET signaling is also regulated by miR-145 as determined by luciferase reporter assay and gene expression analysis, respectively. In addition, co-injection of GrnA mRNA with miR-145 mimic or MO-GrnA with miR-145 inhibitor restores the liver defects caused by dysregulation of miR-145 expression. In conclusion, our findings suggest an important role of miR-145 in regulating GrnA-dependent hepatic outgrowth in zebrafish embryonic development. PMID:28531199
Curcumin eliminates the inhibitory effect of advanced glycation end-products (AGEs) on gene expression of AGE receptor-1 in hepatic stellate cells in vitro

PubMed Central

Lin, Jianguo; Tang, Youcai; Kang, Qiaohua; Chen, Anping

2012-01-01

Diabetes is featured by hyperglycemia, which facilitates the formation of advanced glycation end-products (AGEs). AGEs are a causal factor in development of diabetic complications. AGE receptor-1 (AGE-R1) is responsible for detoxification and clearance of AGEs. Type 2 diabetes mellitus is commonly accompanied by non-alcoholic steatohepatitis, which could cause hepatic fibrosis. Little attention has been paid to effects of AGEs on hepatic fibrogenesis. Curcumin, a phytochemical from turmeric, has been reported to inhibit the activation of hepatic stellate cells (HSCs), the major effectors during hepatic fibrogenesis, and to protect against hepatic fibrogenesis in vitro and in vivo. The current study was designed to evaluate effects of AGEs on inducing HSC activation, to assess the role of curcumin in diminishing the AGE effects and to explore the underlying mechanisms. Our results showed that AGEs stimulated HSC activation by inducing cell proliferation and expression of genes relevant to HSC activation, which were abrogated by curcumin. Curcumin induced gene expression of AGE-R1 in passaged HSCs, which might facilitate the attenuation of the stimulatory effects of AGEs on the activation of HSCs. Further experiments revealed that curcumin inhibited the activity of extracellular signal-regulated kinase (ERK) and induced gene expression and the activity of peroxisome proliferator-activated receptor-gamma (PPARγ), leading to the induction of AGE-R1 gene expression. In summary, AGEs stimulated HSC activation. Curcumin eliminated the AGE effects at least partially by inducing AGE-R1 gene expression. The process was mediated by inhibiting ERK activity, inducing gene expression of PPARγ and stimulating its trans-activity. PMID:22449800
Single administration of recombinant IL-6 restores the gene expression of lipogenic enzymes in liver of fasting IL-6-deficient mice.

PubMed

Gavito, A L; Cabello, R; Suarez, J; Serrano, A; Pavón, F J; Vida, M; Romero, M; Pardo, V; Bautista, D; Arrabal, S; Decara, J; Cuesta, A L; Valverde, A M; Rodríguez de Fonseca, F; Baixeras, E

2016-03-01

Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution. © 2016 The British Pharmacological Society.
Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

PubMed Central

Souza-Mello, Vanessa

2015-01-01

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs. PMID:26052390

[Autosomal-recessive renal cystic disease and congenital hepatic fibrosis: clinico-anatomic case].

PubMed

Rostol'tsev, K V; Burenkov, R A; Kuz'micheva, I A

2012-01-01

Clinico-anatomic observation of autosomal-recessive renal cystic disease and congenital hepatic fibrosis at two fetuses from the same family was done. Mutation of His3124Tyr in 58 exon of PKHD1 gene in heterozygous state was found out. The same pathomorphological changes in the epithelium of cystic renal tubules and bile ducts of the liver were noted. We suggest that the autopsy research of fetuses with congenital abnormalities, detected after prenatal ultrasonic screening, has high diagnostic importance.
Abnormal scintigraphic evolution in AA hepatic amyloidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lomena, F.; Rosello, R.; Pons, F.

1988-03-01

A patient with AA amyloidosis secondary to ankylosing spondylitis showed intense liver uptake of Tc-99m MDP on bone imaging. The biopsy showed hepatic amyloid deposition. A repeat bone scan with Tc-99m MDP 1 year later was negative, although the clinical signs and liver function tests of the patient had not changed. A mechanism might exist, other than the affinity of amyloid to calcium, which would explain the extraosseous uptake of pyrophosphates and diphosphonates in organs and soft tissues affected by systemic amyloidosis.
Effect of ergot alkaloids associated with fescue toxicosis on hepatic cytochrome P450 and antioxidant proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Settivari, Raja S.; Evans, Tim J.; Rucker, Ed

Intake of ergot alkaloids found in endophyte-infected tall fescue grass is associated with decreased feed intake and reduction in body weight gain. The liver is one of the target organs of fescue toxicosis with upregulation of genes involved in xenobiotic metabolism and downregulation of genes associated with antioxidant pathways. It was hypothesized that short-term exposure of rats to ergot alkaloids would change hepatic cytochrome P450 (CYP) and antioxidant expression, as well as reduce antioxidant enzyme activity and hepatocellular proliferation rates. Hepatic gene expression of various CYPs, selected nuclear receptors associated with the CYP induction, and antioxidant enzymes were measured usingmore » real-time PCR. Hepatic expression of CYP, antioxidant and proliferating cell nuclear antigen (PCNA) proteins were measured using Western blots. The CYP3A1 protein expression was evaluated using primary rat hepatocellular cultures treated with ergovaline, one of the major ergot alkaloids produced by fescue endophyte, in order to assess the direct role of ergot alkaloids in CYP induction. The enzyme activities of selected antioxidants were assayed spectrophotometrically. While hepatic CYP and nuclear receptor expression were increased in ergot alkaloid-exposed rats, the expression and activity of antioxidant enzymes were reduced. This could potentially lead to increased oxidative stress, which might be responsible for the decrease in hepatocellular proliferation after ergot alkaloid exposure. This study demonstrated that even short-term exposure to ergot alkaloids can potentially induce hepatic oxidative stress which can contribute to the pathogenesis of fescue toxicosis.« less
Effect of Morinda citrifolia (Noni)-Enriched Diet on Hepatic Heat Shock Protein and Lipid Metabolism-Related Genes in Heat Stressed Broiler Chickens.

PubMed

Flees, Joshua; Rajaei-Sharifabadi, Hossein; Greene, Elizabeth; Beer, Lesleigh; Hargis, Billy M; Ellestad, Laura; Porter, Tom; Donoghue, Annie; Bottje, Walter G; Dridi, Sami

2017-01-01

Heat stress (HS) has been reported to alter fat deposition in broilers, however the underlying molecular mechanisms are not well-defined. The objectives of the current study were, therefore: (1) to determine the effects of acute (2 h) and chronic (3 weeks) HS on the expression of key molecular signatures involved in hepatic lipogenic and lipolytic programs, and (2) to assess if diet supplementation with dried Noni medicinal plant (0.2% of the diet) modulates these effects. Broilers (480 males, 1 d) were randomly assigned to 12 environmental chambers, subjected to two environmental conditions (heat stress, HS, 35°C vs. thermoneutral condition, TN, 24°C) and fed two diets (control vs. Noni) in a 2 × 2 factorial design. Feed intake and body weights were recorded, and blood and liver samples were collected at 2 h and 3 weeks post-heat exposure. HS depressed feed intake, reduced body weight, and up regulated the hepatic expression of heat shock protein HSP60, HSP70, HSP90 as well as key lipogenic proteins (fatty acid synthase, FASN; acetyl co-A carboxylase alpha, ACCα and ATP citrate lyase, ACLY). HS down regulated the hepatic expression of lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (LIPC), but up-regulated ATGL. Although it did not affect growth performance, Noni supplementation regulated the hepatic expression of lipogenic proteins in a time- and gene-specific manner. Prior to HS, Noni increased ACLY and FASN in the acute and chronic experimental conditions, respectively. During acute HS, Noni increased ACCα, but reduced FASN and ACLY expression. Under chronic HS, Noni up regulated ACCα and FASN but it down regulated ACLY. In vitro studies, using chicken hepatocyte cell lines, showed that HS down-regulated the expression of ACCα, FASN, and ACLY. Treatment with quercetin, one bioactive ingredient in Noni, up-regulated the expression of ACCα, FASN, and ACLY under TN conditions, but it appeared to down-regulate ACCα and increase ACLY levels under HS exposure. In conclusion, our findings indicate that HS induces hepatic lipogenesis in chickens and this effect is probably mediated via HSPs. The modulation of hepatic HSP expression suggest also that Noni might be involved in modulating the stress response in chicken liver.
Effect of Morinda citrifolia (Noni)-Enriched Diet on Hepatic Heat Shock Protein and Lipid Metabolism-Related Genes in Heat Stressed Broiler Chickens

PubMed Central

Flees, Joshua; Rajaei-Sharifabadi, Hossein; Greene, Elizabeth; Beer, Lesleigh; Hargis, Billy M.; Ellestad, Laura; Porter, Tom; Donoghue, Annie; Bottje, Walter G.; Dridi, Sami

2017-01-01

Heat stress (HS) has been reported to alter fat deposition in broilers, however the underlying molecular mechanisms are not well-defined. The objectives of the current study were, therefore: (1) to determine the effects of acute (2 h) and chronic (3 weeks) HS on the expression of key molecular signatures involved in hepatic lipogenic and lipolytic programs, and (2) to assess if diet supplementation with dried Noni medicinal plant (0.2% of the diet) modulates these effects. Broilers (480 males, 1 d) were randomly assigned to 12 environmental chambers, subjected to two environmental conditions (heat stress, HS, 35°C vs. thermoneutral condition, TN, 24°C) and fed two diets (control vs. Noni) in a 2 × 2 factorial design. Feed intake and body weights were recorded, and blood and liver samples were collected at 2 h and 3 weeks post-heat exposure. HS depressed feed intake, reduced body weight, and up regulated the hepatic expression of heat shock protein HSP60, HSP70, HSP90 as well as key lipogenic proteins (fatty acid synthase, FASN; acetyl co-A carboxylase alpha, ACCα and ATP citrate lyase, ACLY). HS down regulated the hepatic expression of lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (LIPC), but up-regulated ATGL. Although it did not affect growth performance, Noni supplementation regulated the hepatic expression of lipogenic proteins in a time- and gene-specific manner. Prior to HS, Noni increased ACLY and FASN in the acute and chronic experimental conditions, respectively. During acute HS, Noni increased ACCα, but reduced FASN and ACLY expression. Under chronic HS, Noni up regulated ACCα and FASN but it down regulated ACLY. In vitro studies, using chicken hepatocyte cell lines, showed that HS down-regulated the expression of ACCα, FASN, and ACLY. Treatment with quercetin, one bioactive ingredient in Noni, up-regulated the expression of ACCα, FASN, and ACLY under TN conditions, but it appeared to down-regulate ACCα and increase ACLY levels under HS exposure. In conclusion, our findings indicate that HS induces hepatic lipogenesis in chickens and this effect is probably mediated via HSPs. The modulation of hepatic HSP expression suggest also that Noni might be involved in modulating the stress response in chicken liver. PMID:29230177
Spontaneous Rupture of the Hepatic Artery in a Patient with Type 1 Neurofibromatosis Treated by Embolization: A Case Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rao, V.; Day, C.P.; Manimaran, N.

We report the case of a 48-year-old man with neurofibromatosis presenting with sudden-onset abdominal pain, profound hypotension, and a drop in hemoglobin. CT scan demonstrated a massive hematoma within the right lobe of the liver with rupture into the peritoneal cavity. Angiography demonstrated diffuse abnormalities of the hepatic circulation with fusifom, ectatic, and stenotic segments. Acute extravasation from a peripheral branch of the right hepatic artery was identified and successfully embolized with subsequent hemodynamic stabilization of the patient. To the best of our knowledge this is the first case report of this kind in a patient with type I neurofibromatosis.
[Portal vein thrombosis associated with hepatic encephalopathy].

PubMed

Iwatani, Nao; Inatomi, Yuichiro; Yonehara, Toshiro; Fujioka, Shodo; Hashimoto, Yoichiro; Hirano, Teruyuki; Uchino, Makoto

2005-03-01

A 54-year-old man who had been administered chlormadinone acetate 3 months after prostatectomy for prostate cancer, acutely developed disorientation and memory disturbance. Six days later, he experienced high grade fever and epigastralgia. He was suspected to have hepatic encephalopathy, because the Fischer ratio was low although serum ammonia level remained normal. Further examinations including abdominal echography and CT scan disclosed a thrombus extending from the portal vein to the superior mesenteric vein together with abnormal collateral vessels originating from the portal vein. He was successfully treated with warfarin potassium, urokinase and heparin sodium. It was suggested that the patient developed hepatic encephalopathy due to portal-systemic circulation shunting secondary to portal vein thrombosis.
Peroxisomal abnormalities in the immortalized human hepatocyte (IHH) cell line.

PubMed

Klouwer, Femke C C; Koster, Janet; Ferdinandusse, Sacha; Waterham, Hans R

2017-04-01

The immortalized human hepatocyte (IHH) cell line is increasingly used for studies related to liver metabolism, including hepatic glucose, lipid, lipoprotein and triglyceride metabolism, and the effect of therapeutic interventions. To determine whether the IHH cell line is a good model to investigate hepatic peroxisomal metabolism, we measured several peroxisomal parameters in IHH cells and, for comparison, HepG2 cells and primary skin fibroblasts. This revealed a marked plasmalogen deficiency and a deficient fatty acid α-oxidation in the IHH cells, due to a defect of PEX7, a cytosolic receptor protein required for peroxisomal import of a subset of peroxisomal proteins. These abnormalities have consequences for the lipid homeostasis of these cells and thus should be taken into account for the interpretation of data previously generated by using this cell line and when considering using this cell line for future research.
Emphysematous cystitis occurred in the case treated with steroid for autoimmune hepatitis.

PubMed

Yoshino, Tateki; Ohara, Shinya; Moriyama, Hiroyuki

2013-01-01

Emphysematous cystitis is a rare clinically entity, more commonly seen in diabetic, immunocompromised patients, which was characterized by air within the bladder wall and lumen. A 83-year-old woman was introduced to our department with fever elevation and abnormal findings of computed tomography (CT). She took orally prednisolone for autoimmune hepatitis. Pelvic CT revealed diffuse air throughout the bladder wall. Urinalysis showed combined hematuria and pyuria. Escherichia coli was detected in blood culture. Abnormal findings of complete blood count and laboratory examination included an elevated WBC count (12,200/μL), C-reactive protein (11.7 mg/dL), and creatinine (1.07 mg/dL). Cystoscopy confirmed diffuse submucosal emphysema throughout. On the basis of diagnosis with emphysematous cystitis, she was treated with antibiotics based on the results of blood culture and indwelling Foley catheter. After treatment, the improvement of inflammatory findings and submucosal emphysema on cystoscopy and CT were achieved.
Acquired partial lipodystrophy is associated with increased risk for developing metabolic abnormalities.

PubMed

Akinci, Baris; Koseoglu, Fatos Dilan; Onay, Huseyin; Yavuz, Sevgi; Altay, Canan; Simsir, Ilgin Yildirim; Ozisik, Secil; Demir, Leyla; Korkut, Meltem; Yilmaz, Nusret; Ozen, Samim; Akinci, Gulcin; Atik, Tahir; Calan, Mehmet; Secil, Mustafa; Comlekci, Abdurrahman; Demir, Tevfik

2015-09-01

Acquired partial lipodystrophy (APL) is a rare disorder characterized by progressive selective fat loss. In previous studies, metabolic abnormalities were reported to be relatively rare in APL, whilst they were quite common in other types of lipodystrophy syndromes. In this nationwide cohort study, we evaluated 21 Turkish patients with APL who were enrolled in a prospective follow-up protocol. Subjects were investigated for metabolic abnormalities. Fat distribution was assessed by whole body MRI. Hepatic steatosis was evaluated by ultrasound, MRI and MR spectroscopy. Patients with diabetes underwent a mix meal stimulated C-peptide/insulin test to investigate pancreatic beta cell functions. Leptin and adiponectin levels were measured. Fifteen individuals (71.4%) had at least one metabolic abnormality. Six patients (28.6%) had diabetes, 12 (57.1%) hypertrigylceridemia, 10 (47.6%) low HDL cholesterol, and 11 (52.4%) hepatic steatosis. Steatohepatitis was further confirmed in 2 patients with liver biopsy. Anti-GAD was negative in all APL patients with diabetes. APL patients with diabetes had lower leptin and adiponectin levels compared to patients with type 2 diabetes and healthy controls. However, contrary to what we observed in patients with congenital generalized lipodystrophy (CGL), we did not detect consistently very low leptin levels in APL patients. The mix meal test suggested that APL patients with diabetes had a significant amount of functional pancreatic beta cells, and their diabetes was apparently associated with insulin resistance. Our results show that APL is associated with increased risk for developing metabolic abnormalities. We suggest that close long-term follow-up is required to identify and manage metabolic abnormalities in APL. Copyright © 2015 Elsevier Inc. All rights reserved.
Acute quadriplegic myopathy in a 17-month-old boy.

PubMed

Salviati, L; Laverda, A M; Zancan, L; Fanin, M; Angelini, C; Meznaric-Petrusa, M

2000-01-01

Acute quadriplegic myopathy is a rare condition associated with the use of nondepolarizing muscle-blocking agents and corticosteroids in the course of severe systemic illness. A 17-month-old boy underwent liver transplantation for fulminant hepatitis. He was intubated for 24 days and treated with vecuronium bromide and high-dose methylprednisolone. The child was weaned from the ventilator and presented extreme weakness in the upper limbs and total paralysis of the lower limbs. Serum creatine kinase level was normal and electromyography showed myopathic abnormalities. Muscle biopsy showed severe type-1 fiber atrophy and selective loss of myosin thick filaments was seen on electron microscopy. Scattered regenerating fetal myosin-positive fibers were present, mu calpain was absent, while m calpain was diffusely expressed. Physical therapy was immediately started and the child recovered even though corticosteroids were not discontinued. The pathogenesis of acute quadriplegic myopathy is still unknown. We suggest that it could be due to abnormal protein turnover in the muscle. Several independent factors, such as corticosteroid treatment, immobilization, or cytokines, could take part in a cascade of events that leads to an excessive yet selective degradation of proteins involving myosin thick filaments and possibly components of sarcolemma, causing muscle inexcitability.
Characterization of the Regulation and Function of Zinc-Dependent Histone Deacetylases During Mouse Liver Regeneration

PubMed Central

Huang, Jiansheng; Barr, Emily; Rudnick, David A.

2013-01-01

The studies reported here were undertaken to define the regulation and functional importance of zinc-dependent histone deacetylase (Zn-HDAC) activity during liver regeneration using the mouse partial hepatectomy (PH) model. The results showed that hepatic HDAC activity was significantly increased in nuclear and cytoplasmic fractions following PH. Further analyses showed isoform-specific effects of PH on HDAC mRNA and protein expression, with increased expression of the class I HDACs, 1 and 8, and class II HDAC4 in regenerating liver. Hepatic expression of (class II) HDAC5 was unchanged after PH; however HDAC5 exhibited transient nuclear accumulation in regenerating liver. These changes in hepatic HDAC expression, subcellular localization, and activity coincided with diminished histone acetylation in regenerating liver. The significance of these events was investigated by determining the effects of suberoylanilide hydroxyamic acid (SAHA, a specific inhibitor of Zn-HDAC activity) on hepatic regeneration. The results showed that SAHA-treatment suppressed the effects of PH on histone deacetylation and hepatocellular BrdU incorporation. Further examination showed that SAHA blunted hepatic expression and activation of cell cycle signals downstream of induction of cyclin D1 expression in mice subjected to PH. Conclusion The data reported here demonstrate isoform-specific regulation of Zn-HDAC expression, subcellular localization, and activity in regenerating liver. These studies also indicate that HDAC activity promotes liver regeneration by regulating hepatocellular cell cycle progression at a step downstream of cyclin D1 induction. PMID:23258575
Glucocorticoid receptor is involved in the differential expression of hepatic 3β-hydroxysteroid dehydrogenase between barrows and boars at finishing stage.

PubMed

Li, Xian; Cong, Rihua; Yao, Wen; Jia, Yimin; Li, Runsheng; Sun, Zhiyuan; Li, Xi; Zhao, Ruqian

2018-01-01

The enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) plays an important role in androstenone metabolism in pig liver, and its defective expression is related to the development of boar taint. Early age castration is a common practice in many countries to avoid boar taint, yet whether and how castration affects porcine hepatic 3β-HSD expression are still poorly understood. In this study, we aimed to compare the expression of 3β-HSD between intact (boars) and castrated (barrows) male pigs, and to explore the potential factors regulating 3β-HSD transcription. Compared to barrows, boars showed worse carcass quality. Boars had significantly higher levels of serum androstenone (P < 0.01), testosterone (P < 0.01) and hepatic cortisol (P < 0.05), which were contrary to significantly lower expression of 3β-HSD messenger RNA (P < 0.01) and protein (P < 0.01) in the liver. Significant differences were detected for the hepatic expression of androgen receptor (AR) and CCAAT/enhancer binding protein β (C/EBPβ). Chromatin immunoprecipitation (ChIP) assay demonstrated reduced histone H3 acetylation (P < 0.05) but increased glucocorticoid receptor (GR) binding to 3β-HSD gene promoter in boars (P < 0.05). These results indicate that GR binding to 3β-HSD promoter is involved in the differential hepatic 3β-HSD expression between boars and barrows. © 2017 Japanese Society of Animal Science.
Gender-related difference in altered gene expression of a sterol regulatory element binding protein, SREBP-2, by lead nitrate in rats: correlation with development of hypercholesterolemia.

PubMed

Kojima, Misaki; Degawa, Masakuni

2006-01-01

Changes in gene expression levels of hepatic sterol regulatory element binding protein-2 (SREBP-2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) after a single i.v. injection of lead nitrate (LN, 100 micromol kg(-1) body weight) were examined comparatively by real time reverse transcriptase-polymerase chain reaction (RT-PCR) in male and female rats. Significant increases in the gene expression level of SREBP-2, a transcription factor for the HMGR gene, occurred at 6-12 h in male and at 24-36 h in female rats after LN-treatment. The gene expression level of HMGR, a rate-limiting enzyme for cholesterol biosynthesis, significantly increased at 3-48 h in male rats and 12-48 h in female rats. Subsequently, significant increases in the amount of hepatic total cholesterol in male and female rats were also observed at 3-48 h and 24-48 h, respectively. The present findings demonstrate that increases in gene expressions of hepatic SREBP-2 and HMGR and the amount of hepatic total cholesterol by LN occur earlier in male rats than in the females, and that increases in the gene expression level of HMGR and the amount of hepatic total cholesterol occur prior to the increase in the gene expression level of SREBP-2 in either sex of rats. Copyright (c) 2006 John Wiley & Sons, Ltd.
Long-Term Selenium-Deficient Diet Induces Liver Damage by Altering Hepatocyte Ultrastructure and MMP1/3 and TIMP1/3 Expression in Growing Rats.

PubMed

Han, Jing; Liang, Hua; Yi, Jianhua; Tan, Wuhong; He, Shulan; Wang, Sen; Li, Feng; Wu, Xiaofang; Ma, Jing; Shi, Xiaowei; Guo, Xiong; Bai, Chuanyi

2017-02-01

The effects of selenium (Se)-deficient diet on the liver were evaluated by using growing rats which were fed with normal and Se-deficient diets, respectively, for 109 days. The results showed that rats fed with Se-deficient diet led to a decrease in Se concentration in the liver, particularly among male rats from the low-Se group. This causes alterations to the ultrastructure of hepatocytes with condensed chromatin and swelling mitochondria observed after low Se intake. Meanwhile, pathological changes and increased fibrosis in hepatic periportal were detected by hematoxylin and eosin and Masson's trichrome staining in low-Se group. Furthermore, through immunohistochemistry (IHC) staining, higher expressions of metalloproteinases (MMP1/3) and their tissue inhibitors of metalloproteinases (TIMP1/3) were observed in the hepatic periportal of rats from the low-Se group. However, higher expressions of MMP1/3 and lower expressions of TIMP1/3 were detected in hepatic central vein and hepatic sinusoid. In addition, upregulated expressions of MMP1/3 and downregulated expressions of TIMP1/3 at the messenger RNA (mRNA) and protein levels also appeared to be relevant to low Se intake. In conclusion, Se-deficient diet could cause low Se concentration in the liver, alterations of hepatocyte ultrastructure, differential expressions of MMP1/3 and TIMP1/3 as well as fibrosis in the liver hepatic periportal.
HIV-1 viral protein R (Vpr) induces fatty liver in mice via LXRα and PPARα dysregulation: implications for HIV-specific pathogenesis of NAFLD.

PubMed

Agarwal, Neeti; Iyer, Dinakar; Gabbi, Chiara; Saha, Pradip; Patel, Sanjeet G; Mo, Qianxing; Chang, Benny; Goswami, Biman; Schubert, Ulrich; Kopp, Jeffrey B; Lewis, Dorothy E; Balasubramanyam, Ashok

2017-10-17

HIV patients develop hepatic steatosis. We investigated hepatic steatosis in transgenic mice expressing the HIV-1 accessory protein Vpr (Vpr-Tg) in liver and adipose tissues, and WT mice infused with synthetic Vpr. Vpr-Tg mice developed increased liver triglyceride content and elevated ALT, bilirubin and alkaline phosphatase due to three hepatic defects: 1.6-fold accelerated de novo lipogenesis (DNL), 45% slower fatty acid ß-oxidation, and 40% decreased VLDL-triglyceride export. Accelerated hepatic DNL was due to coactivation by Vpr of liver X receptor-α (LXRα) with increased expression of its lipogenic targets Srebp1c, Chrebp, Lpk, Dgat, Fasn and Scd1, and intranuclear SREBP1c and ChREBP. Vpr enhanced association of LXRα with Lxrα and Srebp1c promoters, increased LXRE-LXRα binding, and broadly altered hepatic expression of LXRα-regulated lipid metabolic genes. Diminished hepatic fatty acid ß-oxidation was associated with decreased mRNA expression of Pparα and its targets Cpt1, Aox, Lcad, Ehhadh, Hsd10 and Acaa2, and blunted VLDL export with decreased expression of Mttp and its product microsomal triglyceride transfer protein. With our previous findings that Vpr circulates in HIV patients (including those with undetectable plasma HIV-1 RNA), co-regulates the glucocorticoid receptor and PPARγ and transduces hepatocytes, these data indicate a potential role for Vpr in HIV-associated fatty liver disease.
Regressive Effect of Myricetin on Hepatic Steatosis in Mice Fed a High-Fat Diet

PubMed Central

Xia, Shu-Fang; Le, Guo-Wei; Wang, Peng; Qiu, Yu-Yu; Jiang, Yu-Yu; Tang, Xue

2016-01-01

Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet, w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway. PMID:27973423
Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKα in the liver.

PubMed

Tobita, Hiroshi; Sato, Shuichi; Yazaki, Tomotaka; Mishiro, Tsuyoshi; Ishimura, Norihisa; Ishihara, Shunnji; Kinoshita, Yoshikazu

2018-05-01

Pioglitazone (PIO) has been reported to be effective for nonalcoholic fatty liver disease (NAFLD) and alogliptin (ALO) may have efficacy against NAFLD progression in patients with type 2 diabetes mellitus (T2DM). The present study examined the effectiveness of ALO in a rodent model of NAFLD and diabetes mellitus. KK‑Ay mice were used to produce an NAFLD model via administration of a choline‑deficient (CD) diet. To examine the effects of alogliptin, KK‑Ay mice were provided with a CD diet with 0.03% ALO and/or 0.02% PIO orally for 8 weeks. Biochemical parameters, pathological alterations and hepatic mRNA levels associated with fatty acid metabolism were assessed. Severe hepatic steatosis was observed in KK‑Ay mice fed with a CD diet, which was alleviated by the administration of ALO and/or PIO. ALO administration increased the hepatic carnitine palmitoyltransferase 1a (CPT1a) mRNA expression level and enhanced the Thr172 phosphorylation of AMP‑activated protein kinase α (AMPKα) in the liver. PIO administration tended to decrease the hepatic fatty acid synthase mRNA expression level and increase the serum adiponectin level. Homeostasis model of assessment‑insulin resistance values tended to improve with ALO and PIO administration. ALO and PIO alleviated hepatic steatosis in KK‑Ay mice fed with a CD diet. ALO increased hepatic mRNA expression levels associated with fatty acid oxidation. In addition, the results of the present study suggested that ALO promotes CPT1a expression via Thr172 phosphorylation of AMPKα.
Petroselinum crispum extract attenuates hepatic steatosis in rats fed with fructose enriched diet.

PubMed

Nair, V Yuneesha; Balakrishanan, N; Antony Santiago, J Victor

2015-01-01

Non alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and ongoing research efforts are focused on understanding the underlying pathophysiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. This study investigated the Petroselinum crispum extract in hepatic steatosis in rats fed with fructose enriched diet. Rats were divided into the 4 groups: Group 1 rats received standard pellet diet with corn starch for the entire experimental period of 8 weeks. Group 2 rats received standard pellet diet and 2 gm/kg body weight crude Parsley leaf ethanol extract for the entire experimental period of 8 weeks. Group 3 rats received modified fructose diet. Group 4 rats received modified fructose diet and 2gm/kg crude Parsley leaf ethanol extract. Hepatic function and structure was evaluated in these rats. Modified fructose diet produced dyslipidemia, hepatic steatosis and infiltration of inflammatory cells in the liver and higher plasma hepatic markers. Petroselinum crispum extract reversed metabolic changes such as abnormal crispum extract attenuated chronic changes in modified fructose diet induced NAFLD (Tab. 2, Fig. 3, Ref. 43).
Growth and development of children prenatally exposed to telbivudine administered for the treatment of chronic hepatitis B in their mothers.

PubMed

Zeng, Huihui; Cai, Haodong; Wang, Ying; Shen, Ying

2015-04-01

We studied the growth and development of children prenatally exposed to telbivudine used to treat chronic hepatitis B virus (HBV) infection in their mothers. Maternal abnormalities during pregnancy and delivery and infant congenital anomalies, physical development status, developmental quotient (DQ), HBV vertical transmission status, and HBV vaccination outcomes of 54 infants were evaluated (2010-2013). No fetal abnormalities were observed during pregnancy or delivery. Postpartum, three infants (5.56%) had abnormalities: ankyloglossia, cutaneous hemangioma, and vaginal canal leak. Height and weight were within the normal range at birth and at 6 weeks, but were higher than the reference at 12 months (p<0.05). Body mass index increased gradually with age (p<0.05). DQ scores were normal (84.81%, 229/270) in 37 children (68.52%), abnormal or suspicious for a developmental delay (15.19%, 41/270) in 17 children (31.48%), and indicated a developmental delay (4.07%, 11/270) in seven children (12.96%). There were no significant differences in developmental delay between children prenatally exposed to telbivudine and controls (p>0.05). HBV vertical transmission was successfully blocked in all infants. The effective HBV vaccination rate was 98.15% (53/54). The growth and development of children prenatally exposed to telbivudine was normal, indicating that telbivudine treatment during pregnancy is safe and effective. Copyright © 2015. Published by Elsevier Ltd.

Contaminants in eggs of colonial waterbirds and hepatic cytochrome P450 enzyme levels in pipped tern embryos, Washington State.

PubMed

Blus, L J; Melancon, M J; Hoffman, D J; Henny, C J

1998-10-01

Eggs of Forster's terns (Sterna forsteri) collected in 1991 from nesting colonies on Crescent Island (Columbia River) and the Potholes Reservoir in south central Washington generally contained low residues of organochlorine pesticides and metabolites, 2,3,7, 8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and polychlorinated biphenyls (PCBs). Hepatic cytochrome P450 enzyme activity in pipped embryos of Forster's terns from the two colonies seemed unaffected by contaminants. At Crescent Island, examination of 23 Forster's tern eggs with large embryos (19 viable [10 pipped] and four dead [two pipped]) revealed developmental abnormalities in two viable pipped embryos (missing maxilla and deformed pelvic girdle) and a viable prepipping embryo (shortened beak). Our limited sample sizes and number of compounds analyzed preclude us from determining whether or not the abnormalities are related to contaminants. No abnormalities were noted in 10 pipped eggs (nine viable and one dead at collection) of Forster's terns collected from the Potholes Reservoir colony. Eggs of Caspian terns (Sterna caspia) collected from Crescent Island in 1991 also contained generally low residues of contaminants, only one developmental abnormality was noted, and limited data indicated that cytochrome P450 enzyme activity apparently was unaffected by contaminants. Organochlorine contaminants were generally low in addled eggs of American white pelicans (Pelecanus erythrorhynchos) collected from Crescent Island in 1994.
Contaminants in eggs of colonial waterbirds and hepatic cytochrome P450 enzyme levels in pipped tern embryos, Washington State

USGS Publications Warehouse

Blus, L.J.; Melancon, M.J.; Hoffman, D.J.; Henny, C.J.

1998-01-01

Eggs of Forster's terns (Sterna forsteri) collected in 1991 from nesting colonies on Crescent Island (Columbia River) and the Potholes Reservoir in south central Washington generally contained low residues of organochlorine pesticides and metabolites, 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzofuran, and polychlorinated biphenyls (PCBs). Hepatic cytochrome P450 enzyme activity in pipped embryos of Forster's terns from the two colonies seemed unaffected by contaminants. At Crescent Island, examination of 23 Forster's tern eggs with large embryos (19 viable [10 pipped] and four dead [two pipped]) revealed developmental abnormalities in two viable pipped embryos (missing maxilla and deformed pelvic girdle) and a viable prepipping embryo (shortened beak). Our limited sample sizes and number of compounds analyzed preclude us from determining whether or not the abnormalities are related to contaminants. No abnormalities were noted in 10 pipped eggs (nine viable and one dead at collection) of Forster's terns collected from the Potholes Reservoir colony. Eggs of Caspian terns (Sterna caspia) collected from Crescent Island in 1991 also contained generally low residues of contaminants, only one developmental abnormality was noted, and limited data indicated that cytochrome P450 enzyme activity apparently was unaffected by contaminants. Organochlorine contaminants were generally low in addled eggs of American white pelicans (Pelecanus erythrorhynchos) collected from Crescent Island in 1994.
Differences in antiproliferative effect of STAT3 inhibition in HCC cells with versus without HBV expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Yun; Zhou, Lin; Xie, Haiyang

2015-06-05

Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between themore » two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. - Highlights: • HBV endows HCC cells with resistance to STAT3 inactivation on proliferation. • Abnormal ERK activation after STAT3 inhibition in HBV-related HCC cells. • Combined ERK and STAT3 inhibition eliminates the discrepancy. • STAT3 inhibition moderately reduces HBV expression.« less
Correlation between Gd-EOB-DTPA-enhanced MR imaging findings and OATP1B3 expression in chemotherapy-associated sinusoidal obstruction syndrome.

PubMed

Yoneda, Norihide; Matsui, Osamu; Ikeno, Hiroshi; Inoue, Dai; Yoshida, Kotaro; Kitao, Azusa; Kozaka, Kazuto; Kobayashi, Satoshi; Gabata, Toshifumi; Ikeda, Hiroko; Nakamura, Keishi; Ohta, Tetsuo

2015-10-01

We report a female case of sinusoidal obstruction syndrome (SOS) diagnosed pathologically after chemotherapy (Pmab+m-FOLFOX6) for ascending colon cancer with multiple liver metastases, focusing on the findings of gadoxetic acid-enhanced MRI (EOB-MRI) and the organic anion transporting polypeptide 1B3 (OATP1B3) expression of in the liver. The patient was a 75-year-old female. She had received chemotherapy (Pmab+m-FOLFOX6) as six cycles for preoperative chemotherapy. After the preoperative chemotherapy, tumor sizes of hepatic metastases were reduced and hepatobiliary phase of EOB-MRI clearly depicted diffuse reticular hypointensity in the background liver. On the other hand, dynamic CT and/or other sequences of EOB-MRI did not show definite abnormality in the background liver. After the operation, this patient was pathologically confirmed as SOS demonstrating centrilobular congestion, sinusoidal dilatation, and perisinusoidal fibrosis. In normal liver parenchyma, OATP1B3 (uptake transporter of the EOB-MRI) expression is observed predominantly in centrilobular hepatocytes (zone 3). On the other hand, OATP1B3 expression was remarkably reduced because of the damages in the centrilobular (zone 3) hepatocytes in this SOS case. This indicated that EOB-MRI might be extremely sensitive in diagnosing SOS in its early stage.
Non-alcoholic fatty liver disease and subclinical atherosclerosis: A comparison of metabolically- versus genetically-driven excess fat hepatic storage.

PubMed

Di Costanzo, Alessia; D'Erasmo, Laura; Polimeni, Licia; Baratta, Francesco; Coletta, Paola; Di Martino, Michele; Loffredo, Lorenzo; Perri, Ludovica; Ceci, Fabrizio; Montali, Anna; Girelli, Gabriella; De Masi, Bruna; Angeloni, Antonio; Catalano, Carlo; Maranghi, Marianna; Del Ben, Maria; Angelico, Francesco; Arca, Marcello

2017-02-01

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with atherosclerosis. However, it is unclear whether this association is related to excess fat liver storage per se or to metabolic abnormalities that typically accompany NAFLD. To investigate this, we compared individuals with hepatic steatosis driven by metabolic disturbances to those with hepatic steatosis associated with the rs738409 GG genotype in the patatin-like phospholipase domain-containing 3 gene (PNPLA3). Carotid intima-media thickness (CIMT), as a surrogate marker of subclinical atherosclerosis, was measured in 83 blood donors with the mutant GG genotype (group G), 100 patients with features of metabolic syndrome (MetS) but the wildtype CC genotype (group M), and 74 blood donors with the wildtype CC genotype (controls). Fatty liver was evaluated by ultrasonography and hepatic fat fraction (HFF) was measured using magnetic resonance (MRS/MRI) in 157 subjects. Compared with group G and controls, group M subjects were older and had increased adiposity indices, dyslipidemia, insulin resistance and elevated transaminase levels (all p < 0.05). They also had a more fatty liver on both ultrasonography and MRS/MRI. After adjustment for confounders (including severity of hepatic steatosis), the median CIMT in group M (0.84 [0.70-0.95] mm) was significantly greater than that in group G (0.66 [0.55-0.74] mm; p < 0.001), which was similar to that in controls (0.70 [0.64-0.81] mm). Results were similar in the subgroup evaluated using MRS/MRI. Excess liver fat accumulation appeared to increase the burden of subclinical atherosclerosis only when it is associated with metabolic abnormalities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Effects of buprenorphine and hepatitis C on liver enzymes in adolescents and young adults.

PubMed

Bogenschutz, Michael P; Abbott, Patrick J; Kushner, Robert; Tonigan, J Scott; Woody, George E

2010-12-01

The purpose of this study was to explore changes in transaminase values associated with buprenorphine treatment and hepatitis C status among opioid dependent subjects aged 15-21. 152 subjects seeking treatment for opioid dependence were randomized to 2-week detoxification with buprenorphine/naloxone (DETOX) or 12 weeks buprenorphine/naloxone (BUP). Liver chemistries including transaminases were obtained baseline and at 4, 8, and 12 weeks. 111 patients had at least one set of transaminases during treatment and were included in analyses of treatment effects. Overall, 8/60 BUP participants vs. 12/51 DETOX participants had at least one elevated ALT value during follow-up (Chi-square n.s.). 5/60 BUP participants vs. 11/51 DETOX participants had at least one elevated AST value (Chi-square = 3.194, p = .048). Twenty-eight out of 152 participants were hepatitis C (HCV) positive at baseline, and 4 seroconverted within 12 weeks, 2 in each group. HCV status was significantly associated with transaminase abnormalities (p = .009 and p = .006 for ALT an AST, respectively). HCV status had a strong effect on transaminase abnormalities among participants assigned to DETOX, but not among those assigned to BUP. No evidence was found for hepatotoxicity of buprenorphine in this exploratory analysis. HCV was present in a significant minority of participants and was a significant predictor of transaminase elevation. Results suggest that stabilization on buprenorphine may decrease the frequency of transaminase abnormalities associated with HCV in opioid dependent young people. The high rate of seroconversion underscores the importance of effective treatment and prevention.
Effects of Buprenorphine and Hepatitis C on Liver Enzymes in Adolescents and Young Adults

PubMed Central

Bogenschutz, Michael P.; Abbott, Patrick J.; Kushner, Robert; Tonigan, J. Scott; Woody, George E.

2010-01-01

Objective The purpose of this study was to explore changes in transaminase values associated with buprenorphine treatment and hepatitis C status among opioid dependent subjects aged 15–21. Methods 152 subjects seeking treatment for opioid dependence were randomized to 2-week detoxification with buprenorphine/naloxone (DETOX) or 12 weeks buprenorphine/naloxone (BUP). Liver chemistries including transaminases were obtained baseline and at 4, 8, and 12 weeks. 111 patients had at least one set of transaminases during treatment and were included in analyses of treatment effects. Results Overall, 8/60 BUP participants vs. 12/51 DETOX participants had at least one elevated ALT value during follow-up (Chi-square n.s.). 5/60 BUP participants vs. 11/51 DETOX participants had at least one elevated AST value (Chi-square = 3.194, p = .048). Twenty-eight out of 152 participants were hepatitis C (HCV) positive at baseline, and 4 seroconverted within 12 weeks, 2 in each group. HCV status was significantly associated with transaminase abnormalities (p = .009 and p = .006 for ALT an AST, respectively). HCV status had a strong effect on transaminase abnormalities among participants assigned to DETOX, but not among those assigned to BUP. Conclusions No evidence was found for hepatotoxicity of buprenorphine in this exploratory analysis. HCV was present in a significant minority of participants and was a significant predictor of transaminase elevation. Results suggest that stabilization on buprenorphine may decrease the frequency of transaminase abnormalities associated with HCV in opioid dependent young people. The high rate of seroconversion underscores the importance of effective treatment and prevention. PMID:21170166
Long-term treatment with tenofovir in Asian-American chronic hepatitis B patients is associated with abnormal renal phosphate handling.

PubMed

Tien, Connie; Xu, Jason J; Chan, Linda S; Chang, Mimi; Lim, Carolina; Lee, Sue; Huh, Brian; Shinada, Shuntaro; Bae, Ho S; Fong, Tse-Ling

2015-02-01

Increased risk of defective urinary phosphate reabsorption and osteoporosis has been reported in HIV and chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF). Goals of this study were to evaluate the prevalence of renal phosphate wasting and abnormal bone mineral density in CHB patients taking TDF compared to CHB patients treated with entecavir (ETV) and untreated CHB patients. This is a cross-sectional study of 146 consecutive Asian-American CHB patients who were treatment naïve (n = 60) or treated with either TDF (n = 42) or ETV (n = 44). Proximal tubular handling of phosphate was assessed by the maximal rate of tubular reabsorption of phosphate (TmPO4) divided by glomerular filtration rate (GFR) (TmPO4/GFR). Bone mineral density (BMD) was measured using dual X-ray absorptiometry. TmPO4/GFR was similar among CHB patients treated with TDF compared to untreated patients and patients taking ETV. However, among patients treated with ≥18 months of TDF or ETV, prevalence of abnormal TmPO4/GFR was higher among patients treated with TDF compared to ETV (48.5 % (16/33) vs. 12.5 % (3/24), p = 0.005). Overall prevalence of osteoporosis in this cohort of CHB patients was 14 %, with no significant difference between the three groups. Renal phosphate handling did not correlate with osteoporosis. Chronic hepatitis B patients treated with ≥18 months of TDF experienced an increased risk of proximal tubular dysfunction. TDF did not increase the risk of osteoporosis. Longitudinal studies are needed to confirm these findings.
Role of splenic reservoir monocytes in pulmonary vascular monocyte accumulation in experimental hepatopulmonary syndrome

PubMed Central

Wu, Wei; Zhang, Junlan; Yang, Wenli; Hu, Bingqian

2016-01-01

Abstract Background and Aim Pulmonary monocyte infiltration plays a significant role in the development of angiogenesis in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Hepatic monocytes are also increased after CBDL, but the origins remain unclear. Splenic reservoir monocytes have been identified as a major source of monocytes that accumulate in injured tissues. Whether splenic monocytes contribute to monocyte alterations after CBDL is unknown. This study evaluates monocyte distributions and assesses effects of splenectomy on monocyte levels and pulmonary vascular and hepatic abnormalities in experimental HPS. Methods Splenectomy was performed in CBDL animals. Monocyte levels in different tissues and circulation were assessed with CD68. Pulmonary alterations of HPS were evaluated with vascular endothelial growth factor‐A (VEGF‐A) levels, angiogenesis, and alveolar–arterial oxygen gradient (AaPO2). Liver abnormalities were evaluated with fibrosis (Sirius red), bile duct proliferation (CK‐19), and enzymatic changes. Results Monocyte levels increased in the lung and liver after CBDL and were accompanied by elevated circulating monocyte numbers. Splenectomy significantly decreased monocyte accumulation, VEGF‐A levels, and angiogenesis in CBDL animal lung and improved AaPO2 levels. In contrast, hepatic monocyte levels, fibrosis, and functional abnormalities were further exacerbated by spleen removal. Conclusions Splenic reservoir monocytes are a major source for lung monocyte accumulation after CBDL, and spleen removal attenuates the development of experimental HPS. Liver monocytes may have different origins, and accumulation is exacerbated after depletion of splenic reservoir monocytes. Tissue specific monocyte alterations, influenced by the spleen reservoir, have a significant impact on pulmonary complications of liver disease. PMID:27029414
Hepatic Overexpression of Endothelial Lipase Lowers HDL (High-Density Lipoprotein) but Maintains Reverse Cholesterol Transport in Mice: Role of SR-BI (Scavenger Receptor Class B Type I)/ABCA1 (ATP-Binding Cassette Transporter A1)-Dependent Pathways.

PubMed

Takiguchi, Shunichi; Ayaori, Makoto; Yakushiji, Emi; Nishida, Takafumi; Nakaya, Kazuhiro; Sasaki, Makoto; Iizuka, Maki; Uto-Kondo, Harumi; Terao, Yoshio; Yogo, Makiko; Komatsu, Tomohiro; Ogura, Masatsune; Ikewaki, Katsunori

2018-05-10

Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo. Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3 H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3 H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3 HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3 H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol. Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways. © 2018 American Heart Association, Inc.
An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells

PubMed Central

Cebula, Marcin; Ochel, Aaron; Hillebrand, Upneet; Pils, Marina C.; Schirmbeck, Reinhold; Hauser, Hansjörg; Wirth, Dagmar

2013-01-01

The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreERT2 mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred Kb/OVA257-264-specific OT-I T cells to OVA_X_CreERT2 mice or generated triple transgenic OVA_X CreERT2_X_OT-I mice. OT-I T cells become activated in OVA_X_CreERT2 mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreERT2_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreERT2_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance. PMID:23869228
Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh

PubMed Central

Tabassum, Shahina; Ullah Munshi, Saif; Hossain, Marufa; Imam, Akhter

2014-01-01

ABSTRACT Background and aim Assessment of therapeutic response is important for monitoring the prognosis and to take decision for cessation of nucleoside analogues therapy in chronic hepatitis B patients. In addition to serum alanine aminotransferase (ALT), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load and HBeAg status, identification of molecular markers associated with host immune response would be essential to assess therapeutic response. In this regard the current study was performed with the aim to detect expression of platelet endothelial cell adhesion molecule (PECAM)-I gene in peripheral blood monocytes (PBMCs) of treated chronic hepatitis B patients and also to correlate expression of this gene with serum HBV DNA load and serum ALT levels. Materials and methods The study analyzed 60 chronic hepatitis B (CHB) patients, including 30 untreated and 30 nucleoside analogs treated and 10 healthy controls. PECAM-1 gene expression/ transcripts were detected by conventional RT-PCR. Results The expression PECAM-1 mRNA in the PBMCs of CHB patients was significantly higher in untreated (3.17 ± 0.75) than the treated patients (1.64 ± 0.29) (p < 0.01). Expression of PECAM-1 was positively correlated with serum ALT levels of both untreated (r = 0.580) and treated (r = 0.566) CHB patients. Moreover, in both untreated and treated groups, these gene expressions were positively correlated to serum HBV DNA load with the correlation coefficient r = 0.545 and r = 0.591 respectively. Conclusion PECAM-1 may be used as a biomarker for assessment of inflammatory activity as well as therapeutic response in CHB patients. How to cite this article: Sultana N, Tabassum S, Munshi SU, Hossain M, Imam A. Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(2):87-91. PMID:29699354
A new systematic classification of peripheral anatomy of the right hepatic duct: experience from adult live liver donor transplantation.

PubMed

Radtke, A; Sgourakis, G; Sotiropoulos, G C; Molmenti, E P; Nadalin, S; Fouzas, I; Schroeder, T; Saner, F H; Cicinnati, V R; Schenk, A; Malagó, M; Lang, H

2008-11-01

The peripheral intrahepatic biliary anatomy, especially at the sectorial level on the right side, has not been adequately described. The purpose of our study was to systematically describe this complex anatomy in clinically applicable fashion. We analyzed three-dimensional computed tomography (CT) imaging reconstructions of 139 potential living liver donors evaluated at our institution between January 2003 and June 2007. Eighty-nine (64%) donors had a normal right bile duct sectorial anatomy. In the other 50/139 (36%) cases, we observed abnormal sectorial branching patterns, with 45/50 abnormalities as trifurcations, whereas the remaining ones were quadrifurcations. In 22/50 (44%) abnormalities, a linear branching pattern (types B1/C1) and an early segmental origin off the right hepatic duct (types B3/C3) were present, a finding of particular danger when performing a right graft hepatectomy. In 2 cases, we noted a mixed type (B6/C6) of a rare complex anatomy. Our proposed classification of the right sectorial bile duct system clearly displays the "area at risk" encountered when performing right graft adult live donor liver transplantation and tumor resections involving the right lobe of the liver.
Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse.

PubMed

Kok, Tineke; Wolters, Henk; Bloks, Vincent W; Havinga, Rick; Jansen, Peter L M; Staels, Bart; Kuipers, Folkert

2003-01-01

Fatty acids are natural ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha). Synthetic ligands of this nuclear receptor, i.e., fibrates, induce the hepatic expression of the multidrug resistance 2 gene (Mdr2), encoding the canalicular phospholipid translocator, and affect hepatobiliary lipid transport. We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner. A 24-hour fasting/48-hour refeeding schedule was used in wild-type and Pparalpha((-/-)) mice. Expression of genes involved in the control of bile formation was determined and related to secretion rates of biliary components. Expression of Pparalpha, farnesoid X receptor, and liver X receptor alpha genes encoding nuclear receptors that control hepatic bile salt and sterol metabolism was induced on fasting in wild-type mice only. The expression of Mdr2 was 5-fold increased in fasted wild-type mice and increased only marginally in Pparalpha((-/-)) mice, and it normalized on refeeding. Mdr2 protein levels and maximal biliary phospholipid secretion rates were clearly increased in fasted wild-type mice. Hepatic expression of the liver X receptor target genes ATP binding cassette transporter a1 (Abca1), Abcg5, and Abcg8, implicated in hepatobiliary cholesterol transport, was induced in fasted wild-type mice only. However, the maximal biliary cholesterol secretion rate was reduced by approximately 50%. Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice. Fasting also induces expression of the putative hepatobiliary cholesterol transport genes Abca1, Abcg5, and Abcg8, but, nonetheless, maximal biliary cholesterol excretion is decreased after fasting.
Histidine augments the suppression of hepatic glucose production by central insulin action.

PubMed

Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-Ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

2013-07-01

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.
Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

PubMed Central

Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

2013-01-01

Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes. PMID:23474485
Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia.

PubMed

Zhang, Na; Geng, Tingting; Wang, Zhangsheng; Zhang, Ruling; Cao, Tiefeng; Camporez, Joao Paulo; Cai, Shi-Ying; Liu, Ya; Dandolo, Luisa; Shulman, Gerald I; Carmichael, Gordon G; Taylor, Hugh S; Huang, Yingqun

2018-05-17

Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP. Using genome-wide methylation and transcriptome analyses, we demonstrate that H19 knockdown in hepatic cells alters promoter methylation and expression of Hnf4a, a master gluconeogenic transcription factor, and that this regulation is recapitulated in vivo. Our findings offer a mechanistic explanation of lncRNA H19's role in the pathogenesis of diabetic hyperglycemia and suggest that targeting hepatic H19 may hold the potential of new treatment for this disease.
Assessment of biological effects of pollutants in a hyper eutrophic tropical water body, Lake Beira, Sri Lanka using multiple biomarker responses of resident fish, Nile tilapia (Oreochromis niloticus).

PubMed

Pathiratne, Asoka; Pathiratne, K A S; De Seram, P K C

2010-08-01

Biomarkers measured at the molecular and cellular level in fish have been proposed as sensitive "early warning" tools for biological effect measurements in environmental quality assessments. Lake Beira is a hypertrophic urban water body with a complex mixture of pollutants including polycyclic aromatic hydrocarbons (PAHs) and Microcystins. In this study, a suite of biomarker responses viz. biliary fluorescent aromatic compounds (FACs), hepatic ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST), brain and muscle cholinesterases (ChE), serum sorbitol dehydrogenase (SDH), and liver histology of Oreochromis niloticus, the dominant fish inhabiting this tropical Lake were evaluated to assess the pollution exposure and biological effects. Some fish sampled in the dry periods demonstrated prominent structural abnormalities in the liver and concomitant increase in serum SDH and reduction in hepatic GST activities in comparison to the control fish and the fish sampled in the rainy periods. The resident fish with apparently normal liver demonstrated induction of hepatic EROD and GST activities and increase in biliary FACs irrespective of the sampling period indicating bioavailability of PAHs. Muscle ChE activities of the resident fish were depressed significantly indicating exposure to anticholinesterase substances. The results revealed that fish populations residing in this Lake is under threat due to the pollution stress. Hepatic abnormalities in the fish may be mainly associated with the pollution stress due to recurrent exposure to PAHs and toxigenic Microcystis blooms in the Lake.
Loss of tumor suppressor miR-126 contributes to the development of hepatitis B virus-related hepatocellular carcinoma metastasis through the upregulation of ADAM9.

PubMed

Xiang, Le-Yang; Ou, Huo-Hui; Liu, Xin-Cheng; Chen, Zhan-Jun; Li, Xiang-Hong; Huang, Yu; Yang, Ding-Hua

2017-06-01

Hepatocellular carcinoma is the most common histological type of primary liver cancer, which represents the second leading cause of cancer-related mortality. MiR-126 was reported to be downregulated in hepatocellular carcinoma tissues, compared with its levels in noncancerous tissues. However, baseline miR-126 expression levels in hepatitis B virus-related hepatocellular carcinoma patients who did not undergo pre-operational treatment remains unknown since hepatitis B virus infection and pre-operational transcatheter arterial chemoembolization were shown to upregulate miR-126 expression. Here, we demonstrated that miR-126 is generally downregulated in a homogeneous population of pre-operational treatment-naïve hepatitis B virus-related hepatocellular carcinoma patients (84.0%, 84/100), and its expression is significantly associated with pre-operational alpha-fetoprotein levels ( p < 0.05), microvascular invasion ( p < 0.05), tumor metastasis ( p < 0.05), as well as early recurrence (12 months after surgery; p < 0.01). Furthermore, the results of our study revealed that miR-126 is negatively correlated with ADAM9 expression in hepatitis B virus-related hepatocellular carcinoma patients. Overexpression of miR-126 was shown to attenuate ADAM9 expression in hepatocellular carcinoma cells, which subsequently inhibits cell migration and invasion in vitro. In addition, Cox proportional hazards regression model analysis showed that ADAM9 levels, tumor number, microvascular invasion, and tumor metastasis rate represent independent prognostic factors for shorter recurrence-free survival. In conclusion, we demonstrated that the loss of tumor suppressor miR-126 in hepatitis B virus-related hepatocellular carcinoma cells contributes to the development of metastases through the upregulated expression of its target gene, ADAM9. MiR-126-ADAM9 pathway-based therapeutic targeting may represent a novel approach for the inhibition of hepatitis B virus-related hepatocellular carcinoma metastases.
Maintaining HNF6 expression prevents AdHNF3beta-mediated decrease in hepatic levels of Glut-2 and glycogen.

PubMed

Tan, Yongjun; Adami, Guy; Costa, Robert H

2002-04-01

The hepatocyte nuclear factor 3 (HNF-3) proteins are members of the Forkhead Box (Fox) family of transcription factors that play important roles in regulating expression of genes involved in cellular proliferation, differentiation, and metabolic homeostasis. In previous studies we increased liver expression of HNF-3beta by using either transgenic mice (transthyretin HNF-3beta) or recombinant adenovirus infection (AdHNF3beta), and observed diminished hepatic levels of glycogen, and glucose transporter 2 (Glut-2), as well as the HNF-6, HNF-3, HNF-1alpha, HNF-4alpha, and C/EBPalpha transcription factors. We conducted the present study to determine whether maintaining HNF-6 protein expression during AdHNF3beta infection prevents reduction of hepatic levels of glycogen and the earlier-mentioned genes. Here, we show that AdHNF3beta- and AdHNF6-infected mouse liver displayed increased hepatic levels of glycogen, Glut-2, HNF-3gamma, HNF-1alpha, and HNF-4alpha at 2 and 3 days postinfection (PI). Furthermore, restoration of hepatic glycogen levels after AdHNF3beta and AdHNF6 coinfection was associated with increased Glut-2 expression. AdHNF6 infection alone caused a 2-fold increase in hepatic Glut-2 levels, suggesting that HNF 6 stimulates in vivo transcription of the Glut-2 gene. DNA binding assays showed that only recombinant HNF-6 protein, but not the HNF-3 proteins, binds to the mouse -185 to -144 bp Glut-2 promoter sequences. Cotransfection assays in human hepatoma (HepG2) cells with either HNF-3 or HNF-6 expression vectors show that only HNF-6 provided significant transcriptional activation of the Glut-2 promoter. In conclusion, these studies show that the hepatic Glut-2 promoter is a direct target for HNF-6 transcriptional activation.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice.

PubMed

Yamamoto, Takaya; Nakade, Yukiomi; Yamauchi, Taeko; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sato, Ken; Fukuzawa, Yoshitaka; Yoneda, Masashi

2016-02-28

To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model.
A Proinflammatory Role of Type 2 Innate Lymphoid Cells in Murine Immune-Mediated Hepatitis.

PubMed

Neumann, Katrin; Karimi, Khalil; Meiners, Jana; Voetlause, Ruth; Steinmann, Silja; Dammermann, Werner; Lüth, Stefan; Asghari, Farahnaz; Wegscheid, Claudia; Horst, Andrea K; Tiegs, Gisa

2017-01-01

Type 2 innate lymphoid cells (ILC2) mediate inflammatory immune responses in the context of diseases triggered by the alarmin IL-33. In recent years, IL-33 has been implicated in the pathogenesis of immune-mediated liver diseases. However, the immunoregulatory function of ILC2s in the inflamed liver remains elusive. Using the murine model of Con A-induced immune-mediated hepatitis, we showed that selective expansion of ILC2s in the liver was associated with highly elevated hepatic IL-33 expression, severe liver inflammation, and infiltration of eosinophils. CD4 + T cell-mediated tissue damage and subsequent IL-33 release were responsible for the activation of hepatic ILC2s that produced the type 2 cytokines IL-5 and IL-13 during liver inflammation. Interestingly, ILC2 depletion correlated with less severe hepatitis and reduced accumulation of eosinophils in the liver, whereas adoptive transfer of hepatic ILC2s aggravated liver inflammation and tissue damage. We further showed that, despite expansion of hepatic ILC2s, 3-d IL-33 treatment before Con A challenge potently suppressed development of immune-mediated hepatitis. We found that IL-33 not only activated hepatic ILC2s but also expanded CD4 + Foxp3 + regulatory T cells (Treg) expressing the IL-33 receptor ST2 in the liver. This Treg subset also accumulated in the liver during resolution of immune-mediated hepatitis. In summary, hepatic ILC2s are poised to respond to the release of IL-33 upon liver tissue damage through expression of type 2 cytokines thereby participating in the pathogenesis of immune-mediated hepatitis. Inflammatory activity of ILC2s might be regulated by IL-33-elicited ST2 + Tregs that also arise in immune-mediated hepatitis. Copyright © 2016 by The American Association of Immunologists, Inc.
Chemokine Receptor Ccr6 Deficiency Alters Hepatic Inflammatory Cell Recruitment and Promotes Liver Inflammation and Fibrosis

PubMed Central

Blaya, Delia; Morales-Ibanez, Oriol; Coll, Mar; Millán, Cristina; Altamirano, José; Arroyo, Vicente; Caballería, Joan; Bataller, Ramón; Ginès, Pere; Sancho-Bru, Pau

2015-01-01

Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6 -/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6 -/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6 -/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6 -/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis. PMID:26691857
Euterpe oleracea Mart.-Derived Polyphenols Protect Mice from Diet-Induced Obesity and Fatty Liver by Regulating Hepatic Lipogenesis and Cholesterol Excretion.

PubMed

de Oliveira, Paola Raquel B; da Costa, Cristiane A; de Bem, Graziele F; Cordeiro, Viviane S C; Santos, Izabelle B; de Carvalho, Lenize C R M; da Conceição, Ellen Paula S; Lisboa, Patrícia Cristina; Ognibene, Dayane T; Sousa, Pergentino José C; Martins, Gabriel R; da Silva, Antônio Jorge R; de Moura, Roberto S; Resende, Angela C

2015-01-01

The aim of this study was to investigate the effect of a polyphenol-rich Açaí seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis.
Euterpe oleracea Mart.-Derived Polyphenols Protect Mice from Diet-Induced Obesity and Fatty Liver by Regulating Hepatic Lipogenesis and Cholesterol Excretion

PubMed Central

de Bem, Graziele F.; Cordeiro, Viviane S. C.; Santos, Izabelle B.; de Carvalho, Lenize C. R. M.; da Conceição, Ellen Paula S.; Lisboa, Patrícia Cristina; Ognibene, Dayane T.; Sousa, Pergentino José C.; Martins, Gabriel R.; da Silva, Antônio Jorge R.; de Moura, Roberto S.; Resende, Angela C.

2015-01-01

The aim of this study was to investigate the effect of a polyphenol-rich Açaí seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis. PMID:26630290
Lack of kinin B₁ receptor potentiates leptin action in the liver.

PubMed

Fonseca, Raphael Gomes; Sales, Vicencia Micheline; Ropelle, Eduardo; Barros, Carlos Castilho; Oyama, Lila; Ihara, Silvia Saiuli Iuki; Saad, Mário Jose Abdalla; Araújo, Ronaldo Carvalho; Pesquero, João Bosco

2013-07-01

Kinins B1 and B2 receptors (B1R and B2R) are classically associated with inflammation, but our group has recently demonstrated new roles for B1R in metabolism using a knockout model (B1 (-/-)). B1 (-/-) mice display improvement on leptin and insulin sensitivity and is protected from high fat diet (HFD)-induced obesity. Here, we evaluate the hepatic effects of the B1R ablation and its role on hepatic function. Despite no expression of hepatic B1R, HFD-induced hepatic lipid accumulation was lower than in control animals. B1 (-/-) mice also presented lower hepatic lipogenesis and SCD1 protein content in the liver. When stimulated with exogenous leptin, B1 (-/-) mice exhibited increased hepatic pJAK2. Similarly, leptin signaling was enhanced in the liver of ob/ob-B1 (-/-) mice, as demonstrated by increased levels of pSTAT3 compared to ob/ob. Plasma concentrations of intercellular adhesion molecule 1, fetuin A, leukemia inhibitory factor, tissue inhibitor of metalloprotease-1, resistin, and oncostatin M were reduced in B1 (-/-). Finally, B1 (-/-) mice have increased gene expression of hepatic B2 receptor, but no difference in leptin receptor expression. Our results show that B1 (-/-) mice are protected from non-alcoholic fatty liver disease (NAFLD) after HFD treatment. Since B1R expression was not observed in the liver after HFD, we propose that the cross talk between the adipose tissue and the liver, mainly through leptin, is an important factor contributing to the observed results. Besides that, several other inflammatory mediators already correlated with NAFLD or liver function were found to be altered in our model. Taken together, our data suggest that B1R plays an important role in hepatic steatosis development.
Markers of hepatic regeneration associated with surgical attenuation of congenital portosystemic shunts in dogs.

PubMed

Tivers, Michael S; Lipscomb, Victoria J; Smith, Kenneth C; Wheeler-Jones, Caroline P D; House, Arthur K

2014-05-01

Dogs with congenital portosystemic shunts (CPSS) have liver hypoplasia and hepatic insufficiency. Surgical CPSS attenuation results in liver growth associated with clinical improvement. The mechanism of this hepatic response is unknown, although liver regeneration is suspected. This study investigated whether markers of liver regeneration were associated with CPSS attenuation. Dogs treated with CPSS attenuation were prospectively recruited. Residual liver tissue was collected for gene expression analysis (seven genes) from 24 CPSS dogs that tolerated complete attenuation, 25 dogs that tolerated partial attenuation and seven control dogs. Relative gene expression was measured using quantitative polymerase chain reaction (qPCR). Blood samples were collected before, 24 h and 48 h post-surgery from 36 CPSS dogs and from 10 control dogs. Serum hepatocyte growth factor (HGF) concentration was measured using a canine specific enzyme-linked immunosorbent assay (ELISA). HGF mRNA expression was significantly decreased in CPSS compared with control dogs (P = 0.046). There were significant increases in HGF (P = 0.050) and methionine adenosyltransferase 2 A (MAT2A; P = 0.002) mRNA expression following partial CPSS attenuation. Dogs with complete attenuation had significantly greater MAT2A (P = 0.024) mRNA expression compared with dogs with partial attenuation. Serum HGF concentration significantly increased 24 h following CPSS attenuation (P < 0.001). Hepatic mRNA expression of two markers of hepatocyte proliferation (HGF and MAT2A) was associated with the response to surgery in dogs with CPSS, and serum HGF significantly increased following surgery, suggesting hepatocyte proliferation. These findings support the concept that hepatic regeneration is important in the hepatic response to CPSS surgery. Copyright © 2014 Elsevier Ltd. All rights reserved.
Expression of scavenger receptor‐AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis

PubMed Central

Labonte, Adam C.; Sung, Sun‐Sang J.; Jennelle, Lucas T.; Dandekar, Aditya P.

2016-01-01

The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that expression of C‐type lectin receptor scavenger receptor‐AI (SR‐AI) is crucial for promoting M2‐like Mϕ activation and polarization during hepatic inflammation. Liver Mϕ uniquely up‐regulated SR‐AI during hepatotropic viral infection and displayed increased expression of alternative Mϕ activation markers, such as YM‐1, arginase‐1, and interleukin‐10 by activation of mer receptor tyrosine kinase associated with inhibition of mammalian target of rapamycin. Expression of these molecules was reduced on Mϕ obtained from livers of infected mice deficient for the gene encoding SR‐AI (msr1). Furthermore, in vitro studies using an SR‐AI‐deficient Mϕ cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild‐type (WT) cell line, but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR‐AI–/– mice following hepatic infection and adoptive transfer of WT bone‐marrow–derived Mϕ conferred protection against fibrosis in these mice. Conclusion: SR‐AI expression on liver Mϕ promotes recovery from infection‐induced tissue damage by mediating a switch to a proresolving Mϕ polarization state. (Hepatology 2017;65:32‐43). PMID:27770558
Delineation of molecular pathways that regulate hepatic PCSK9 and LDL receptor expression during fasting in normolipidemic hamsters

PubMed Central

Wu, Minhao; Dong, Bin; Cao, Aiqin; Li, Hai; Liu, Jingwen

2015-01-01

Background PCSK9 has emerged as a key regulator of serum LDL-C metabolism by promoting the degradation of hepatic LDL receptor (LDLR). In this study, we investigated the effect of fasting on serum PCSK9, LDL-C, and hepatic LDLR expression in hamsters and further delineated the molecular pathways involved in fasting-induced repression of PCSK9 transcription. Results Fasting had insignificant effects on serum total cholesterol and HDL-C levels, but reduced LDL-C, triglyceride and insulin levels. The decrease in serum LDL-C was accompanied by marked reductions of hepatic PCSK9 mRNA and serum PCSK9 protein levels with concomitant increases of hepatic LDLR protein amounts. Fasting produced a profound impact on SREBP1 expression and its transactivating activity, while having modest effects on mRNA expressions of SREBP2 target genes in hamster liver. Although PPARα mRNA levels in hamster liver were elevated by fasting, ligand-induced activation of PPARα with WY14643 compound in hamster primary hepatocytes did not affect PCSK9 mRNA or protein expressions. Further investigation on HNF1α, a critical transactivator of PCSK9, revealed that fasting did not alter its mRNA expression, however, the protein abundance of HNF1α in nuclear extracts of hamster liver was markedly reduced by prolonged fasting. Conclusion Fasting lowered serum LDL-C in hamsters by increasing hepatic LDLR protein amounts via reductions of serum PCSK9 levels. Importantly, our results suggest that attenuation of SREBP1 transactivating activity owing to decreased insulin levels during fasting is primarily responsible for compromised PCSK9 gene transcription, which was further suppressed after prolonged fasting by a reduction of nuclear HNF1α protein abundance. PMID:22954675
Alterations in specific gene expression and focal neoplastic growth during spontaneous hepatocarcinogenesis in albumin-SV40 T antigen transgenic rats.

PubMed

Dragan, Yvonne P; Sargent, Linda M; Babcock, Karlee; Kinunen, Nina; Pitot, Henry C

2004-07-01

Transgenic rats containing the mouse albumin promoter and enhancer directing the expression of simian virus (SV40) T antigen (T Ag) exhibited a 100% incidence of hepatic neoplasms by 24-36 wk of age. These transgenic rats exhibited expression of large T Ag and c-myc protein within focal basophilic lesions and nodules, but not in surrounding hepatocytes. At 24 wk of age, female TG+ rats exhibited a significantly greater number of lesions and a much greater percentage of the liver occupied by TG+ focal hepatic lesions than did their male TG+ littermates. Previous studies on these animals [Sargent et al., Cancer Res 1997;57:3451-3456] demonstrate that at 12 wk of age approximately one-third of metaphases in hepatocytes exhibit a duplication of the 1q3.7-1q4.1 region of rat chromosome 1, with the smallest common region of duplication being that of 1q4.1. Duplication of the 1q3.7-1q4.3 region is also noted in many primary hepatic neoplasms resulting from the multistage model of Initiation-Promotion-Progression (IPP) [Sargent et al., Cancer Res 1996;56:2985-2991]. This region is syntenic with human 11p15.5 and mouse 7ter, which have been implicated in the development of specific neoplasms. Within the syntenic region was a cluster of imprinted genes whose expression we investigated in livers and neoplasms of TG+ rats. H19 was expressed in almost all of the neoplasms, but not in normal adult liver cells. Igf2 expression was detected in the majority of hepatic neoplasms of female TG+ rats, but in a relatively smaller number of neoplasms of TG+ males. The expression of p57Kip2 (Kip2), a cyclin-dependent kinase inhibitor that was also in the imprinted region, exhibited some variable increased expression predominantly in hepatic neoplasms from livers of female TG+ rats. Other imprinted genes within the imprinted gene cluster-insulin II (Ins2), Mash2 (which codes for a basic helix-loop-helix transcription factor), and Kvlqt1 (coding for a component of a potassium transport channel)-showed no consistently different expression from that seen in normal hepatocytes. Another gene, also located on the long arm of chromosome 1, that showed changes was the ribonucleotide reductase M1 subunit (Rrm1), in which an increase in its expression was found. This was seen in hepatic neoplasms of TG+ rats of both sexes compared with surrounding normal-appearing liver. Because hepatic neoplasms developing in livers of rats treated with chemical carcinogens commonly exhibit an increased expression of c-myc mRNA, expression of this gene was investigated in focal lesions and livers of TG+ rats, although c-myc was not located on chromosome 1. c-myc mRNA was increased in focal lesions, nodules, and neoplasms in both male and female TG+ rats compared with adult and surrounding liver. Immunostaining for c-myc protein demonstrated detectable levels in isolated single cells as well as focal lesions and neoplasms. Thus, the enhanced c-myc expression, common to all hepatic neoplasms in this system, coupled with enhanced expression of Igf2 in female TG+ rats, may be responsible for the increase in growth rate in hepatic neoplasms of female TG+ rats compared with that in livers of male TG+ rats and may contribute to neoplastic progression in the liver of this transgenic model.
Hepatitis B Virus X Protein Impairs Hepatic Insulin Signaling Through Degradation of IRS1 and Induction of SOCS3

PubMed Central

Kim, KyeongJin; Kim, Kook Hwan; Cheong, JaeHun

2010-01-01

Background Hepatitis B virus (HBV) is a major cause of chronic liver diseases, and frequently results in hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The role of HCV in associations with insulin signaling has been elucidated. However, the pathogenesis of HBV-associated insulin signaling remains to be clearly characterized. Therefore, we have attempted to determine the mechanisms underlying the HBV-associated impairment of insulin signaling. Methodology The expressions of insulin signaling components were investigated in HBx-transgenic mice, HBx-constitutive expressing cells, and transiently HBx-transfected cells. Protein and gene expression was examined by Western blot, immunohistochemistry, RT-PCR, and promoter assay. Protein-protein interaction was detected by coimmunoprecipitation. Principal Findings HBx induced a reduction in the expression of IRS1, and a potent proteasomal inhibitor blocked the downregulation of IRS1. Additionally, HBx enhanced the expression of SOCS3 and induced IRS1 ubiquitination. Also, C/EBPα and STAT3 were involved in the HBx-induced expression of SOCS3. HBx interfered with insulin signaling activation and recovered the insulin-mediated downregulation of gluconeogenic genes. Conclusions/Significance These results provide direct experimental evidences for the contribution of HBx in the impairment of insulin signaling. PMID:20351777
Influence of Expression Plasmid of Connective Tissue Growth Factor and Tissue Inhibitor of Metalloproteinase-1 shRNA on Hepatic Precancerous Fibrosis in Rats.

PubMed

Zhang, Qun; Shu, Fu-Li; Jiang, Yu-Feng; Huang, Xin-En

2015-01-01

In this study, influence caused by expression plasmids of connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) short hairpin RNA (shRNA) on mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII in hepatic tissue with hepatic fibrosis, a precancerous condition, in rats is analyzed. To screen and construct shRNA expression plasimid which effectively interferes RNA targets of CTGF and TIMP-1 in rats. 50 cleaning Wistar male rats are allocated randomly at 5 different groups after precancerous fibrosis models and then injection of shRNA expression plasimids. Plasmid psiRNA-GFP-Com (CTGF and TIMP-1 included), psiRNA-GFP-CTGF, psiRNA-GFP-TIMP-1 and psiRNA- DUO-GFPzeo of blank plasmid are injected at group A, B, C and D, respectively, and as model control group that none plasimid is injected at group E. In 2 weeks after last injection, to hepatic tissue at different groups, protein expression of CTGF, TIMP-1, procol-α1and PC III is tested by immunohistochemical method and,mRNA expression of CTGF,TIMP-1,procol-α1 and PCIII is measured by real-time PCR. One-way ANOVA is used to comparison between-groups. Compared with model group, there is no obvious difference of mRNA expression among CTGF,TIMP-1,procol-α1,PC III and of protein expression among CTGF, TIMP-1, procol-α1, PC III in hepatic tissue at group injected with blank plasmid. Expression quantity of mRNA of CTGF, TIMP-1, procol-α1 and PCIII at group A, B and C decreases, protein expression of CTGF, TIMP-1, procol-α1, PC III in hepatic tissue is lower, where the inhibition of combination RNA interference group (group A) on procol-α1 mRNA transcription and procol-α1 protein expression is superior to that of single interference group (group B and C) (P<0.01 or P<0.05). RNA interference on CTGF and/or TIMP-1 is obviously a inhibiting factor for mRNA and protein expression of CTGF, TIMP-1, procol-α1 and PCIII. Combination RNA interference on genes of CTGF and TIMP-1 is superior to that of single RNA interference, and this could be a contribution for prevention of precancerous condition.
Expression and function of the atypical cadherin FAT1 in chronic liver disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E.

Highlights: Black-Right-Pointing-Pointer The expression of the atypical cadherin FAT1 is increased in chronic liver disease. Black-Right-Pointing-Pointer FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. Black-Right-Pointing-Pointer FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. Black-Right-Pointing-Pointer FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. -- Abstract: Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCsmore » are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NF{kappa}B activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.« less
Dwarfism and insulin resistance in male offspring caused by α1-adrenergic antagonism during pregnancy.

PubMed

Oelkrug, Rebecca; Herrmann, Beate; Geissler, Cathleen; Harder, Lisbeth; Koch, Christiane; Lehnert, Hendrik; Oster, Henrik; Kirchner, Henriette; Mittag, Jens

2017-10-01

Maternal and environmental factors control the epigenetic fetal programming of the embryo, thereby defining the susceptibility for metabolic or endocrine disorders in the offspring. Pharmacological interventions required as a consequence of gestational problems, e.g. hypertension, can potentially interfere with correct fetal programming. As epigenetic alterations are usually only revealed later in life and not detected in studies focusing on early perinatal outcomes, little is known about the long-term epigenetic effects of gestational drug treatments. We sought to test the consequences of maternal α1-adrenergic antagonism during pregnancy, which can occur e.g. during hypertension treatment, for the endocrine and metabolic phenotype of the offspring. We treated C57BL/6NCrl female mice with the α1-adrenergic antagonist prazosin during pregnancy and analyzed the male and female offspring for endocrine and metabolic abnormalities. Our data revealed that maternal α1-adrenergic blockade caused dwarfism, elevated body temperature, and insulin resistance in male offspring, accompanied by reduced IGF-1 serum concentrations as the result of reduced hepatic growth hormone receptor (Ghr) expression. We subsequently identified increased CpG DNA methylation at the transcriptional start site of the alternative Ghr promotor caused by the maternal treatment, which showed a strong inverse correlation to hepatic Ghr expression. Our results demonstrate that maternal α1-adrenergic blockade can constitute an epigenetic cause for dwarfism and insulin resistance. The findings are of immediate clinical relevance as combined α/β-adrenergic blockers are first-line treatment of maternal hypertension. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.
Ebselen pretreatment attenuates ischemia/reperfusion injury and prevents hyperglycemia by improving hepatic insulin signaling and β-cell survival in gerbils.

PubMed

Park, S; Kang, S; Kim, D S; Shin, B K; Moon, N R; Daily, J W

2014-08-01

Transient carotid artery occlusion causes ischemia/reperfusion (I/R) injury resulting in neuron and pancreatic β-cell death with consequential post-stroke hyperglycemia, which can lead to diabetes and may accelerate the development of Alzheimer's disease. Antioxidants have been shown to protect against the I/R injury and destruction of neurons. However, it is unknown whether the protection against I/R injury extends to the pancreatic β-cells. Therefore, we investigated whether treatment with ebselen, a glutathione peroxidase mimic, prevents neuronal and β-cell death following I/R in gerbils susceptible to stroke. After 28 days post artery occlusion, there was widespread neuronal cell death in the CA1 of the hippocampus and elevated IL-1β and TNF-α levels. Pretreatment with ebselen prevented the death by 56% and attenuated neurological damage (abnormal eyelid drooping, hair bristling, muscle tone, flexor reflex, posture, and walking patterns). Ischemic gerbils also exhibited impaired glucose tolerance and insulin sensitivity which induced post-stroke hyperglycemia associated with decreased β-cell mass due to increased β-cell apoptosis. Ebselen prevented the increased β-cell apoptosis, possibly by decreasing IL-1β and TNF-α in islets. Ischemia also attenuated hepatic insulin signaling, and expression of GLUT2 and glucokinase, whereas ebselen prevented the attenuation and suppressed gluconeogenesis by decreasing PEPCK expression. In conclusion, antioxidant protection by ebselen attenuated I/R injury of neurons and pancreatic β-cells and prevented subsequent impairment of glucose regulation that could lead to diabetes and Alzheimer's disease.
Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages.

PubMed

Moore, Sherri M; Holt, Vivian V; Malpass, Lillie R; Hines, Ian N; Wheeler, Michael D

2015-10-01

The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. Copyright © 2015 Elsevier Ltd. All rights reserved.
Hepatic lymphatics: anatomy and related diseases.

PubMed

Pupulim, Lawrence F; Vilgrain, Valérie; Ronot, Maxime; Becker, Christoph D; Breguet, Romain; Terraz, Sylvain

2015-08-01

The liver normally produces a large amount of lymph. It is estimated that between 25% and 50% of the lymph received by the thoracic duct comes from the liver. In normal conditions, hepatic lymphatics are not depicted on cross-sectional imaging. They are divided in lymphatics of deep system (lymphatics following the hepatic veins and the portal tract) and those of superficial system (convex surface and inferior surface). A variety of diseases may affect hepatic lymphatics and in general they manifest as lymphedema, lymphatic mass, or cystic lesions. Abnormal distended lymphatics are especially seen in periportal spaces as linear hypoattenuations on CT or strong linear hyperintensities on heavily T2-weighted MR imaging. Lymphatic tumor spread as in lymphoma and lymphangitic carcinomatosis manifests as periportal masses and regional lymph node enlargement. Lymphatic disruption after trauma or surgery is depicted as perihepatic fluid collections of lymph (lymphocele). Lymphatic malformation such as lymphangioma is seen on imaging as cystic spaces of variable size.
Long-term Dietary Macronutrients and Hepatic Gene Expression in Aging Mice.

PubMed

Gokarn, Rahul; Solon-Biet, Samantha M; Cogger, Victoria C; Cooney, Gregory J; Wahl, Devin; McMahon, Aisling C; Mitchell, James R; Mitchell, Sarah J; Hine, Christopher; de Cabo, Rafael; Raubenheimer, David; Simpson, Stephen J; Le Couteur, David G

2018-04-23

Nutrition influences both hepatic function and aging, but mechanisms are poorly understood. Here, the effects of lifelong, ad libitum-fed diets varying in macronutrients and energy on hepatic gene expression were studied. Gene expression was measured using Affymetrix mouse arrays in livers of 46 mice aged 15 months fed one of 25 diets varying in protein, carbohydrates, fat, and energy density from 3 weeks of age. Gene expression was almost entirely influenced by protein intake. Carbohydrate and fat intake had few effects on gene expression compared with protein. Pathways and processes associated with protein intake included those involved with mitochondrial function, metabolic signaling (PI3K-Akt, AMPK, mTOR) and metabolism of protein and amino acids. Protein intake had variable effects on genes associated with regulation of longevity and influenced by caloric restriction. Among the genes of interest with expression that were significantly associated with protein intake are Cth, Gls2, Igf1, and Nnmt, which were increased with higher protein intake, and Igf2bp2, Fgf21, Prkab2, and Mtor, which were increased with lower protein intake. Dietary protein has a powerful impact on hepatic gene expression in older mice, with some overlap with genes previously reported to be involved with regulation of longevity or caloric restriction.
β-Carotene-9′,10′-Oxygenase Status Modulates the Impact of Dietary Tomato and Lycopene on Hepatic Nuclear Receptor–, Stress-, and Metabolism-Related Gene Expression in Mice123

PubMed Central

Tan, Hsueh-Li; Moran, Nancy E.; Cichon, Morgan J.; Riedl, Ken M.; Schwartz, Steven J.; Erdman, John W.; Pearl, Dennis K.; Thomas-Ahner, Jennifer M.; Clinton, Steven K.

2014-01-01

Tomato and lycopene (ψ, ψ-carotene) consumption is hypothesized to protect against nonalcoholic steatohepatitis and hepatocarcinogenesis, processes that may depend upon diet and gene interactions. To investigate the interaction of tomato or lycopene feeding with β-carotene-9′,10′-monooxygenase (Bco2) on hepatic metabolic and signaling pathways, male wild-type (WT) and Bco2−/− mice (3-wk-old; n = 36) were fed semi-purified control, 10% tomato powder–containing, or 0.25% lycopene beadlet–containing diets for 3 wk. Serum lycopene concentrations were higher in lycopene- and tomato-fed Bco2−/− mice compared with WT (P = 0.03). Tomato- and lycopene-fed mice had detectable hepatic apolipoprotein (apo)-6′-, apo-8′-, and apo-12′-lycopenal concentrations. Hepatic expression of β-carotene-15,15’-monooxygenase was increased in Bco2−/− mice compared with WT (P = 0.02), but not affected by diet. Evaluation of hepatic gene expression by focused quantitative reverse transcriptase-polymerase chain reaction arrays for nuclear receptors and coregulators (84 genes) and stress and metabolism (82 genes) genes indicates that tomato feeding affected 31 genes (≥1.5-fold, P < 0.05) and lycopene feeding affected 19 genes, 16 of which were affected by both diets. Lycopene down-regulation of 7 nuclear receptors and coregulators, estrogen-related receptor-α, histone deacetylase 3, nuclear receptor coactivator 4, RevErbA-β, glucocorticoid receptor, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ, coactivator 1 β was dependent upon interaction with Bco2 status. Lycopene and tomato feeding induced gene expression patterns consistent with decreased lipid uptake, decreased cell proliferation and mitosis, down-regulated aryl hydrocarbon receptor signaling, and decreased expression of genes involved in retinoid X receptor heterodimer activation. Tomato feeding also caused expression changes consistent with down-regulation of DNA synthesis and terpenoid metabolism. These data suggest tomato components, particularly lycopene, affect hepatic gene expression, potentially affecting hepatic responses to metabolic, infectious, or chemical stress. PMID:24553694
Molecular diagnostics in the neoplasms of the pancreas, liver, gall bladder, and extrahepatic biliary tract.

PubMed

Weindel, Michael; Zulfiqar, Muhammad; Bhalla, Amarpreet; Shidham, Vinod B

2013-12-01

Pancreatic neoplasms, including ductal adenocarcinoma, intraductal papillary mucinous neoplasm, solid pseudopapillary neoplasm, pancreatic endocrine neoplasms, acinar cell carcinoma, and ampullary carcinoma, are associated with different genetic abnormalities. Liver neoplasms, including hepatic adenomas, hepatocellular carcinomas, and cholangiocarcinomas, are associated with identifiable risk factors and genetic changes. Gall bladder adenomas and adenocarcinomas arise from distinct molecular pathways. The molecular abnormalities seen in these tumors are not used routinely in the molecular diagnostic laboratory. Copyright © 2013 Elsevier Inc. All rights reserved.

Characterization of the regulation and function of zinc-dependent histone deacetylases during rodent liver regeneration.

PubMed

Huang, Jiansheng; Barr, Emily; Rudnick, David A

2013-05-01

The studies reported here were undertaken to define the regulation and functional importance of zinc-dependent histone deacetylase (Zn-HDAC) activity during liver regeneration using the mouse partial hepatectomy (PH) model. The results showed that hepatic HDAC activity was significantly increased in nuclear and cytoplasmic fractions following PH. Further analyses showed isoform-specific effects of PH on HDAC messenger RNA (mRNA) and protein expression, with increased expression of the class I HDACs, 1 and 8, and class II HDAC4 in regenerating liver. Hepatic expression of (class II) HDAC5 was unchanged after PH; however, HDAC5 exhibited transient nuclear accumulation in regenerating liver. These changes in hepatic HDAC expression, subcellular localization, and activity coincided with diminished histone acetylation in regenerating liver. The significance of these events was investigated by determining the effects of suberoylanilide hydroxyamic acid (SAHA, a specific inhibitor of Zn-HDAC activity) on hepatic regeneration. The results showed that SAHA treatment suppressed the effects of PH on histone deacetylation and hepatocellular bromodeoxyuridine (BrdU) incorporation. Further examination showed that SAHA blunted hepatic expression and activation of cell cycle signals downstream of induction of cyclin D1 expression in mice subjected to PH. The data reported here demonstrate isoform-specific regulation of Zn-HDAC expression, subcellular localization, and activity in regenerating liver. These studies also indicate that HDAC activity promotes liver regeneration by regulating hepatocellular cell cycle progression at a step downstream of cyclin D1 induction. Copyright © 2012 American Association for the Study of Liver Diseases.
Fructose, high fructose corn syrup, sucrose, and non-alcoholic liver disease

USDA-ARS?s Scientific Manuscript database

Nonalcoholic fatty liver disease (NAFLD), formerly called nonalcoholic steatohepatitis, is characterized by hepatic steatosis and abnormal triglyceride accumulation in liver cells. Its etiology, pathophysiology, and pathogenesis are still poorly understood. Some have suggested that the increased in...
Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

PubMed

Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

2016-11-01

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright Â© 2016. Published by Elsevier B.V.
Expression of TNF-alpha and immunohistochemical distribution of hepatic macrophage surface markers in carbon tetrachloride-induced chronic liver injury in rats.

PubMed

Orfila, C; Lepert, J C; Alric, L; Carrera, G; Beraud, M; Vinel, J P; Pipy, B

1999-10-01

In liver injury induced by carbon tetrachloride, secondary hepatic injury occurs from inflammatory processes originating from products released by activated Kupffer cells, which play a central role in hepatic inflammation. The purpose of our study was to demonstrate, in rats, the relationships between a function of the hepatic macrophages, TNF-alpha production and the state of activation of these cells, characterized by their phenotype, in the different phases of the process and development of fibrosis in a carbon tetrachloride-induced cirrhosis model. The immunohistochemical localization of proinflammatory cytokine TNF-alpha and surface surface makers (ED1 and ED2) was studied in hepatitis and cirrhosis in response to 3 and 9 weeks ingestion of carbon tetrachloride. After carbon tetrachloride ingestion, accompanying the increased necrosis, immunohistochemical analysis of liver tissue sections demonstrated the significantly increased number of cells expressing ED1, ED2 and TNF-alpha, compared to normal. The number of cells expressing the surface phenotypic markers of liver macrophages increased and this change was concomitantly associated with an increased cellular expression of TNF-alpha. Local macrophage proliferation and influx of newly recruited blood monocytes resulted in an increase of the macrophage population. The populational changes involved difference in functional activity and enhanced TNF-alpha expression. This cytokine expressed in the carbon tetrachloride-induced inflammatory process is associated with the development of fibrosis and may contribute to disease severity.
Carbohydrate intake and nonalcoholic fatty liver disease: fructose as a weapon of mass destruction

PubMed Central

Basaranoglu, Gokcen; Bugianesi, Elisabetta

2015-01-01

Excessive accumulation of triglycerides (TG) in liver, in the absence of significant alcohol consumption is nonalcoholic fatty liver disease (NAFLD). NAFLD is a significant risk factor for developing cirrhosis and an independent predictor of cardiovascular disease. High fructose corn syrup (HFCS)-containing beverages were associated with metabolic abnormalities, and contributed to the development of NAFLD in human trials. Ingested carbohydrates are a major stimulus for hepatic de novo lipogenesis (DNL) and are more likely to directly contribute to NAFLD than dietary fat. Substrates used for the synthesis of newly made fatty acids by DNL are primarily glucose, fructose, and amino acids. Epidemiological studies linked HFCS consumption to the severity of fibrosis in patients with NAFLD. New animal studies provided additional evidence on the role of carbohydrate-induced DNL and the gut microbiome in NAFLD. The excessive consumption of HFCS-55 increased endoplasmic reticulum stress, activated the stress-related kinase, caused mitochondrial dysfunction, and increased apoptotic activity in the liver. A link between dietary fructose intake, increased hepatic glucose transporter type-5 (Glut5) (fructose transporter) gene expression and hepatic lipid peroxidation, MyD88, TNF-α levels, gut-derived endotoxemia, toll-like receptor-4, and NAFLD was reported. The lipogenic and proinflammatory effects of fructose appear to be due to transient ATP depletion by its rapid phosphorylation within the cell and from its ability to raise intracellular and serum uric acid levels. However, large prospective studies that evaluated the relationship between fructose and NAFLD were not performed yet. PMID:26005677
Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice.

PubMed

Lerat, Hervé; Imache, Mohamed Rabah; Polyte, Jacqueline; Gaudin, Aurore; Mercey, Marion; Donati, Flora; Baudesson, Camille; Higgs, Martin R; Picard, Alexandre; Magnan, Christophe; Foufelle, Fabienne; Pawlotsky, Jean-Michel

2017-08-04

Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice

PubMed Central

Nørgaard, Rikke C.; Bindesbøll, Christian; Lucas, Christin; Dalen, Knut Tomas; Itkonen, Harri M.; Matthews, Jason; Nebb, Hilde I.; Grønning-Wang, Line M.

2017-01-01

Liver X receptors (LXRα/β) and carbohydrate response element-binding proteins (ChREBPα/β) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRα/β double knockout (LXRα−/−/β−/−) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPα activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXRα knockout (LXRα−/−) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXRα−/− mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebpβ, indicating reduced ChREBPα activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXRα−/− mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXRβ, suggesting a role for LXRβ in regulating ChREBPα activity upon fructose feeding. In conclusion, we propose that LXRα is an important regulator of hepatic lipogenesis and ChREBPα activity upon glucose, but not fructose feeding in mice. PMID:28661453
Induction of miR-96 by Dietary Saturated Fatty Acids Exacerbates Hepatic Insulin Resistance through the Suppression of INSR and IRS-1

PubMed Central

Yang, Won-Mo; Min, Kyung-Ho

2016-01-01

Obesity is defined as the excessive accumulation of body fat that ultimately leads to chronic metabolic diseases. Diets rich in saturated fatty acids (SFA) exacerbate obesity and hepatic steatosis, which increase the risk of hepatic insulin resistance and type 2 diabetes (T2DM). Although microRNAs (miRNAs) play an important role in a range of biological processes, the implications of SFA-induced miRNAs in metabolic dysregulation, particularly in the pathogenesis of hepatic insulin resistance, are not well understood. This study investigated the implications of miR-96, which is induced strongly by SFA, in the development of hepatic insulin resistance. The liver of HFD mice and the palmitate-treated hepatocytes exhibited an impairment of insulin signaling due to the significant decrease in INSR and IRS-1 expression. According to expression profiling and qRT-PCR analysis of the miRNAs, the expression level of miR-96 was higher in hepatocytes treated with palmitate. Moreover, miR-96 was also upregulated in the liver of HFD mice. Interestingly, miR-96 targeted the 3’UTRs of INSR and IRS-1 directly, and repressed the expression of INSR and IRS-1 at the post-transcriptional level. Accordingly, the overexpression of miR-96 was found to cause a significant decrease in INSR and IRS-1 expression, thereby leading to an impairment of insulin signaling and glycogen synthesis in hepatocytes. These results reveal a novel mechanism whereby miR-96 promotes the pathogenesis of hepatic insulin resistance resulted from SFA or obesity. PMID:28036389
Differential effects of low-fat and high-fat diets on fed-state hepatic triacylglycerol secretion, hepatic fatty acid profiles, and DGAT-1 protein expression in obese-prone Sprague-Dawley rats.

PubMed

Heden, Timothy D; Morris, E Matthew; Kearney, Monica L; Liu, Tzu-Wen; Park, Young-Min; Kanaley, Jill A; Thyfault, John P

2014-04-01

The purpose of this study was to compare the effects of short-term low-fat (LF) and high-fat (HF) diets on fed-state hepatic triacylglycerol (TAG) secretion, the content of proteins involved in TAG assembly and secretion, fatty acid oxidation (FAO), and the fatty acid profile of stored TAG. Using selectively bred obese-prone Sprague-Dawley rats, we directly measured fed-state hepatic TAG secretion, using Tyloxapol (a lipoprotein lipase inhibitor) and a standardized oral mixed meal (45% carbohydrate, 40% fat, 15% protein) bolus in animals fed a HF or LF diet for 2 weeks, after which the rats were maintained on their respective diet for 1 week (washout) prior to the liver being excised to measure protein content, FAO, and TAG fatty acid profiles. Hepatic DGAT-1 protein expression was ∼27% lower in HF- than in LF-fed animals (p < 0.05); the protein expression of all other molecules was similar in the 2 diets. The fed-state hepatic TAG secretion rate was ∼39% lower (p < 0.05) in HF- (4.62 ± 0.18 mmol·h(-1)) than in LF- (7.60 ± 0.57 mmol·h(-1)) fed animals. Hepatic TAG content was ∼2-fold higher (p < 0.05) in HF- (1.07 ± 0.15 nmol·g(-1) tissue) than in LF- (0.50 ± 0.16 nmol·g(-1) tissue) fed animals. In addition, the fatty acid profile of liver TAG in HF-fed animals closely resembled the diet, whereas in LF-fed animals, the fatty acid profile consisted of mostly de novo synthesized fatty acids. FAO was not altered by diet. LF and HF diets differentially alter fed-state hepatic TAG secretion, hepatic fatty acid profiles, and DGAT-1 protein expression.
Differential effects of low-fat and high-fat diets on fed-state hepatic triacylglycerol secretion, hepatic fatty acid profiles, and DGAT-1 protein expression in obese-prone Sprague–Dawley rats

PubMed Central

Heden, Timothy D.; Morris, E. Matthew; Kearney, Monica L.; Liu, Tzu-Wen; Park, Young-min; Kanaley, Jill A.; Thyfault, John P.

2015-01-01

The purpose of this study was to compare the effects of short-term low-fat (LF) and high-fat (HF) diets on fed-state hepatic triacylglycerol (TAG) secretion, the content of proteins involved in TAG assembly and secretion, fatty acid oxidation (FAO), and the fatty acid profile of stored TAG. Using selectively bred obese-prone Sprague–Dawley rats, we directly measured fed-state hepatic TAG secretion, using Tyloxapol (a lipoprotein lipase inhibitor) and a standardized oral mixed meal (45% carbohydrate, 40% fat, 15% protein) bolus in animals fed a HF or LF diet for 2 weeks, after which the rats were maintained on their respective diet for 1 week (washout) prior to the liver being excised to measure protein content, FAO, and TAG fatty acid profiles. Hepatic DGAT-1 protein expression was ~27% lower in HF- than in LF-fed animals (p < 0.05); the protein expression of all other molecules was similar in the 2 diets. The fed-state hepatic TAG secretion rate was ~39% lower (p < 0.05) in HF- (4.62 ± 0.18 mmol·h−1) than in LF- (7.60 ± 0.57 mmol·h−1) fed animals. Hepatic TAG content was ~2-fold higher (p < 0.05) in HF- (1.07 ± 0.15 nmol·g−1 tissue) than in LF- (0.50 ± 0.16 nmol·g−1 tissue) fed animals. In addition, the fatty acid profile of liver TAG in HF-fed animals closely resembled the diet, whereas in LF-fed animals, the fatty acid profile consisted of mostly de novo synthesized fatty acids. FAO was not altered by diet. LF and HF diets differentially alter fed-state hepatic TAG secretion, hepatic fatty acid profiles, and DGAT-1 protein expression. PMID:24669989
Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model

PubMed Central

Okamoto, Toshiaki; Koda, Masahiko; Miyoshi, Kennichi; Onoyama, Takumi; Kishina, Manabu; Matono, Tomomitsu; Sugihara, Takaaki; Hosho, Keiko; Okano, Junichi; Isomoto, Hajime; Murawaki, Yoshikazu

2016-01-01

AIM To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model. METHODS Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver. RESULTS In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups. CONCLUSION Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis. PMID:27574547
Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model.

PubMed

Okamoto, Toshiaki; Koda, Masahiko; Miyoshi, Kennichi; Onoyama, Takumi; Kishina, Manabu; Matono, Tomomitsu; Sugihara, Takaaki; Hosho, Keiko; Okano, Junichi; Isomoto, Hajime; Murawaki, Yoshikazu

2016-08-08

To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model. Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver. In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups. Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.
Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics

PubMed Central

Wang, Li; Collins, Carol; Kelly, Edward J.; Chu, Xiaoyan; Ray, Adrian S.; Salphati, Laurent; Xiao, Guangqing; Lee, Caroline; Lai, Yurong; Liao, Mingxiang; Mathias, Anita; Evers, Raymond; Humphreys, William; Hop, Cornelis E. C. A.; Kumer, Sean C.

2016-01-01

Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance–associated protein (MRP)2, MRP3, MRP4, sodium taurocholate–cotransporting polypeptide (NTCP), organic anion–transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers. Compared with control livers, the yield of membrane protein from alcoholic and hepatitis C cirrhosis livers was significantly reduced by 56 and 67%, respectively. The impact of liver cirrhosis on transporter protein expression was transporter-dependent. Generally, reduced protein expression (per gram of liver) was found in alcoholic cirrhosis livers versus control livers, with the exception that the expression of MRP3 was increased, whereas no change was observed for MATE1, MRP2, OATP2B1, and P-gp. In contrast, the impact of hepatitis C cirrhosis on protein expression of transporters (per gram of liver) was diverse, showing an increase (MATE1), decrease (BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp), or no change (BCRP, MRP3, OATP1B1, and 2B1). The expression of hepatobiliary transporter protein differed in different diseases (alcoholic versus hepatitis C cirrhosis). Finally, incorporation of protein expression of OATP1B1 in alcoholic cirrhosis into the Simcyp physiologically based pharmacokinetics cirrhosis module improved prediction of the disposition of repaglinide in liver cirrhosis patients. These transporter expression data will be useful in the future to predict transporter-mediated drug disposition in liver cirrhosis patients. PMID:27543206
Coexpression of CD14 and CD326 discriminate hepatic precursors in the human fetal liver.

PubMed

Fomin, Marina E; Tai, Lung-Kuo; Bárcena, Alicia; Muench, Marcus O

2011-07-01

The molecular and cellular profile of liver cells during early human development is incomplete, complicating the isolation and study of hepatocytes, cholangiocytes, and hepatic stem cells from the complex amalgam of hepatic and hematopoietic cells, that is, the fetal liver. Epithelial cell adhesion molecule, CD326, has emerged as a marker of hepatic stem cells, and lipopolysaccharide receptor CD14 is known to be expressed on adult hepatocytes. Using flow cytometry, we studied the breadth of CD326 and CD14 expression in midgestation liver. Both CD45(+) hematopoietic and CD45(-) nonhematopoietic cells expressed CD326. Moreover, diverse cell types expressing CD326 were revealed among CD45(-) cells by costaining for CD14. Fluorescence-activated cell sorting was used to isolate nonhematopoietic cells distinguished by expression of high levels of CD326 and low CD14 (CD326(++)CD14(lo)), which were characterized for gene expression associated with liver development. CD326(++)CD14(lo) cells expressed the genes albumin, α-fetoprotein, hepatic nuclear factor 3α, prospero-related homeobox 1, cytochrome P450 3A7, α(1)-antitrypsin, and transferrin. Proteins expressed included cell-surface CD24, CD26, CD29, CD34, CD49f, CD243, and CD324 and, in the cytoplasm, cytokeratins-7/8 (CAM 5.2 antigen) and some cytokeratin-19. Cultured CD326(++)CD14(lo) cells yielded albumin(+) hepatocytes, cytokeratin-19(+) cholangiocytes, and hepatoblasts expressing both markers. Using epifluorescence microscopy we observed CD326 and CD14 expression on fetal hepatocytes comprising the liver parenchyma, as well as on cells associated with ductal plates and surrounding large vessels. These findings indicate that expression of CD14 and CD326 can be used to identify functionally distinct subsets of fetal liver cells, including CD326(++)CD14(lo) cells, representing a mixture of parenchymal cells, cholangiocytes, and hepatoblasts.
Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity

PubMed Central

Wang, Yun; Botolin, Daniela; Xu, Jinghua; Christian, Barbara; Mitchell, Ernestine; Jayaprakasam, Bolleddula; Nair, Muraleedharan; Peters, Jeffery M.; Busik, Julia; Olson, L. Karl; Jump, Donald B.

2009-01-01

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor α (PPARα)-deficient mice establish that PPARα was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Δ5 desaturase (Δ5D), Δ6D, and Δ9D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Δ5D, Δ6D, and Δ9D. Only Δ9D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of L-type pyruvate kinase, Δ9D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Δ9D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lepob/ob), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Δ9D expression and the massive accumulation of monoun-saturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARα, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition. PMID:16790840
Hepatic expression of spermatogenic genes and their transiently remarkable downregulations in Wistar-Kyoto rats in response to lead-nitrate administration: strain-difference in the gene expression patterns.

PubMed

Nemoto, Kiyomitsu; Ito, Sei; Yoshida, Chiaki; Miyata, Misaki; Kojima, Misaki; Degawa, Masakuni

2011-06-01

Administration of lead ion (Pb) to rats and mice affects hepatic functions such as the induction of hepatic cell proliferation and upregulation of cholesterol biosynthesis. To identify the genes for which expression changes in response to Pb-administration, we analyzed hepatic gene expression patterns in stroke-prone spontaneously hypertensive rat (SHRSP), its normotensive control, Wistar-Kyoto rat (WKY), and Spraque-Dawley (SD) rat strains, 3, 6, and 12 hr later after single i.v. injection of lead nitrate (LN) at a dose of 100 µmol using a DNA microarray technique. The data analysis demonstrated that the expression of a great number of genes was transiently and remarkably downregulated 3 hr after LN-injection, and then recovered to control levels only in LN-injected WKY. These normal hepatic expression levels in WKY and SHRSP were much higher than those in SD rats. Furthermore, most of these genes were ones thought to be expressed specifically in the spermatids and/or testes; i.e. genes encoding protamin 1, transition protein 1, and transition protein 2. These findings suggest that the regulation system common to expression of all of these genes could be a target site of Pb-toxic action, at least, in the liver of WKY, and that this system might be similar to the system essential for spermatogenesis, especially spermiogenesis, in the testis. In addition, it appears that clarifying the cause of the difference between the systems of WKY and SHRSP might aid in identifying the pathologic genes in SHRSP. Finally, it will be an important to clarify how the products of the genes related to spermatogenesis, including spermiogenesis, are functional in the livers of WKY and SHRSP.
Duodenal-jejunal bypass surgery up-regulates the expression of the hepatic insulin signaling proteins and the key regulatory enzymes of intestinal gluconeogenesis in diabetic Goto-Kakizaki rats.

PubMed

Sun, Dong; Wang, Kexin; Yan, Zhibo; Zhang, Guangyong; Liu, Shaozhuang; Liu, Fengjun; Hu, Chunxiao; Hu, Sanyuan

2013-11-01

Duodenal-jejunal bypass (DJB), which is not routinely applied in metabolic surgery, is an effective surgical procedure in terms of type 2 diabetes mellitus resolution. However, the underlying mechanisms are still undefined. Our aim was to investigate the diabetic improvement by DJB and to explore the changes in hepatic insulin signaling proteins and regulatory enzymes of gluconeogenesis after DJB in a non-obese diabetic rat model. Sixteen adult male Goto-Kakizaki rats were randomly divided into DJB and sham-operated groups. The body weight, food intake, hormone levels, and glucose metabolism were measured. The levels of protein expression and phosphorylation of insulin receptor-beta (IR-β) and insulin receptor substrate 2 (IRS-2) were evaluated in the liver. We also detected the expression of key regulatory enzymes of gluconeogenesis [phosphoenoylpyruvate carboxykinase-1 (PCK1), glucose-6-phosphatase-alpha (G6Pase-α)] in small intestine and liver. DJB induced significant diabetic improvement with higher postprandial glucagons-like peptide 1, peptide YY, and insulin levels, but without weight loss. The DJB group exhibited increased expression and phosphorylation of IR-β and IRS-2 in liver, up-regulated the expression of PCK1 and G6Pase-α in small intestine, and down-regulated the expression of these enzymes in liver. DJB is effective in up-regulating the expression of the key proteins in the hepatic insulin signaling pathway and the key regulatory enzymes of intestinal gluconeogenesis and down-regulating the expression of the key regulatory enzymes of hepatic gluconeogenesis without weight loss. Our study helps to reveal the potential role of hepatic insulin signaling pathway and intestinal gluconeogenesis in ameliorating insulin resistance after metabolic surgery.
Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

PubMed

Liu, Chun-Hung; Chan, Kun-Ming; Chiang, Tsaiyu; Liu, Jia-Yu; Chern, Guann-Gen; Hsu, Fu-Fei; Wu, Yu-Hsuan; Liu, Ya-Chi; Chen, Yunching

2016-07-05

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.
The Relationship between Selenoprotein P and Glucose Metabolism in Experimental Studies

PubMed Central

Mao, Jinyuan; Teng, Weiping

2013-01-01

Selenium is an essential trace element in the diet of mammals which is important for many physiological functions. However, a number of epidemiological studies have suggested that high selenium status is a possible risk factor for the development of type 2 diabetes, although they cannot distinguish between cause and effect. Selenoprotein P (Sepp1) is central to selenium homeostasis and widely expressed in the organism. Here we review the interaction between Sepp1 and glucose metabolism with an emphasis on experimental evidence. In models with or without gene modification, glucose and insulin can regulate Sepp1 expression in the pancreas and liver, and vice versa. Especially in the liver, Sepp1 is regulated virtually like a gluconeogenic enzyme. Combining these data suggests that there could be a feedback regulation between hepatic Sepp1 and pancreatic insulin and that increasing circulating Sepp1 might be the result rather than the cause of abnormal glucose metabolism. Future studies specifically designed to overexpress Sepp1 are needed in order to provide a more robust link between Sepp1 and type 2 diabetes. PMID:23760059
Canine Breed-Specific Hepatopathies.

PubMed

Watson, Penny

2017-05-01

Canine hepatopathies, both congenital and acquired, arise from an interaction between genes and environment. Many show increased breed prevalences. This article reviews the current understanding on breed predispositions for congenital portosystemic shunts; microvascular dysplasia and portal vein hypoplasia; ductal plate abnormalities (congenital hepatic fibrosis and Caroli disease); chronic hepatitis (both copper associated and idiopathic); vacuolar hepatopathies; and gallbladder mucocele. Although all these diseases can occur in many breeds and crossbreeds, understanding breed predispositions helps recognition and will guide future research to improve understanding of causes and treatments. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Imaging features of non-traumatic vascular liver emergencies.

PubMed

Onur, Mehmet Ruhi; Karaosmanoglu, Ali Devrim; Akca, Onur; Ocal, Osman; Akpinar, Erhan; Karcaaltincaba, Musturay

2017-05-01

Acute non-traumatic liver disorders can originate from abnormalities of the hepatic artery, portal vein and hepatic veins. Ultrasonography and computed tomography can be used in non-traumatic acute vascular liver disorders according to patient status, indication and appropriateness of imaging modality. Awareness of the imaging findings, in the appropriate clinical context, is crucial for prompt and correct diagnosis, as delay may cause severe consequences with significant morbidity and mortality. This review article will discuss imaging algorithms, and multimodality imaging findings for suspected acute vascular disorders of the liver.
Biochemical studies on hepatic involvement in infectious mononucleosis

PubMed Central

Baron, D. N.; Bell, Joyce L.; Dunnet, W. N.

1965-01-01

Eighty cases of infectious mononucleosis have been investigated by serum enzyme studies and other liver function tests. Maximum abnormalities occurred between the second and fourth weeks of illness and all tests were usually normal by the sixth week. Serum isocitric dehydrogenase activity was increased in 93% of cases and serum glutamic-oxaloacetic transaminase in 74%. Conventional liver function tests were less sensitive. Serum bilirubin was above normal in 40% of cases; in 17% of cases the increase was sufficient to show as clinical jaundice. No patient has developed chronic hepatitis. PMID:14276157
Hepatic CT image query using Gabor features

NASA Astrophysics Data System (ADS)

Zhao, Chenguang; Cheng, Hongyan; Zhuang, Tiange

2004-07-01

A retrieval scheme for liver computerize tomography (CT) images based on Gabor texture is presented. For each hepatic CT image, we manually delineate abnormal regions within liver area. Then, a continuous Gabor transform is utilized to analyze the texture of the pathology bearing region and extract the corresponding feature vectors. For a given sample image, we compare its feature vector with those of other images. Similar images with the highest rank are retrieved. In experiments, 45 liver CT images are collected, and the effectiveness of Gabor texture for content based retrieval is verified.
Dietary Supplementation of Blueberry Juice Enhances Hepatic Expression of Metallothionein and Attenuates Liver Fibrosis in Rats

PubMed Central

Wang, Yuping; Cheng, Mingliang; Zhang, Baofang; Nie, Fei; Jiang, Hongmei

2013-01-01

Aim To investigate the effect of blueberry juice intake on rat liver fibrosis and its influence on hepatic antioxidant defense. Methods Rabbiteye blueberry was used to prepare fresh juice to feed rats by daily gastric gavage. Dan-shao-hua-xian capsule (DSHX) was used as a positive control for liver fibrosis protection. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injection of CCl4 and feeding a high-lipid/low-protein diet for 8 weeks. Hepatic fibrosis was evaluated by Masson staining. The expression of α-smooth muscle actin (α-SMA) and collagen III (Col III) were determined by immunohistochemical techniques. The activities of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenates were determined. Metallothionein (MT) expression was detected by real-time RT-PCR and immunohistochemical techniques. Results Blueberry juice consumption significantly attenuates CCl4-induced rat hepatic fibrosis, which was associated with elevated expression of metallothionein (MT), increased SOD activity, reduced oxidative stress, and decreased levels of α-SMA and Col III in the liver. Conclusion Our study suggests that dietary supplementation of blueberry juice can augment antioxidative capability of the liver presumably via stimulating MT expression and SOD activity, which in turn promotes HSC inactivation and thus decreases extracellular matrix collagen accumulation in the liver, and thereby alleviating hepatic fibrosis. PMID:23554912
Expression of inflammation-related genes is altered in gastric tissue of patients with advanced stages of NAFLD.

PubMed

Mehta, Rohini; Birerdinc, Aybike; Neupane, Arpan; Shamsaddini, Amirhossein; Afendy, Arian; Elariny, Hazem; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

2013-01-01

Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD.
Expression of Inflammation-Related Genes Is Altered in Gastric Tissue of Patients with Advanced Stages of NAFLD

PubMed Central

Mehta, Rohini; Birerdinc, Aybike; Neupane, Arpan; Shamsaddini, Amirhossein; Afendy, Arian; Elariny, Hazem; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M.

2013-01-01

Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD. PMID:23661906
Dynamic gene expression changes precede dioxin-induced liver pathogenesis in medaka fish.

PubMed

Volz, David C; Hinton, David E; Law, J McHugh; Kullman, Seth W

2006-02-01

A major challenge for environmental genomics is linking gene expression to cellular toxicity and morphological alteration. Herein, we address complexities related to hepatic gene expression responses after a single injection of the aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and illustrate an initial stress response followed by cytologic and adaptive changes in the teleost fish medaka. Using a custom 175-gene array, we find that overall hepatic gene expression and histological changes are strongly dependent on dose and time. The most pronounced dioxin-induced gene expression changes occurred early and preceded morphologic alteration in the liver. Following a systematic search for putative Ah response elements (AHREs) (5'-CACGCA-3') within 2000 bp upstream of the predicted transcriptional start site, the majority (87%) of genes screened in this study did not contain an AHRE, suggesting that gene expression was not solely dependent on AHRE-mediated transcription. Moreover, in the highest dosage, we observed gene expression changes associated with adaptation that persisted for almost two weeks, including induction of a gene putatively identified as ependymin that may function in hepatic injury repair. These data suggest that the cellular response to dioxin involves both AHRE- and non-AHRE-mediated transcription, and that coupling gene expression profiling with analysis of morphologic pathogenesis is essential for establishing temporal relationships between transcriptional changes, toxicity, and adaptation to hepatic injury.
Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial.

PubMed

Buchman, A L; Ament, M E; Sohel, M; Dubin, M; Jenden, D J; Roch, M; Pownall, H; Farley, W; Awal, M; Ahn, C

2001-01-01

Previous studies have shown that plasma free choline concentrations are significantly decreased in many long-term home total parenteral nutrition (TPN) patients. Furthermore, low choline status has been associated with both hepatic morphologic and hepatic aminotransferase abnormalities. A preliminary pilot study suggested choline-supplemented TPN may be useful in reversal of these hepatic abnormalities. Fifteen patients (10 M, 5 F) who had required TPN for > or =80% of their nutritional needs were randomized to receive their usual TPN (n = 8), or TPN to which 2 g choline chloride had been added (n = 7) for 24 weeks. Baseline demographic data were similar between groups. Patients had CT scans of the liver and spleen, and blood for plasma free and phospholipid-bound choline, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma glutamyl transferase (GGT), bilirubin, serum lipids, complete blood count (CBC), and chemistry profile obtained at baseline, and weeks 2, 4, 6, 12, 16, 20, 24, and 34. CT scans were analyzed for Hounsfield unit (HU) densities. There were no significant differences in any measured parameters after 2 weeks. However, at 4 weeks, a significant difference in liver HU between groups was observed (13.3+/-5.0 HU [choline] vs 5.8+/-5.2 HU [placebo], p = .04). This significant trend continued through week 24. Recurrent hepatic steatosis and decreased HU were observed at week 34, 10 weeks after choline supplementation had been discontinued. A significant increase in the liver-spleen differential HU was also observed in the choline group (10.6+/-6.2 HU [choline] vs 1.3+/-3.3 HU [placebo], p = .01). Serum ALT decreased significantly (p = .01 to .05) in the choline group vs placebo at weeks 6,12, 20, and 24. Serum AST was significantly decreased in the choline group by week 24 (p = .02). The serum alkaline phosphatase was significantly reduced in the choline group at weeks 2, 12, 20, 24, and 34 (p = .02 to 0.07). Total bilirubin was normal in these patients and remained unchanged during the study. Serum GGT tended to decrease more in the choline group, but the greater decrease was not statistically significant. Choline deficiency is a significant contributor to the development of TPN-associated liver disease. The data suggest choline is a required nutrient for long-term home TPN patients.
Involvement of hepatic peroxisome proliferator-activated receptor α/γ in the therapeutic effect of osthole on high-fat and high-sucrose-induced steatohepatitis in rats.

PubMed

Zhao, Xi; Xue, Jie; Wang, Xiao-Li; Zhang, Yan; Deng, Min; Xie, Mei-Lin

2014-09-01

Our previous studies have indicated that osthole may be a dual agonist of peroxisome proliferator-activated receptor (PPAR) α/γ and decrease the hepatic lipid accumulation. But there has been no report about therapeutic effect on steatohepatitis. In the present study, we investigated the action of osthole and its potential mechanisms. The rats with steatohepatitis induced by orally feeding high-fat and high-sucrose emulsion were given osthole 5-20 mg/kg for 4 weeks. The results showed that after treatment with osthole, the serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride (TG), and free fatty acid (FFA) levels, the hepatic TG, FFA, tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6, and interleukin-8 contents, and the hepatic weight and liver index were lowered, especially in the osthole 20 mg/kg group. The histological evaluation of liver specimens demonstrated that osthole might improve the hepatic steatosis and inflammation. At the same time, osthole treatment increased the hepatic protein expressions of PPARα/γ and lipoprotein lipase, and decreased the hepatic protein expressions of nuclear factor-κB, sterol regulatory element-binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase. These findings demonstrate that osthole is effective in treating rat steatohepatitis, and the PPARα/γ may be involved in the osthole-induced modulation of hepatic lipogenic gene expressions and inflammatory cytokine production. Copyright © 2014 Elsevier B.V. All rights reserved.
The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation.

PubMed

Li, Min; Tang, Yuxiao; Wu, Lusha; Mo, Fengfeng; Wang, Xin; Li, Hongxia; Qi, Ruirui; Zhang, Hongwei; Srivastava, Arun; Ling, Chen

2017-08-24

Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe -/- ) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy. © 2017 by The American Society of Hematology.
Bariatric surgery emphasizes biological sex differences in rodent hepatic lipid handling.

PubMed

Grayson, Bernadette E; Gutierrez-Aguilar, Ruth; Sorrell, Joyce E; Matter, Emily K; Adams, Michelle R; Howles, Philip; Karns, Rebekah; Seeley, Randy J; Sandoval, Darleen A

2017-01-01

Eighty percent of patients who receive bariatric surgery are women, yet the majority of preclinical studies are in male rodents. Because sex differences drive hepatic gene expression and overall lipid metabolism, we sought to determine whether sex differences were also apparent in these endpoints in response to bariatric surgery. Two cohorts of age-matched virgin male and female Long-Evans rats were placed on a high fat diet for 3 weeks and then received either Sham or vertical sleeve gastrectomy (VSG), a surgery which resects 80% of the stomach with no intestinal rearrangement. Each sex exhibited significantly decreased body weight due to a reduction in fat mass relative to Sham controls ( p < 0.05). Microarray and follow-up qPCR on liver revealed striking sex differences in gene expression after VSG that reflected a down-regulation of hepatic lipid metabolism and an up-regulation of hepatic inflammatory pathways in females vs. males after VSG. While the males had a significant reduction in hepatic lipids after VSG, there was no reduction in females. Ad lib -fed and fasting circulating triglycerides, and postprandial chylomicron production were significantly lower in VSG relative to Sham animals of both sexes ( p < 0.01). However, hepatic VLDL production, highest in sham-operated females, was significantly reduced by VSG in females but not males. Taken together, although both males and females lose weight and improve plasma lipids, there are large-scale sex differences in hepatic gene expression and consequently hepatic lipid metabolism after VSG.
Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2.

PubMed

Gao, Qiang; Gu, Yunyan; Jiang, Yanan; Fan, Li; Wei, Zixiang; Jin, Haobin; Yang, Xirui; Wang, Lijuan; Li, Xuguang; Tai, Sheng; Yang, Baofeng; Liu, Yan

2018-05-22

Long non-coding RNAs (lncRNAs) are a new class of regulators of various human diseases. This study was designed to explore the potential role of lncRNAs in experimental hepatic damage. In vivo hepatic damage in mice and in vitro hepatocyte damage in AML12 and NCTC1469 cells were induced by carbon tetrachloride (CCl 4 ) treatments. Expression profiles of lncRNAs and mRNAs were analyzed by microarray. Bioinformatics analyses were conducted to predict the potential functions of differentially expressed lncRNAs with respect to hepatic damage. Overexpression of lncRNA Gm2199 was achieved by transfection of the pEGFP-N1-Gm2199 plasmid in vitro and adeno-associated virus-Gm2199 in vivo. Cell proliferation and viability was detected by cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assay. Protein and mRNA expressions of extracellular signal-regulated kinase-1/2 (ERK1/2) were detected by western blot and quantitative real-time reverse-transcription PCR (qRT-PCR). Microarray analysis identified 190 and 148 significantly differentially expressed lncRNAs and mRNAs, respectively. The analyses of lncRNA-mRNA co-expression and lncRNA-biological process networks unraveled potential roles of the differentially expressed lncRNAs including Gm2199 in the pathophysiological processes leading to hepatic damage. Gm2199 was downregulated in both damaged livers and hepatocyte lines. Overexpression of Gm2199 restored the reduced proliferation of damaged hepatocyte lines and increased the expression of ERK1/2. Overexpression of Gm2199 also promoted the proliferation and viability of normal hepatocyte lines and increased the level of p-ERK1/2. Overexpression of Gm2199 in vivo also protected mouse liver injury induced by CCl 4 , evidenced by more proliferating hepatocytes, less serum alanine aminotransferase, less serum aspartate aminotransferase, and decreased hepatic hydroxyproline. The ability of Gm2199 to maintain hepatic proliferation capacity indicates it as a novel anti-liver damage lncRNA.
Single administration of recombinant IL‐6 restores the gene expression of lipogenic enzymes in liver of fasting IL‐6‐deficient mice

PubMed Central

Gavito, AL; Cabello, R; Suarez, J; Serrano, A; Pavón, F J; Vida, M; Romero, M; Pardo, V; Bautista, D; Arrabal, S; Decara, J; Cuesta, AL; Valverde, A M; Rodríguez de Fonseca, F

2016-01-01

Background and Purpose Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL‐6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL‐6 in mediating fasting/re‐feeding changes in the expression of hepatic lipogenic enzymes. Experimental Approach Gene and protein expression of lipogenic enzymes were examined in livers of wild‐type (WT) and IL‐6‐deficient (IL‐6−/−) mice during fasting and re‐feeding conditions. Effects of exogenous IL‐6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL‐6 responses was investigated by using siRNA in human HepG2 cells. Key Results During feeding, the up‐regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL‐6−/− mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL‐6−/− mice. Protein levels of hepatic lipogenic enzymes were lower in IL‐6−/− than in WT mice at the end of the fasting period. In WT, circulating IL‐6 levels paralleled gene expression of hepatic lipogenic enzymes. IL‐6 administration in vivo and in vitro showed that IL‐6‐mediated signalling was associated with the up‐regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL‐6 mediated up‐regulation of lipogenic gene transcription levels. Conclusions and Implications IL‐6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3‐associated signalling cytokines, particularly against steatosis, should be undertaken with caution. PMID:26750868
Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

PubMed

Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo-Yeon; Kim, Gyu Hee; Lee, DaeYeon; Lee, Yoo Jeong; Song, Eun Hyun; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won-Ho

2017-08-01

Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D. Copyright © 2017 European Association for the Study of the Liver. All rights reserved.
Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver.

PubMed

Rojas-Feria, María; Castro, Manuel; Suárez, Emilio; Ampuero, Javier; Romero-Gómez, Manuel

2013-11-14

Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn's disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.
Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity

USDA-ARS?s Scientific Manuscript database

The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid tran...
ALTERED HEPATIC GENE EXPRESSION IN MORBIDLY OBESE WOMEN AND ITS IMPLICATIONS FOR SUSCEPTIBILITY TO OTHER DISEASES

EPA Science Inventory

The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women un...
The Vagal Nerve Stimulates Activation of the Hepatic Progenitor Cell Compartment via Muscarinic Acetylcholine Receptor Type 3

PubMed Central

Cassiman, David; Libbrecht, Louis; Sinelli, Nicoletta; Desmet, Valeer; Denef, Carl; Roskams, Tania

2002-01-01

In the rat the hepatic branch of the nervus vagus stimulates proliferation of hepatocytes after partial hepatectomy and growth of bile duct epithelial cells after bile duct ligation. We studied the effect of hepatic vagotomy on the activation of the hepatic progenitor cell compartment in human and rat liver. The number of hepatic progenitor cells and atypical reactive ductular cells in transplanted (denervated) human livers with hepatitis was significantly lower than in innervated matched control livers and the number of oval cells in vagotomized rat livers with galactosamine hepatitis was significantly lower than in livers of sham-operated rats with galactosamine hepatitis. The expression of muscarinic acetylcholine receptors (M1-M5 receptor) was studied by immunohistochemistry and reverse transcriptase-polymerase chain reaction. In human liver, immunoreactivity for M3 receptor was observed in hepatic progenitor cells, atypical reactive ductules, intermediate hepatocyte-like cells, and bile duct epithelial cells. mRNA for the M1-M3 and the M5 receptor, but not the M4 receptor, was detected in human liver homogenates. In conclusion, the hepatic vagus branch stimulates activation of the hepatic progenitor cell compartment in diseased liver, most likely through binding of acetylcholine to the M3 receptor expressed on these cells. These findings may be of clinical importance for patients with a transplant liver. PMID:12163377
Review: Occult hepatitis C virus infection: still remains a controversy.

PubMed

Vidimliski, Pavlina Dzekova; Nikolov, Igor; Geshkovska, Nadica Matevska; Dimovski, Aleksandar; Rostaing, Lionel; Sikole, Aleksandar

2014-09-01

Occult hepatitis C virus (HCV) infection is characterized by the presence of HCV RNA in the liver cells or peripheral blood mononuclear cells of the patients whose serum samples test negative for HCV RNA, with or without presence of HCV antibodies. The present study reviews the existing literature on the persistence of occult hepatitis C virus infection, with description of the clinical characteristics and methods for identification of occult hepatitis C. Occult hepatitis C virus infection was detected in patients with abnormal results of liver function tests of unknown origin, with HCV antibodies and HCV RNA negativity in serum, and also in patients with spontaneous or treatment-induced recovery from hepatitis C. The viral replication in the liver cells and/or peripheral blood mononuclear cells was present in all clinical presentations of occult hepatitis C. The peripheral blood mononuclear cells represent an extra-hepatic site of HCV replication. The reason why HCV RNA was not detectable in the serum of patients with occult hepatitis C, could be the low number of circulating viral particles not detectable by the diagnostic tests with low sensitivity. It is uncertain whether occult hepatitis C is a different clinical entity or just a form of chronic hepatitis C virus infection. Data accumulated over the last decade demonstrated that an effective approach to the diagnosis of HCV infection would be the implementation of more sensitive HCV RNA diagnostic assays, and also, examination of the presence of viral particles in the cells of the immune system. © 2014 Wiley Periodicals, Inc.
Increasing cyanosis early after cavopulmonary connection caused by abnormal systemic venous channels.

PubMed

Gatzoulis, M A; Shinebourne, E A; Redington, A N; Rigby, M L; Ho, S Y; Shore, D F

1995-02-01

To show that abnormal systemic venous channels in patients who undergo cavopulmonary anastomoses can become manifest and haemodynamically important only after surgery despite detailed preoperative investigation. Descriptive study of patients fulfilling the above criteria selected from hospital records over the past three years. A tertiary referral centre. Of the three cases identified, two were isomeric, one with left atrial isomerism and hemiazygos continuation of the inferior vena cava who underwent bilateral bidirectional Glenn anastomoses and one with right isomerism who underwent total cavopulmonary anastomosis. Case 3 had absent left atrioventricular connection with a hypoplastic left lung and underwent a classic right Glenn procedure. All three cases presented with progressive cyanosis in the early postoperative period. Postoperative angiography in case 1 showed a remnant of a left inferior vena cava draining to the atrium to have become grossly dilated causing cyanosis, which resolved after redirection of this vessel and of the hepatic veins into the right pulmonary artery with an intra-atrial baffle. Cyanosis in case 2 was caused by intra-hepatic shunting to a hepatic vein draining to the left of the intra-atrial baffle. The diagnosis was made at necropsy, being overlooked on postoperative angiography. Repeat angiography in case 3 showed progressive dilatation of a small left superior vena cava to coronary sinus. Test occlusion with a view to embolisation revealed hitherto an undemonstrated hemiazygos continuation of inferior caval to brachiocephalic vein. The patient underwent surgical ligation of these two venous channels. Despite appropriate investigation some "abnormal" venous pathways manifest themselves, dilate, and become haemodynamically important only after surgical cavopulmonary anastomoses. In the presence of early postoperative cyanosis "new" systemic venous collateral channels should be considered as a possible cause, which may require reintervention.

Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats.

PubMed

Liu, Chih-Wei; Tsai, Hung-Cheng; Huang, Chia-Chang; Tsai, Chang-Youh; Su, Yen-Bo; Lin, Ming-Wei; Lee, Kuei-Chuan; Hsieh, Yun-Cheng; Li, Tzu-Hao; Huang, Shiang-Fen; Yang, Ying-Ying; Hou, Ming-Chih; Lin, Han-Chieh; Lee, Fa-Yauh; Lee, Shou-Dong

2018-05-01

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.
Increased hepatic mitochondrial FA oxidation reduces plasma and liver TG levels and is associated with regulation of UCPs and APOC-III in rats

PubMed Central

Lindquist, Carine; Bjørndal, Bodil; Rossmann, Christine Renate; Tusubira, Deusdedit; Svardal, Asbjørn; Røsland, Gro Vatne; Tronstad, Karl Johan; Hallström, Seth; Berge, Rolf Kristian

2017-01-01

Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of β-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for β-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered. PMID:28473603
Effect of Liver Disease on Hepatic Transporter Expression and Function.

PubMed

Thakkar, Nilay; Slizgi, Jason R; Brouwer, Kim L R

2017-09-01

Liver disease can alter the disposition of xenobiotics and endogenous substances. Regulatory agencies such as the Food and Drug Administration and the European Medicines Evaluation Agency recommend, if possible, studying the effect of liver disease on drugs under development to guide specific dose recommendations in these patients. Although extensive research has been conducted to characterize the effect of liver disease on drug-metabolizing enzymes, emerging data have implicated that the expression and function of hepatobiliary transport proteins also are altered in liver disease. This review summarizes recent developments in the field, which may have implications for understanding altered disposition, safety, and efficacy of new and existing drugs. A brief review of liver physiology and hepatic transporter localization/function is provided. Then, the expression and function of hepatic transporters in cholestasis, hepatitis C infection, hepatocellular carcinoma, human immunodeficiency virus infection, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and primary biliary cirrhosis are reviewed. In the absence of clinical data, nonclinical information in animal models is presented. This review aims to advance the understanding of altered expression and function of hepatic transporters in liver disease and the implications of such changes on drug disposition. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Morphological changes in the liver and kidneys of rats subjected to terminal ileum exclusion during obstructive cholestasis.

PubMed

Costa, Evandro Luis de Oliveira; Azevedo, Geraldo Magela de; Petroianu, Andy

2014-06-01

To investigate the effects of ileal exclusion on hepatic and renal morphology in extra-hepatic cholestasis. Twenty four rats were distributed into three groups. Group 1 (control) underwent laparotomy and laparorrhaphy. The animals in groups 2 and 3 underwent hepatic duct ligature and kept in cholestasis for four weeks. After this period, the rats in groups 2 and 3 underwent internal biliary derivation. In Group 3, the last ten centimeters of the terminal ileum were by passed and excluded. Four weeks later, histological and biochemical analysis were performed in all animals of the three groups. In Group 1, no abnormalities regarding hepatic morphology were observed. All animals from groups 2 and 3 presented hepatic fibrosis. No difference was observed between the two groups. No morphological differences in renal histology could be identified among the three groups. There were differences in AST (p<0.05), ALT (p<0.05), direct bilirubin (p<0.05), ƔGT (p<0.05), urea (p<0.05) and creatinine (p<0.05) in Group 3 compared to control. The distal ileum exclusion had no influence upon the hepatic and renal morphological alterations, and biochemical liver and kidney tests have worsened.
The correlation between NK cell and liver function in patients with primary hepatocellular carcinoma.

PubMed

Sha, Wei Hong; Zeng, Xiao Hui; Min, Lu

2014-05-01

This study aimed to detect the expression of natural killer (NK) cell receptor natural killer group 2D (NKG2D) in the peripheral blood of patients with primary hepatocellular carcinoma and to discuss the correlation between NK cell cytotoxicity and liver function. The number of NK cells and the expression of NK cell receptor NKG2D in peripheral blood were determined by flow cytometry in patients with primary hepatocellular carcinoma, hepatitis B cirrhosis, chronic hepatitis B, and healthy controls. When compared with patients in the healthy and the chronic hepatitis B groups, the primary hepatocellular carcinoma group showed significant decreases in all parameters, including the cytotoxicity of NK cells on K562 cells, expression rate of NKG2D in NK cells, number of NKG2D(+) NK cells, expression level of NKG2D, and number of NK cells (p<0.05). The activity of NK cells showed a positive correlation, whereas the Child-Pugh scores in the primary hepatocellular carcinoma and the hepatitis B cirrhosis groups showed a negative correlation with all parameters detected above. The decrease of NK cell activity in patients with primary hepatocellular carcinoma is closely related to their lower expression of NKG2D. Liver function affects the expression of NKG2D and the activity of NK cells.
Role of heparanase on hepatic uptake of intestinal derived lipoprotein and fatty streak formation in mice.

PubMed

Planer, David; Metzger, Shulamit; Zcharia, Eyal; Wexler, Isaiah D; Vlodavsky, Israel; Chajek-Shaul, Tova

2011-04-04

Heparanase modulates the level of heparan sulfate proteoglycans (HSPGs) which have an important role in multiple cellular processes. Recent studies indicate that HSPGs have an important function in hepatic lipoprotein handling and processes involving removal of lipoprotein particles. To determine the effects of decreased HSPGs chain length on lipoprotein metabolism and atherosclerosis, transgenic mice over-expressing the human heparanase gene were studied. Hepatic lipid uptake in hpa-Tg mice were evaluated by giving transgenic mice oral fat loads and labeled retinol. Sections of aorta from mice over-expressing heparanase (hpa-Tg) and controls (C57/BL6) fed an atherogenic diet were examined for evidence of atherosclerosis. Heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta. The mean lesion cross-sectional area in heparanase over-expressing mice was almost 6 times higher when compared to control mice (23,984 µm(2)±5,922 vs. 4,189 µm(2)±1,130, p<0.001). Over-expression of heparanase demonstrates the importance of HSPGs for the uptake of intestinal derived lipoproteins and its role in the formation of fatty streaks.
Role of Heparanase on Hepatic Uptake of Intestinal Derived Lipoprotein and Fatty Streak Formation in Mice

PubMed Central

Planer, David; Metzger, Shulamit; Zcharia, Eyal; Wexler, Isaiah D.; Vlodavsky, Israel; Chajek-Shaul, Tova

2011-01-01

Background Heparanase modulates the level of heparan sulfate proteoglycans (HSPGs) which have an important role in multiple cellular processes. Recent studies indicate that HSPGs have an important function in hepatic lipoprotein handling and processes involving removal of lipoprotein particles. Principal Findings To determine the effects of decreased HSPGs chain length on lipoprotein metabolism and atherosclerosis, transgenic mice over-expressing the human heparanase gene were studied. Hepatic lipid uptake in hpa-Tg mice were evaluated by giving transgenic mice oral fat loads and labeled retinol. Sections of aorta from mice over-expressing heparanase (hpa-Tg) and controls (C57/BL6) fed an atherogenic diet were examined for evidence of atherosclerosis. Heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta. The mean lesion cross-sectional area in heparanase over-expressing mice was almost 6 times higher when compared to control mice (23,984 µm2±5,922 vs. 4,189 µm2±1,130, p<0.001). Conclusions Over-expression of heparanase demonstrates the importance of HSPGs for the uptake of intestinal derived lipoproteins and its role in the formation of fatty streaks. PMID:21483695
Activation of farnesoid X receptor promotes triglycerides lowering by suppressing phospholipase A2 G12B expression.

PubMed

Liu, Qingli; Yang, Meng; Fu, Xuekun; Liu, Renzhong; Sun, Caijun; Pan, Haobo; Wong, Chi-Wai; Guan, Min

2016-11-15

As a novel mediator of hepatic very low-density lipoproteins (VLDL) secretion, phospholipase A2 G12B (PLA2G12B) is transcriptionally regulated by hepatocyte nuclear factor-4 alpha (HNF-4α). Farnesoid X receptor (FXR) plays a critical role in maintaining bile acids and triglycerides (TG) homeostasis. Here we report that FXR regulates serum TG level in part through PLA2G12B. Activation of FXR by chenodeoxycholic acid (CDCA) or GW4064 significantly decreased PLA2G12B expression in HepG2 cells. PLA2G12B expression was transcriptionally repressed due to an FXR-mediated up-regulation of small heterodimer partner (SHP) which functionally suppresses HNF-4α activity. We found that hepatic PLA2G12B expression was suppressed and serum TG level reduced in high fat diet mice treated with CDCA. Concurrently, CDCA treatment lowered hepatic VLDL-TG secretion. Our data demonstrate that activation of FXR promotes TG lowering, not only by decreasing de novo lipogenesis but also reducing hepatic secretion of TG-rich VLDL particles in part through suppressing PLA2G12B expression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Regulation of Hepatic ApoC3 Expression by PGC-1β Mediates Hypolipidemic Effect of Nicotinic Acid

PubMed Central

Hernandez, Carlos; Molusky, Matthew; Li, Yaqiang; Li, Siming; Lin, Jiandie D.

2010-01-01

SUMMARY Peroxisome-proliferator activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects. PMID:20889132
Regulation of hepatic ApoC3 expression by PGC-1β mediates hypolipidemic effect of nicotinic acid.

PubMed

Hernandez, Carlos; Molusky, Matthew; Li, Yaqiang; Li, Siming; Lin, Jiandie D

2010-10-06

Peroxisome proliferator-activated receptor (PPAR) γ coactivator-1β (PGC-1β) is a transcriptional coactivator that induces hypertriglyceridemia in response to dietary fats through activating hepatic lipogenesis and lipoprotein secretion. The expression of PGC-1β is regulated by free fatty acids. Here we show that PGC-1β regulates plasma triglyceride metabolism through stimulating apolipoprotein C3 (APOC3) expression and elevating APOC3 levels in circulation. Remarkably, liver-specific knockdown of APOC3 significantly ameliorates PGC-1β-induced hypertriglyceridemia in mice. Hepatic expression of PGC-1β and APOC3 is reduced in response to acute and chronic treatments with nicotinic acid, a widely prescribed drug for lowering plasma triglycerides. Adenoviral-mediated knockdown of PGC-1β or APOC3 in the liver recapitulates the hypolipidemic effect of nicotinic acid. Proteomic analysis of hepatic PGC-1β transcriptional complex indicates that it stimulates APOC3 expression through coactivating orphan nuclear receptor ERRα and recruiting chromatin-remodeling cofactors. Together, these studies identify PGC-1β as an important regulator of the APOC3 gene cluster and reveal a mechanism through which nicotinic acid achieves its therapeutic effects. Copyright © 2010 Elsevier Inc. All rights reserved.
NFIL3 is a negative regulator of hepatic gluconeogenesis.

PubMed

Kang, Geon; Han, Hye-Sook; Koo, Seung-Hoi

2017-12-01

Nuclear factor interleukin-3 regulated (NFIL3) has been known as an important transcriptional regulator of the development and the differentiation of immune cells. Although expression of NFIL3 is regulated by nutritional cues in the liver, the role of NFIL3 in the glucose metabolism has not been extensively studied. Thus, we wanted to explore the potential role of NFIL3 in the control of hepatic glucose metabolism. Mouse primary hepatocytes were cultured to perform western blot analysis, Q-PCR and chromatin immunoprecipitation assay. 293T cells were cultured to perform luciferase assay. Male C57BL/6 mice (fed a normal chow diet or high fat diet for 27weeks) as well as ob/ob mice were used for experiments with adenoviral delivery. We observed that NFIL3 reduced glucose production in hepatocytes by reducing expression of gluconeogenic gene transcription. The repression by NFIL3 required its basic leucine zipper DNA binding domain, and it competed with CREB onto the binding of cAMP response element in the gluconeogenic promoters. The protein levels of hepatic NFIL3 were decreased in the mouse models of genetic- and diet-induced obesity and insulin resistance, and ectopic expression of NFIL3 in the livers of insulin resistant mice ameliorated hyperglycemia and glucose intolerance, with concomitant reduction in expression of hepatic gluconeogenic genes. Finally, we witnessed that knockdown of NFIL3 in the livers of normal chow-fed mice promoted elevations in the glucose levels and expression of hepatic gluconeogenic genes. In this study, we showed that NFIL3 functions as an important regulator of glucose homeostasis in the liver by limiting CREB-mediated hepatic gluconeogenesis. Thus, enhancement of hepatic NFIL3 activity in insulin resistant state could be potentially beneficial in relieving glycemic symptoms in the metabolic diseases. Copyright © 2017 Elsevier Inc. All rights reserved.
Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

PubMed Central

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P.J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a high-fat diet (SFL model) or a methionine-choline-deficient diet (NASH model) for eight weeks. Hepatic uptake transporter function was determined by bromosulfophthalein (BSP) disposition. Transporter expression was determined by branched DNA signal amplification assay and western blotting; inflammation was identified by immunostaining of liver slices for interleukin 1 beta (IL-1β). MC- rats showed significant retention of BSP in the plasma when compared to control rats. Hepatic NTCP, OATP1a1, 1a4, 1b2 and 2b1; and OAT 2 and 3 mRNA levels were significantly decreased in high-fat and MC- diet rats when compared to control. Protein expression of OATP1a1 was significantly decreased in high-fat animals, while OATP1a1 and OATP1b2 expression was significantly lower in MC- rats when compared to control. Liver tissue from high-fat and MC- rats stained positive for IL-1β, a pro-inflammatory cytokine known to decrease expression of NTCP, OATP and OAT transporters, suggesting a plausible mechanism for the observed transporter alterations. These data suggest that different stages of NAFLD result in altered hepatic uptake transporter expression that can lead to a functional impairment of xenobiotic uptake from the blood. Furthermore, NAFLD may alter the plasma retention time of clinically relevant drugs that are reliant on these transporters and may increase the potential drug toxicity. PMID:19358839
Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

PubMed Central

Yamamoto, Takaya; Nakade, Yukiomi; Yamauchi, Taeko; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sato, Ken; Fukuzawa, Yoshitaka; Yoneda, Masashi

2016-01-01

AIM: To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition of hepatic FFA influx and oxidative stress in a non-obese NASH model. PMID:26937139
Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Noelle; Department of Obstetrics and Gynecology, The University of Western Ontario; The Lawson Health Research Institute, The University of Western Ontario

While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1 mg/kg/day) for two weeks prior to mating until weaning. At postnatal daymore » 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway. - Highlights: • Our data reveals the links nicotine exposure in utero and long-term hypertriglyceridemia. • It is due to nicotine-induced augmented expression of hepatic FAS and LXRα activity. • Moreover, this involves nicotine-induced enhanced acetylation of histone H3 [K9,14]. • This provides a mechanism for developmental origins of health and disease (DOHaD)« less
Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury.

PubMed

Ruddell, Richard G; Knight, Belinda; Tirnitz-Parker, Janina E E; Akhurst, Barbara; Summerville, Lesa; Subramaniam, V Nathan; Olynyk, John K; Ramm, Grant A

2009-01-01

Lymphotoxin-beta (LTbeta) is a proinflammatory cytokine and a member of the tumor necrosis factor (TNF) superfamily known for its role in mediating lymph node development and homeostasis. Our recent studies suggest a role for LTbeta in mediating the pathogenesis of human chronic liver disease. We hypothesize that LTbeta co-ordinates the wound healing response in liver injury via direct effects on hepatic stellate cells. This study used the choline-deficient, ethionine-supplemented (CDE) dietary model of chronic liver injury, which induces inflammation, liver progenitor cell proliferation, and portal fibrosis, to assess (1) the cellular expression of LTbeta, and (2) the role of LTbeta receptor (LTbetaR) in mediating wound healing, in LTbetaR(-/-) versus wild-type mice. In addition, primary isolates of hepatic stellate cells were treated with LTbetaR-ligands LTbeta and LTbeta-related inducible ligand competing for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT), and mediators of hepatic stellate cell function and fibrogenesis were assessed. LTbeta was localized to progenitor cells immediately adjacent to activated hepatic stellate cells in the periportal region of the liver in wild-type mice fed the CDE diet. LTbetaR(-/-) mice fed the CDE diet showed significantly reduced fibrosis and a dysregulated immune response. LTbetaR was demonstrated on isolated hepatic stellate cells, which when stimulated by LTbeta and LIGHT, activated the nuclear factor kappa B (NF-kappaB) signaling pathway. Neither LTbeta nor LIGHT had any effect on alpha-smooth muscle actin, tissue inhibitor of metalloproteinase 1, transforming growth factor beta, or procollagen alpha(1)(I) expression; however, leukocyte recruitment-associated factors intercellular adhesion molecule 1 and regulated upon activation T cells expressed and secreted (RANTES) were markedly up-regulated. RANTES caused the chemotaxis of a liver progenitor cell line expressing CCR5. This study suggests that LTbetaR on hepatic stellate cells may be involved in paracrine signaling with nearby LTbeta-expressing liver progenitor cells mediating recruitment of progenitor cells, hepatic stellate cells, and leukocytes required for wound healing and regeneration during chronic liver injury.
Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A-I variant.

PubMed

Parolini, Cinzia; Caligari, Silvia; Gilio, Donatella; Manzini, Stefano; Busnelli, Marco; Montagnani, Marco; Locatelli, Marcello; Diani, Erika; Giavarini, Flavio; Caruso, Donatella; Roda, Enrico; Roda, Aldo; Sirtori, Cesare R; Chiesa, Giulia

2012-10-01

Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA-I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines. © 2012 John Wiley & Sons A/S.
Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis.

PubMed

Moreno-Carranza, Bibiana; Goya-Arce, Maite; Vega, Claudia; Adán, Norma; Triebel, Jakob; López-Barrera, Fernando; Quintanar-Stéphano, Andrés; Binart, Nadine; Martínez de la Escalera, Gonzalo; Clapp, Carmen

2013-10-01

Prolactin (PRL) is a potent liver mitogen and proangiogenic hormone. Here, we used hyperprolactinemic rats and PRL receptor-null mice (PRLR(-/-)) to study the effect of PRL on liver growth and angiogenesis before and after partial hepatectomy (PH). Liver-to-body weight ratio (LBW), hepatocyte and sinusoidal endothelial cell (SEC) proliferation, and hepatic expression of VEGF were measured before and after PH in hyperprolactinemic rats, generated by placing two anterior pituitary glands (AP) under the kidney capsule. Also, LBW and hepatic expression of IL-6, as well as suppressor of cytokine signaling-3 (SOCS-3), were evaluated in wild-type and PRLR(-/-) mice before and after PH. Hyperprolactinemia increased the LBW, the proliferation of hepatocytes and SECs, and VEGF hepatic expression. Also, liver regeneration was increased in AP-grafted rats and was accompanied by elevated hepatocyte and SEC proliferation, and VEGF expression compared with nongrafted controls. Lowering circulating PRL levels with CB-154, an inhibitor of AP PRL secretion, prevented AP-induced stimulation of liver growth. Relative to wild-type animals, PRLR(-/-) mice had smaller livers, and soon after PH, they displayed an approximately twofold increased mortality and elevated and reduced hepatic IL-6 and SOCS-3 expression, respectively. However, liver regeneration was improved in surviving PRLR(-/-) mice. PRL stimulates normal liver growth, promotes survival, and regulates liver regeneration by mechanisms that may include hepatic downregulation of IL-6 and upregulation of SOCS-3, increased hepatocyte proliferation, and angiogenesis. PRL contributes to physiological liver growth and has potential clinical utility for ensuring survival and regulating liver mass in diseases, injuries, or surgery of the liver.
Postprandial changes in high density lipoproteins in rats subjected to gavage administration of virgin olive oil.

PubMed

Martínez-Beamonte, Roberto; Navarro, María A; Acin, Sergio; Guillén, Natalia; Barranquero, Cristina; Arnal, Carmen; Surra, Joaquín; Osada, Jesus

2013-01-01

The present study was designed to verify the influence of acute fat loading on high density lipoprotein (HDL) composition, and the involvement of liver and different segments of small intestine in the changes observed. To address these issues, rats were administered a bolus of 5-ml of extra-virgin olive oil and sacrificed 4 and 8 hours after feeding. In these animals, lipoproteins were analyzed and gene expressions of apolipoprotein and HDL enzymes were assessed in duodenum, jejunum, ileum and liver. Using this experimental design, total plasma and HDL phospholipids increased at the 8-hour-time-point due to increased sphingomyelin content. An increase in apolipoprotein A4 was also observed mainly in lipid-poor HDL. Increased expression of intestinal Apoa1, Apoa4 and Sgms1 mRNA was accompanied by hepatic decreases in the first two genes in liver. Hepatic expression of Abcg1, Apoa1bp, Apoa2, Apoe, Ptlp, Pon1 and Scarb1 decreased significantly following fat gavage, while no changes were observed for Abca1, Lcat or Pla2g7. Significant associations were also noted for hepatic expression of apolipoproteins and Pon1. Manipulation of postprandial triglycerides using an inhibitor of microsomal transfer protein -CP-346086- or of lipoprotein lipase -tyloxapol- did not influence hepatic expression of Apoa1 or Apoa4 mRNA. All these data indicate that dietary fat modifies the phospholipid composition of rat HDL, suggesting a mechanism of down-regulation of hepatic HDL when intestine is the main source of those particles and a coordinated regulation of hepatic components of these lipoproteins at the mRNA level, independently of plasma postprandial triglycerides.
ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

PubMed Central

Parsa, Kishore V. L.; Kain, Vasundhara; Behera, Soma; Suraj, Sashidhara Kaimal; Babu, Phanithi Prakash; Kar, Anand; Panda, Sunanda; Zhu, Yi-jun; Jia, Yuzhi; Thimmapaya, Bayar; Reddy, Janardan K.; Misra, Parimal

2013-01-01

PRIP-Interacting protein with methyl transferase domain (PIMT) serves as a molecular bridge between CREB-binding protein (CBP)/ E1A binding protein p300 (Ep300) -anchored histone acetyl transferase and the Mediator complex sub-unit1 (Med1) and modulates nuclear receptor transcription. Here, we report that ERK2 phosphorylates PIMT at Ser298 and enhances its ability to activate PEPCK promoter. We observed that PIMT is recruited to PEPCK promoter and adenoviral-mediated over-expression of PIMT in rat primary hepatocytes up-regulated expression of gluconeogenic genes including PEPCK. Reporter experiments with phosphomimetic PIMT mutant (PIMTS298D) suggested that conformational change may play an important role in PIMT-dependent PEPCK promoter activity. Overexpression of PIMT and Med1 together augmented hepatic glucose output in an additive manner. Importantly, expression of gluconeogenic genes and hepatic glucose output were suppressed in isolated liver specific PIMT knockout mouse hepatocytes. Furthermore, consistent with reporter experiments, PIMTS298D but not PIMTS298A augmented hepatic glucose output via up-regulating the expression of gluconeogenic genes. Pharmacological blockade of MAPK/ERK pathway using U0126, abolished PIMT/Med1-dependent gluconeogenic program leading to reduced hepatic glucose output. Further, systemic administration of T4 hormone to rats activated ERK1/2 resulting in enhanced PIMT ser298 phosphorylation. Phosphorylation of PIMT led to its increased binding to the PEPCK promoter, increased PEPCK expression and induction of gluconeogenesis in liver. Thus, ERK2-mediated phosphorylation of PIMT at Ser298 is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia. PMID:24358311
Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5'monophosphate kinase: A study in vitro and in vivo.

PubMed

Wei, Shengnan; Li, Wei; Yu, Yang; Yao, Fan; A, Lixiang; Lan, Xiaoxin; Guan, Fengying; Zhang, Ming; Chen, Li

2015-10-15

Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenoside. We have reported that CK presented anti-diabetic effect via diminishing the expressions of hepatic gluconeogenesis key enzyme. Here, we further explore the possible mechanism of CK on suppression hepatic gluconeogenesis via activation of adenosine-5'monophosphate kinase (AMPK) on type 2 diabetes mice in vivo and in HepG2 cells. Type 2 diabetes mice model was developed by high fat diet combined with STZ injection. 30mg/kg/d CK was orally administrated for 4weeks, the fasting blood glucose level and 2h OGTT were conducted, and the protein expression of AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) were examined. The mechanism of Compound K on hepatic gluconeogenesis was further explored in HepG2 hepatocytes. Glucose production, the protein expression of AMPK, PEPCK, G6pase and PGC-1α, hepatic nuclear factor 4α (HNF-4α) and forkhead transcription factor O1 (FOXO1) were determined after Compound K treatment at the presence of AMPK inhibitor Compound C. We observed that CK inhibited the expression of PEPCK and G6Pase in the liver and in HepG2 hepatocytes. Meanwhile, CK treatment remarkably increased the activation of AMPK, while decreasing the expressions of PGC-1α, HNF-4α and FOXO1. However, AMPK inhibitor Compound C could reverse these effects of CK on gluconeogenesis in part. The results indicated that the effect of CK on suppression hepatic gluconeogenesis might be via the activation the AMPK activity. Copyright © 2015. Published by Elsevier Inc.

Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate-activated protein kinase/proliferator-activated receptor gamma co-activator 1 alpha signaling.

PubMed

Tomiyama, Yasuyuki; Nishina, Sohji; Hara, Yuichi; Kawase, Tomoya; Hino, Keisuke

2014-10-01

Oxidative stress plays an important role in hepatocarcinogenesis of hepatitis C virus (HCV)-related chronic liver diseases. Despite the evidence of an increased proportion of females among elderly patients with HCV-related hepatocellular carcinoma (HCC), it remains unknown whether HCV augments hepatic oxidative stress in postmenopausal women. The aim of this study was to determine whether oxidative stress was augmented in ovariectomized (OVX) transgenic mice expressing the HCV polyprotein and to investigate its underlying mechanisms. OVX and sham-operated female transgenic mice expressing the HCV polyprotein and non-transgenic littermates were assessed for the production of reactive oxygen species (ROS), expression of inflammatory cytokines and antioxidant potential in the liver. Compared with OVX non-transgenic mice, OVX transgenic mice showed marked hepatic steatosis and ROS production without increased induction of inflammatory cytokines, but there was no increase in ROS-detoxifying enzymes such as superoxide dismutase 2 and glutathione peroxidase 1. In accordance with these results, OVX transgenic mice showed less activation of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), which is required for the induction of ROS-detoxifying enzymes, and no activation of adenosine monophosphate-activated protein kinase-α (AMPKα), which regulates the activity of PGC-1α. Our study demonstrated that hepatic oxidative stress was augmented in OVX transgenic mice expressing the HCV polyprotein by attenuation of antioxidant potential through inhibition of AMPK/PGC-1α signaling. These results may account in part for the mechanisms by which HCV-infected women are at high risk for HCC development when some period has passed after menopause. © 2013 The Japan Society of Hepatology.
Postnatal overfeeding promotes early onset and exaggeration of high-fat diet-induced nonalcoholic fatty liver disease through disordered hepatic lipid metabolism in rats.

PubMed

Ji, Chenlin; Dai, Yanyan; Jiang, Weiwei; Liu, Juan; Hou, Miao; Wang, Junle; Burén, Jonas; Li, Xiaonan

2014-11-01

Exposure to overnutrition in critical or sensitive developmental periods may increase the risk of developing obesity and metabolic syndrome in adults. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, but the relationship among postnatal nutrition, lipid metabolism, and NAFLD progression during development remains poorly understood. Here we investigated in a rat model whether postnatal overfeeding increases susceptibility to NAFLD in response to a high-fat diet. Litters from Sprague-Dawley dams were culled to three (small litters) or ten (normal litters) pups and then weaned onto a standard or high-fat diet at postnatal day 21 to generate normal-litter, small-litter, normal-litter/high-fat, and small-litter/high-fat groups. At age 16 weeks, the small-litter and both high-fat groups showed obesity, dyslipidemia, and insulin resistance. Hepatic disorders appeared earlier in the small-litter/high-fat rats with greater liver mass gain and higher hepatic triglycerides and steatosis score versus normal-litter/high-fat rats. Hepatic acetyl-CoA carboxylase activity and mRNA expression were increased in small-litter rats and aggravated in small-litter/high-fat rats but not in normal-litter/high-fat rats. The high expression in small-litter/high-fat rats coincided with high sterol regulatory element-binding protein-1c mRNA and protein expression. However, mRNA expression of enzymes involved in hepatic fatty acid oxidation (carnitine palmitoyltransferase 1) and output (microsomal triglyceride transfer protein) was decreased under a high-fat diet regardless of litter size. In conclusion, overfeeding related to small-litter rearing during lactation contributes to the NAFLD phenotype when combined with a high-fat diet, possibly through up-regulated hepatic lipogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.
Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yap, Chui Sun; Sinha, Rohit Anthony; Ota, Sho

2013-11-01

Highlights: •Thyroid hormone induces miR-181d expression in human hepatic cells and mouse livers. •Thyroid hormone downregulates CDX2 and SOAT2 (or ACAT2) via miR-181d. •miR-181d reduces cholesterol output from human hepatic cells. -- Abstract: Thyroid hormones (THs) regulate transcription of many metabolic genes in the liver through its nuclear receptors (TRs). Although the molecular mechanisms for positive regulation of hepatic genes by TH are well understood, much less is known about TH-mediated negative regulation. Recently, several nuclear hormone receptors were shown to downregulate gene expression via miRNAs. To further examine the potential role of miRNAs in TH-mediated negative regulation, we usedmore » a miRNA microarray to identify miRNAs that were directly regulated by TH in a human hepatic cell line. In our screen, we discovered that miRNA-181d is a novel hepatic miRNA that was regulated by TH in hepatic cell culture and in vivo. Furthermore, we identified and characterized two novel TH-regulated target genes that were downstream of miR-181d signaling: caudal type homeobox 2 (CDX2) and sterol O-acyltransferase 2 (SOAT2 or ACAT2). CDX2, a known positive regulator of hepatocyte differentiation, was regulated by miR-181d and directly activated SOAT2 gene expression. Since SOAT2 is an enzyme that generates cholesteryl esters that are packaged into lipoproteins, our results suggest miR-181d plays a significant role in the negative regulation of key metabolic genes by TH in the liver.« less
Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

PubMed

Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

2008-10-01

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.
Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury

PubMed Central

Issan, Y.; Katz, Y.; Sultan, M.; Safran, M.; Michal, Laniado-Schwartzman; Nader, G. Abraham; Kornowski, R.; Grief, F.; Pappo, O.; Hochhauser, E.

2017-01-01

Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)–dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB’s regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation. PMID:23435964
Dietary sea cucumber cerebroside alleviates orotic acid-induced excess hepatic adipopexis in rats

PubMed Central

2012-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC) extracted from Acaudina molpadioides in fatty liver rats. Methods Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA) to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured. Results Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG) level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS), malic enzyme (ME) and glucose-6-phosphatedehydrogenase (G6PDH) were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c) were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT) in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP) activity was observed in SCC-feeding rats. Conclusions These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver. PMID:22569330
Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S.

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days.more » Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid {beta}-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid {beta}-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights: >Fructose administration as a liquid solution to Sprague-Dawley male rats induced hypertriglyceridemia, hyperleptinemia, hepatic steatosis and necroinflammation. >Atorvastatin administration: >Abolished histological sings of necroinflammation and reduced plasma and liver triglyceride concentrations. >Reduced the expression of phospho-I{kappa}B >Reduced the expression of fructokinase, a key enzyme controlling fructose metabolism« less
Periconceptional undernutrition modifies endocrine profiles and hepatic gene expression in sheep.

PubMed

de Brun, V; Meikle, A; Casal, A; Sequeira, M; Contreras-Solís, I; Carriquiry, M; Forcada, F; Sosa, C; Abecia, J A

2015-08-01

This study investigated whether a 22-day period of undernutrition (half maintenance) could affect maternal endocrine responses and liver gene expression during early pregnancy (day 7). Thirty-five ewes were fed 1.5 (n = 15) or 0.5 (n = 20) their maintenance requirements and slaughtered on day 7 of the oestrus cycle or pregnancy (oestrus = day 0). Insulin, IGF, leptin and non-esterified fatty acids (NEFA) were determined on days -14, 0 and 7. Transcripts of the IGF family and adipokines receptors were determined in the liver by real-time RT-PCR. Underfed animals presented lower body weight and body condition, greater plasma concentration of NEFA, and lower plasma concentrations of leptin, insulin and IGF1 compared to adequately fed animals. Underfed ewes presented greater hepatic expression of IGFBP2 than well-fed ewes, but tended to have lesser expression of IGFBP5. While no effect of undernutrition on IGFBP4 and ADIPOR2 mRNA expressions was observed, they were increased by pregnancy in underfed animals. This study shows that undernutrition modifies endocrine profiles and hepatic gene expression of IGFBP2 and 5. The pregnancy status increased hepatic gene expression of IGFBP4 and ADIPOR2 mRNA in undernourished ewes. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.
Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival.

PubMed

Hang, Hua-Lian; Liu, Xin-Yu; Wang, Hai-Tian; Xu, Ning; Bian, Jian-Min; Zhang, Jian-Jun; Xia, Lei; Xia, Qiang

2017-11-15

Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of β-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote β-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. Copyright © 2017 Elsevier Inc. All rights reserved.
Fructose impairs glucose-induced hepatic triglyceride synthesis

PubMed Central

2011-01-01

Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases. PMID:21261970
Control of leptin by metabolic state and its regulatory interactions with pituitary growth hormone and hepatic growth hormone receptors and insulin like growth factors in the tilapia (Oreochromis mossambicus).

PubMed

Douros, Jonathan D; Baltzegar, David A; Mankiewicz, Jamie; Taylor, Jordan; Yamaguchi, Yoko; Lerner, Darren T; Seale, Andre P; Grau, E Gordon; Breves, Jason P; Borski, Russell J

2017-01-01

Leptin is an important cytokine for regulating energy homeostasis, however, relatively little is known about its function and control in teleost fishes or other ectotherms, particularly with regard to interactions with the growth hormone (GH)/insulin-like growth factors (IGFs) growth regulatory axis. Here we assessed the regulation of LepA, the dominant paralog in tilapia (Oreochromis mossambicus) and other teleosts under altered nutritional state, and evaluated how LepA might alter pituitary growth hormone (GH) and hepatic insulin-like growth factors (IGFs) that are known to be disparately regulated by metabolic state. Circulating LepA, and lepa and lepr gene expression increased after 3-weeks fasting and declined to control levels 10days following refeeding. This pattern of leptin regulation by metabolic state is similar to that previously observed for pituitary GH and opposite that of hepatic GHR and/or IGF dynamics in tilapia and other fishes. We therefore evaluated if LepA might differentially regulate pituitary GH, and hepatic GH receptors (GHRs) and IGFs. Recombinant tilapia LepA (rtLepA) increased hepatic gene expression of igf-1, igf-2, ghr-1, and ghr-2 from isolated hepatocytes following 24h incubation. Intraperitoneal rtLepA injection, on the other hand, stimulated hepatic igf-1, but had little effect on hepatic igf-2, ghr1, or ghr2 mRNA abundance. LepA suppressed GH accumulation and gh mRNA in pituitaries in vitro, but had no effect on GH release. We next sought to test if abolition of pituitary GH via hypophysectomy (Hx) affects the expression of hepatic lepa and lepr. Hypophysectomy significantly increases hepatic lepa mRNA abundance, while GH replacement in Hx fish restores lepa mRNA levels to that of sham controls. Leptin receptor (lepr) mRNA was unchanged by Hx. In in vitro hepatocyte incubations, GH inhibits lepa and lepr mRNA expression at low concentrations, while higher concentration stimulates lepa expression. Taken together, these findings indicate LepA gene expression and secretion increases with fasting, consistent with the hormones function in promoting energy expenditure during catabolic stress. It would also appear that LepA might play an important role in stimulating GHR and IGFs to potentially spare declines in these factors during catabolism. Evidence also suggests for the first time in teleosts that GH may exert important regulatory effects on hepatic LepA production, insofar as physiological levels (0.05-1 nM) suppresse lepa mRNA accumulation. Leptin A, may in turn exert negative feedback effects on basal GH mRNA abundance, but not secretion. Copyright Â© 2016 Elsevier Inc. All rights reserved.
S-nitrosoglutathione reductase in human lung cancer.

PubMed

Marozkina, Nadzeya V; Wei, Christina; Yemen, Sean; Wallrabe, Horst; Nagji, Alykhan S; Liu, Lei; Morozkina, Tatiana; Jones, David R; Gaston, Benjamin

2012-01-01

S-Nitrosoglutathione (GSNO) reductase regulates cell signaling pathways relevant to asthma and protects cells from nitrosative stress. Recent evidence suggests that this enzyme may prevent human hepatocellular carcinoma arising in the setting of chronic hepatitis. We hypothesized that GSNO reductase may also protect the lung against potentially carcinogenic reactions associated with nitrosative stress. We report that wild-type Ras is S-nitrosylated and activated by nitrosative stress and that it is denitrosylated by GSNO reductase. In human lung cancer, the activity and expression of GSNO reductase are decreased. Further, the distribution of the enzyme (including its colocalization with wild-type Ras) is abnormal. We conclude that decreased activity of GSNO reductase could leave the human lung vulnerable to the oncogenic effects of nitrosative stress, as is the case in the liver. This potential should be considered when developing therapies that inhibit pulmonary GSNO reductase to treat asthma and other conditions.
Emphysematous Cystitis Occurred in the Case Treated with Steroid for Autoimmune Hepatitis

PubMed Central

Yoshino, Tateki; Ohara, Shinya; Moriyama, Hiroyuki

2013-01-01

Emphysematous cystitis is a rare clinically entity, more commonly seen in diabetic, immunocompromised patients, which was characterized by air within the bladder wall and lumen. A 83-year-old woman was introduced to our department with fever elevation and abnormal findings of computed tomography (CT). She took orally prednisolone for autoimmune hepatitis. Pelvic CT revealed diffuse air throughout the bladder wall. Urinalysis showed combined hematuria and pyuria. Escherichia coli was detected in blood culture. Abnormal findings of complete blood count and laboratory examination included an elevated WBC count (12,200/μL), C-reactive protein (11.7 mg/dL), and creatinine (1.07 mg/dL). Cystoscopy confirmed diffuse submucosal emphysema throughout. On the basis of diagnosis with emphysematous cystitis, she was treated with antibiotics based on the results of blood culture and indwelling Foley catheter. After treatment, the improvement of inflammatory findings and submucosal emphysema on cystoscopy and CT were achieved. PMID:23936723
White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

PubMed

Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

2016-01-01

Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism.
Estrogenic status modulates aryl hydrocarbon receptor - mediated hepatic gene expression and carcinogenicity

USDA-ARS?s Scientific Manuscript database

Estrogenic status is thought to influence the cancer risk in women and has been reported to affect toxicity of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in animals. The objective of this study was to examine the influence of estradiol (E2) on hepatic gene expression changes mediated by 7,...
HEPATIC GENE EXPRESSION PROFILES OF RATS EXPOSED TO PERFLUOROOCTANE SULFONATE (PFOS) IN UTERO

EPA Science Inventory

Hepatic Gene Expression Profiles of Rats Exposed to Perfluorooctanesulfonate (PFOS) in utero.
J.A. Bjork1, J.M. Berthiaume1, C. Lau2, J. L. Butenhoff3, and K.B. Wallace1

1Department of Biochemistry & Molecular Biology, University of Minnesota School of Medicine, Dulut...
FLUCONAZOLE-INDUCED HEPATIC CYTOCHROME P450 GENE EXPRESSION AND ENZYMATIC ACTIVITIES IN RATS AND MICE

EPA Science Inventory

This study was undertaken to examine the effects of the triazole antifungal agent fluconazole on the expression of hepatic cytochrome P450 (Cyp) genes and the activities of Cyp enzymes in male Sprague-Dawley rats and male CD-1 mice. Alkoxyresorufin O-dealkylation (AROD) methods w...
OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION

EPA Science Inventory

Evaluating the Effects of Methapyrilene and Clofibrate on Hepatic Gene Expression: A Collaboration Between Laboratories and a Comparison of Platform and Analytical Approaches

Roger G. Ulrich1, John C. Rockett2, G. Gordon Gibson3 and Syril Pettit4

1 Rosetta Inpharmat...
Overview of expression of hepatitis B surface antigen in transgenic plants.

PubMed

Guan, Zheng-jun; Guo, Bin; Huo, Yan-lin; Guan, Zheng-ping; Wei, Ya-hui

2010-10-28

Hepatitis B virus (HBV), a pathogen for chronic liver infection, afflicts more than 350 million people world-wide. The effective way to control the virus is to take HBV vaccine. Hepatitis B surface antigen (HBsAg) is an effective protective antigen suitable for vaccine development. At present, "edible" vaccine based on transgenic plants is one of the most promising directions in novel types of vaccines. HBsAg production from transgenic plants has been carried out, and the transgenic plant expression systems have developed from model plants (such as tobacco, potato and tomato) to other various plant platforms. Crude or purified extracts of transformed plants have been found to conduct immunological responses and clinical trials for hepatitis B, which gave the researches of plant-based HBsAg production a big boost. The aim of this review was to summarize the recent data about plant-based HBsAg development including molecular biology of HBsAg gene, selection of expression vector, the expression of HBsAg gene in plants, as well as corresponding immunological responses in animal models or human. Copyright © 2010 Elsevier Ltd. All rights reserved.
Neonatal Persistent Exposure to 6-Propyl-2-thiouracil, a Thyroid-Disrupting Chemical, Differentially Modulates Expression of Hepatic Catalase and C/EBP-β in Adult Rats.

PubMed

Bunker, Suresh Kumar; Dandapat, Jagneshwar; Sahoo, Sunil Kumar; Roy, Anita; Chainy, Gagan B N

2016-02-01

Persistent exposure of rats to 6-propyl-2-thiouracil (PTU) from birth resulted in decreases in plasma thyroid hormone (TH) levels and hepatic expression of catalase and CCAAT enhancer binding protein β (C/EBP-β). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-β showed an augmentation in the methylation level along with a change in methylation pattern of CpG islands in response to PTU treatment. PTU withdrawal on 30 days of birth restored TH levels and C/EBP-β to control rats in adulthood. Although catalase expression was restored to some extent in adult rats in response to PTU withdrawal, a permanent change in its promoter CpG methylation pattern was recorded. The results suggest that downregulation of adult hepatic catalase gene in response to persistent neonatal PTU exposure may not solely be attributed to thyroid-disrupting properties of PTU. It is possible that besides thyroid-disrupting behavior, PTU may impair expression of hepatic catalase by altering methylation pattern of its promoter. © 2015 Wiley Periodicals, Inc.

Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress

PubMed Central

Kim, Min-Hyun; Aydemir, Tolunay B.; Kim, Jinhee; Cousins, Robert J.

2017-01-01

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet–induced ER stress using Zip14−/− (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders. PMID:28673968
Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice[S

PubMed Central

Tripathy, Sasmita; Lytle, Kelli A.; Stevens, Robert D.; Bain, James R.; Newgard, Christopher B.; Greenberg, Andrew S.; Huang, Li-Shin; Jump, Donald B.

2014-01-01

Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6α) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for β-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPARβ-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARβ agonist (GW0742) decreased 14C-18:2,n-6 in TGs but did not affect β-oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARβ activity, ATGL expression, and TG catabolism, but not FA oxidation. PMID:24814977
Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.

PubMed

Ueyama, Jun; Nadai, Masayuki; Zhao, Ying Lan; Kanazawa, Hiroaki; Takagi, Kenji; Kondo, Takaaki; Takagi, Kenzo; Wakusawa, Shinya; Abe, Fumie; Saito, Hiroko; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

2008-08-01

Thalidomide has been reported to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) that are involved in the down-regulation of hepatic cytochrome P450 (CYP) induced by endotoxin. In the present study, we investigated the effects of thalidomide on endotoxin-induced decreases in the activity and expression of hepatic CYP3A2 in rats. Thalidomide (50 mg/kg) was administered orally 22 h and 2 h before intraperitoneal injection of endotoxin (1 mg/kg). Twenty-four hours after the injection of endotoxin, antipyrine clearance experiments were conducted, in which the rats were sacrificed and protein levels of hepatic CYP3A2 were measured. There were no significant differences in the histopathological changes in the liver between the endotoxin-treated and endotoxin plus thalidomide-treated rats. Thalidomide had no effect on the systemic clearance of antipyrine, which is a proper indicator for hepatic CYP3A2 activity, whereas it enhanced endotoxin-induced decrease in the systemic clearance of antipyrine. Western blot analysis revealed that thalidomide had no effect on the protein levels of hepatic CYP3A2, whereas it enhanced the down-regulation of hepatic CYP3A2 by endotoxin. However, there were no significant differences in the concentrations of TNF-alpha and NO in plasma between the endotoxin-treated and endotoxin plus thalidomide-treated rats. The present findings suggest that thalidomide enhances endotoxin-induced decreases in the activity and expression of hepatic CYP3A2.
Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress.

PubMed

Kim, Min-Hyun; Aydemir, Tolunay B; Kim, Jinhee; Cousins, Robert J

2017-07-18

Extensive endoplasmic reticulum (ER) stress damages the liver, causing apoptosis and steatosis despite the activation of the unfolded protein response (UPR). Restriction of zinc from cells can induce ER stress, indicating that zinc is essential to maintain normal ER function. However, a role for zinc during hepatic ER stress is largely unknown despite important roles in metabolic disorders, including obesity and nonalcoholic liver disease. We have explored a role for the metal transporter ZIP14 during pharmacologically and high-fat diet-induced ER stress using Zip14 -/- (KO) mice, which exhibit impaired hepatic zinc uptake. Here, we report that ZIP14-mediated hepatic zinc uptake is critical for adaptation to ER stress, preventing sustained apoptosis and steatosis. Impaired hepatic zinc uptake in Zip14 KO mice during ER stress coincides with greater expression of proapoptotic proteins. ER stress-induced Zip14 KO mice show greater levels of hepatic steatosis due to higher expression of genes involved in de novo fatty acid synthesis, which are suppressed in ER stress-induced WT mice. During ER stress, the UPR-activated transcription factors ATF4 and ATF6α transcriptionally up-regulate Zip14 expression. We propose ZIP14 mediates zinc transport into hepatocytes to inhibit protein-tyrosine phosphatase 1B (PTP1B) activity, which acts to suppress apoptosis and steatosis associated with hepatic ER stress. Zip14 KO mice showed greater hepatic PTP1B activity during ER stress. These results show the importance of zinc trafficking and functional ZIP14 transporter activity for adaptation to ER stress associated with chronic metabolic disorders.
Genomic interval engineering of mice identified a novel modulator of triglyceride production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Y.; Jong, M.C.; Frazer, K.A.

1999-10-01

To accelerate the biological annotation of novel genes discovered in sequenced of mammalian genomes, we are creating large deletions in the mouse genome targeted to include clusters of such genes. Here we describe the targeted deletion of a 450 kb region on mouse chromosome 11 which, based on computational analysis of the deleted murine sequences and human 5q orthologous sequences, codes for nine putative genes. Mice homozygous for the deletion had a variety of abnormalities including severe hypertriglyceridemia, hepatic and cardiac enlargement, growth retardation and premature mortality. Analysis of triglyceride metabolism in these animals demonstrated a several-fold increase in hepaticmore » very-low density lipoprotein (VLDL) triglyceride secretion, the most prevalent mechanism responsible for hypertriglyceridemia in humans. A series of mouse BAC and human YAC transgenes covering different intervals of the 450 kb deleted region were assessed for their ability to complement the deletion induced abnormalities. These studies revealed that OCTN2, a gene recently shown to play a role in carnitine transport, was able to correct the triglyceride abnormalities. The discovery of this previously unappreciated relationship between OCTN2, carnitine and hepatic triglyceride production is of particular importance due to the clinical consequence of hypertriglyceridemia and the paucity of genes known to modulate triglyceride secretion.« less
Double Gallbladder Originating from Left Hepatic Duct: A Case Report and Review of Literature

PubMed Central

Gorecki, Piotr J.; Andrei, Valeriu E; Musacchio, Tito

1998-01-01

Background: Double gallbladder is a rare anomaly of the biliary tract. Double gallbladder arising from the left hepatic duct was previously reported only once in the literature. Case Report: A case of symptomatic cholelithiasis in a double gallbladder, diagnosed on preoperative ultrasound, computed tomography (CT) and endoscopic retrograde cholangiopancreatogram (ERCP) is reported. At laparoscopic cholangiography via the accessory gallbladder no accessory cystic duct was visualized. After conversion to open cholecystectomy, the duplicated gallbladder was found to arise directly from the left hepatic duct; it was resected and the duct repaired. Conclusions: We emphasize that a careful intraoperative cholangiographic evaluation of the accessory gallbladder is mandatory in order to prevent inadvertent injury to bile ducts, since a large variety of ductal abnormality may exist. PMID:10036124
Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis.

PubMed

Strakovsky, Rita S; Wang, Huan; Engeseth, Nicki J; Flaws, Jodi A; Helferich, William G; Pan, Yuan-Xiang; Lezmi, Stéphane

2015-04-15

Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate the potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague-Dawley rats were dosed with vehicle (oil) or BPA (100μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C, and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglyceride (TG) and free fatty acid (FFA) compositions in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet. Copyright © 2015 Elsevier Inc. All rights reserved.
Hepatic OATP Transporter and Thyroid Hormone Receptor Interplay Determines Cholesterol and Glucose Homeostasis

PubMed Central

Meyer zu Schwabedissen, Henriette E.; Ware, Joseph A.; Finkelstein, David; Chaudhry, Amarjit S.; Lemay, Sara; Leon-Ponte, Matilde; Strom, Stephen C.; Zaher, Hani; Schwarz, Ute I.; Freeman, David J.; Schuetz, Erin G.; Tirona, Rommel G.; Kim, Richard B.

2011-01-01

The role of Organic Anion Transporting Polypeptides (OATPs), particularly the members of OATP1B-subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B-subfamily, we previously demonstrated that genetic ablation causes reduced hepatic clearance capacity for substrates. In this report we focused on the physiological function of the hepatic OATP1B transporters. First we studied the influence of the Oatp1b2 deletion on bile acid metabolism showing that lack of the transporter results in a significantly reduced expression of Cyp7a1 the key enzyme of bile acid synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2−/− mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2−/−exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of PEPCK in knockout mice. We show this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR) including the prior mentioned Cyp7a1 and Pepck, but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers where OATP1B1 expression was noted to be highly associated with TR target genes, especially for GLUT2. Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. Conclusion Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis. PMID:21538436
Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fader, Kelly A.; Nault, Rance

Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30 μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resultingmore » in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity. - Highlights: • TCDD represses hepatic hepcidin expression, leading to systemic iron overloading. • Dysregulation of heme biosynthesis is consistent with heme and porphyrin accumulation. • Heme-activated REV-ERBα/β repress circadian-regulated hepatic lipid metabolism. • Disruption of iron homeostasis promotes TCDD-elicited steatohepatitis with fibrosis.« less
Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice.

PubMed

Bijnen, Mitchell; Josefs, Tatjana; Cuijpers, Ilona; Maalsen, Constantijn J; van de Gaar, José; Vroomen, Maria; Wijnands, Erwin; Rensen, Sander S; Greve, Jan Willem M; Hofker, Marten H; Biessen, Erik A L; Stehouwer, Coen D A; Schalkwijk, Casper G; Wouters, Kristiaan

2017-10-26

Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c + proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr -/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c + and CD11c - macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c + ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Obesity-driven prepartal hepatic lipid accumulation in dairy cows is associated with increased CD36 and SREBP-1 expression.

PubMed

Prodanović, Radiša; Korićanac, Goran; Vujanac, Ivan; Djordjević, Ana; Pantelić, Marija; Romić, Snježana; Stanimirović, Zoran; Kirovski, Danijela

2016-08-01

We investigated the hypothesis that obesity in dairy cows enhanced expression of proteins involved in hepatic fatty acid uptake and metabolism. Sixteen Holstein-Friesian close-up cows were divided into 2 equal groups based on their body condition score (BCS) as optimal (3.25≤BCS≤3.5) and high (4.0≤BCS≤4.25). Intravenous glucose tolerance test (GTT) and liver biopsies were carried out at day 10 before calving. Blood samples were collected before (basal) and after glucose infusion, and glucose, insulin and non-esterified fatty acid (NEFA) levels were determined at each sample point. In addition, β-hydroxybutyrate and triglycerides levels were measured in the basal samples. The liver biopsies were analyzed for total lipid content and protein expression of insulin receptor beta (IRβ), fatty acid translocase (FAT/CD36) and sterol regulatory element-binding protein-1 (SREBP-1). Basal glucose and insulin were higher in high-BCS cows, which coincided with higher circulating triglycerides and hepatic lipid content. Clearance rate and AUC for NEFA during GTT were higher in optimal-BCS cows. The development of insulin resistance and fatty liver in obese cows was paralleled by increased hepatic expression of the IRβ, CD36 and SREBP-1. These results suggest that increased expression of hepatic CD36 and SREBP-1 is relevant in the obesity-driven lipid accumulation in the liver of dairy cows during late gestation. Copyright © 2016 Elsevier Ltd. All rights reserved.
Study of Abnormal Liver Function Test during Pregnancy in a Tertiary Care Hospital in Chhattisgarh.

PubMed

Mishra, Nalini; Mishra, V N; Thakur, Parineeta

2016-10-01

Abnormal liver function tests (LFTs) in pregnancy require proper interpretation in order to avoid pitfalls in the diagnosis. The underlying disorder can have a significant effect on the outcome of both mother and foetus. The present study was done with the objective to study the clinical profile, incidence and possible causes of derangements of liver function tests. Eighty pregnant women with abnormal liver dysfunction were studied prospectively. Women with chronic liver disease and drug-induced abnormal liver function test were excluded. All available LFTs including LDH were studied along with some more definitive tests to aid identification of underlying cause. Foetomaternal outcome was noted in all. The incidence of abnormal LFT was 0.9 %. 13/80 (16.75 %) women had liver disorder not specific to pregnancy, whereas 67/80 (83.25 %) women had pregnancy-specific liver dysfunction. Of these, 65(81.25 %) women with liver dysfunction had pre-eclampsia including 11 (13.75 %) with HELLP and six women with eclampsia. 48/65 (60 %) women had pre-eclampsia in the absence of HELLP syndrome or eclampsia. The mean value for bilirubin (mg %) in hypertensive disorders of pregnancy ranged from 1.64 to 3.8, between 5 and 10 for ICP and AFLP and >10 in infective hepatitis. Transaminases were highest in infective hepatitis, whereas alkaline phosphate was highest in ICP. Total 27 (33.75 %) women suffered from adverse outcome with four (5 %) maternal deaths and 23 (28.75 %) major maternal morbidities. 33/80 (41.25 %) women had intrauterine death. 26.25 % babies were small for date. Pregnancy-specific disorders are the leading cause of abnormal liver function test during pregnant state particularly in the third trimester. Pre-eclampsia-related disorder is the commonest. Gestational age of pregnancy and relative values of various liver function tests in different pregnancy-specific and pregnancy nonspecific disorders appear to be the best guide to clinch the diagnosis.
Differential expression profile of membrane proteins in L-02 cells exposed to trichloroethylene.

PubMed

Hong, Wen-Xu; Huang, Aibo; Lin, Sheng; Yang, Xifei; Yang, Linqing; Zhou, Li; Huang, Haiyan; Wu, Desheng; Huang, Xinfeng; Xu, Hua; Liu, Jianjun

2016-10-01

Trichloroethylene (TCE), a halogenated organic solvent widely used in industries, is known to cause severe hepatotoxicity. However, the mechanisms underlying TCE hepatotoxicity are still not well understood. It is predicted that membrane proteins are responsible for key biological functions, and recent studies have revealed that TCE exposure can induce abnormal levels of membrane proteins in body fluids and cultured cells. The aim of this study is to investigate the TCE-induced alterations of membrane proteins profiles in human hepatic L-02 liver cells. A comparative membrane proteomics analysis was performed in combination with two-dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. A total of 15 proteins were identified as differentially expressed (4 upregulated and 11 downregulated) between TCE-treated cells and normal controls. Among this, 14 of them are suggested as membrane-associated proteins by their transmembrane domain and/or subcellular location. Furthermore, the differential expression of β subunit of adenosine triphosphate synthase (ATP5B) and prolyl 4-hydroxylase, β polypeptide (P4HB) were verified by Western blot analysis in TCE-treated L-02 cells. Our work not only reveals the association between TCE exposure and altered expression of membrane proteins but also provides a novel strategy to discover membrane biomarkers and elucidate the potential mechanisms involving with membrane proteins response to chemical-induced toxic effect. © The Author(s) 2015.
Pathways of Polyunsaturated Fatty Acid Utilization: Implications for Brain Function in Neuropsychiatric Health and Disease

PubMed Central

Liu, Joanne J.; Green, Pnina; Mann, J. John; Rapoport, Stanley I.; Sublette, M. Elizabeth

2014-01-01

Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease. PMID:25498862
Withaferin A is a Leptin Sensitizer with Strong Anti-Diabetic Properties in Mice

PubMed Central

Lee, Jaemin; Liu, Junli; Feng, Xudong; Salazar Hernández, Mario Andrés; Mucka, Patrick; Ibi, Dorina; Choi, Jae Won; Ozcan, Umut

2018-01-01

The increasing global prevalence of obesity and its associated disorders point to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules with mRNA expression profiles similar to that of celastrol, a naturally-occurring compound we previously identified as a leptin sensitizer. By this process we identified another natural compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin A treatment of diet-induced obese mice resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities including hepatic steatosis. Withaferin A marginally affects the body weight of ob/ob and db/db mice, which are both deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism independently from its leptin-sensitizing effect. Our results show that the metabolic abnormalities of diet-induced obesity can be mitigated by sensitizing animals to endogenous leptin, and indicate that withaferin A is a potential leptin sensitizer with additional anti-diabetic actions. PMID:27479085
Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice.

PubMed

Lee, Jaemin; Liu, Junli; Feng, Xudong; Salazar Hernández, Mario Andrés; Mucka, Patrick; Ibi, Dorina; Choi, Jae Won; Ozcan, Umut

2016-09-01

The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.
Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.

PubMed

Stock, W; Tsai, T; Golden, C; Rankin, C; Sher, D; Slovak, M L; Pallavicini, M G; Radich, J P; Boldt, D H

2000-04-01

To test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin- compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.
Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis

PubMed Central

Zhang, Xiaoyan; Li, Sha; Zhou, Yunfeng; Su, Wen; Ruan, Xiongzhong; Wang, Bing; Zheng, Feng; Warner, Margaret; Gustafsson, Jan-Åke; Guan, Youfei

2017-01-01

Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a high-fat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD. PMID:28270609
Glial Fibrillary Acidic Protein (GFAP) as a Mesenchymal marker of Early Hepatic Stellate Cells Activation in Liver Fibrosis in Chronic Hepatitis C Infection

PubMed Central

Hassan, Sobia; Syed, Serajuddaula; Kehar, Shahnaz Imdad

2014-01-01

Objective: This study aims to determine expression of Glial Fibrillary Acidic Protein and of Alpha Smooth Muscle Actin (α-SMA) in hepatic stellate cells of CHC cases and their association with stage of fibrosis. Methods: The study was conducted at Ziauddin University, Clifton Campus during the year 2010-2012. Sixty Chronic Hepatitis C cases were immmunostained using anti α-SMA antibody and anti-GFAP antibody. Semi quantitative scoring in pericentral, periportal and perisinusoidal area of each case was done to assess immunoexpression of each marker. Results : Immunoexpression of GFAP showed significant association with α-SMA. GFAP expression was inversely correlated with progression of fibrosis. Conclusion : GFAP could represent a useful marker for early hepatic stellate cells activation. Follow up biopsies showing decline in GFAP levels may help identify the target group requiring aggressive therapy. PMID:25225520
Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat.

PubMed

Sheikh, Nadeem; Dudas, Jozsef; Ramadori, Giuliano

2007-07-01

In the present study, turpentine oil was injected in the hind limb muscle of the rat to stimulate an acute-phase response (APR). The changes in the gene expression of cytokines and proteins known to be involved in the iron regulatory pathway were then studied in the liver and in extra-hepatic tissue. In addition to the strong upregulation of interleukin-6 (IL-6) and IL-1 beta observed in the inflamed muscle, an upregulation of the genes for IL1-beta and tumor necrosis factor-alpha, but not IL-6, were detectable in the liver. Hepatic Hepc gene expression increased to a maximum at 6 h after the onset of APR. An upregulation of transferrin, transferrin receptor 1 (TfR1), TfR2, ferritin-H, iron responsive element binding protein-1 (IRP1), IRP2 and divalent metal transporter gene expression was also found. Hemojuvelin (Hjv)-, ferroportin 1-, Dcytb-, hemochromatosis-gene- and hephaestin gene expression was downregulated. Hepcidin (Hepc) gene expression was not only detectable in extra-hepatic tissues such as heart, small intestine, colon, spleen and kidney but it was also upregulated under acute-phase conditions, with the Hjv gene being regulated antagonistically. Fpn-1 gene expression was downregulated significantly in heart, colon and spleen. Most of the genes of the known proteins involved in iron metabolism are expressed not only in the liver but also in extra-hepatic tissues. Under acute-phase conditions, acute-phase cytokines (eg IL-6) may modulate the gene expression of such proteins not only in the liver but also in other organs.

Liver-specific expression of carboxylesterase 1g/esterase-x reduces hepatic steatosis, counteracts dyslipidemia and improves insulin signaling.

PubMed

Bahitham, Wesam; Watts, Russell; Nelson, Randal; Lian, Jihong; Lehner, Richard

2016-05-01

Ces1g/Es-x deficiency in mice results in weight gain, insulin resistance, fatty liver and hyperlipidemia through upregulation of de novo lipogenesis and oversecretion of triacylglycerol (TG)-rich lipoproteins. Here, we show that restoration of Ces1g/Es-x expression only in the liver significantly reduced hepatic TG concentration accompanied by decreased size of lipid droplets, reduced secretion of very low-density lipoproteins and improved insulin-mediated signal transduction in the liver. Collectively, these results demonstrate that hepatic Ces1g/Es-x plays a critical role in limiting hepatic steatosis, very low-density lipoprotein assembly and in augmenting insulin sensitivity. Copyright © 2016 Elsevier B.V. All rights reserved.
Expression and methylation of microsomal triglyceride transfer protein and acetyl-CoA carboxylase are associated with fatty liver syndrome in chicken.

PubMed

Liu, Zhen; Li, Qinghe; Liu, Ranran; Zhao, Guiping; Zhang, Yonghong; Zheng, Maiqing; Cui, Huanxian; Li, Peng; Cui, Xiaoyan; Liu, Jie; Wen, Jie

2016-06-01

The typical characteristic of fatty liver syndrome (FLS) is an increased hepatic triacylglycerol content, and a sudden decline in egg production often occurs. FLS may develop into fatty liver hemorrhagic syndrome (FLHS), characterized by sudden death from hepatic rupture and hemorrhage. DNA methylation is associated with transcriptional silencing, leading to the etiology and pathogenesis of some animal diseases. The roles of DNA methylation in the genesis of FLS, however, are largely unknown. The lipogenic methyl-deficient diet (MDD) caused FLS similar to human nonalcoholic steatohepatitis (NASH). After 16 Jingxing-Huang (JXH) hens were fed MDD for 10 wk, eight exhibited FLS (designated as FLS-susceptible birds); the remainder, without FLS, served as controls (NFLS). Physiological and biochemical variables, gene expression levels, and DNA methylation were determined in the liver. The development of FLS in JXH hens was accompanied by abnormal lipid accumulation. Relative expression of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and microsomal triglyceride transfer protein (MTTP) were significantly up-regulated in the FLS group in comparison with the NFLS group. The transcript abundance of sterol regulatory element binding protein 1 (SREBP-1c), stearoyl-CoA desaturase (SCD), liver X receptor alpha (LXRα), peroxisome proliferator-activated receptor alpha (PPARα), and peroxisome proliferator-activated receptor gamma (PPARγ) did not differ between the two groups. Interestingly, MTTP and ACC mRNA abundance were negatively correlated with the level of promoter methylation. The extent of DNA methylation of the cytosine-guanine (CpG) sites in the SREBP-1c, FAS, PPARα, and LXRα promoter regions was also analyzed by direct sequencing but none differed between FLS and NFLS birds. Taken together, these results specify link DNA methylation to the pathogenesis of FLS in chickens. © 2016 Poultry Science Association Inc.
Hepatic miRNA profiles and thyroid hormone homeostasis in rats exposed to dietary potassium perfluorooctanesulfonate (PFOS).

PubMed

Dong, Hongyan; Curran, Ivan; Williams, Andrew; Bondy, Genevieve; Yauk, Carole L; Wade, Michael G

2016-01-01

Perfluorooctanesulfonate (PFOS) has been widely used in a variety of industrial and commercial applications as a surfactant and stain repellent. PFOS causes liver damage (including liver tumors) in experimental animals, primarily via interaction with PPARα and CAR/PXR. We investigated the involvement of microRNAs (miRNAs) in PFOS-induced hepatotoxicity, and mechanisms involved in abnormal thyroid hormone (TH) homeostasis, in the livers of adult male rats exposed in feed to 50mg PFOS/kg diet for 28 days. PFOS-treated rats exhibited expected histopathological and clinical chemistry changes, and global gene expression changes consistent with the involvement of PPARα and CAR/PXR. Thirty-eight miRNAs were significantly altered. Three members of the miR-200 family were the most increased, while miR-122-5p and miR-21-5p were the most decreased, in PFOS-treated rats. Expression of the miR-23b-3p/27b-3p/24-3p cluster also decreased in PFOS-treated animals. Pathway analysis of miRNAs and associated gene expression changes suggests involvement of epithelial to mesenchymal transition (EMT), which is a primary process of tumor cell motility and cancer metastasis. Our analysis also revealed transcripts that may mediate PFOS-induced effects on TH homeostasis including: activation of the CAR/PXR pathway, phase II/III enzymes, and deiodinase. These changes are consistent with low serum TH due to enhanced metabolic clearance of TH. However, most TH hepatic target genes were not altered in a manner consistent with reduced TH signaling, suggesting that PFOS exposure did not induce functional hypothyroidism. Collectively, the study suggests an important role for miRNAs in PFOS-induced hepatotoxicity and provides insight into the effects of PFOS on TH homeostasis. Copyright © 2015. Published by Elsevier B.V.
A rise in the plasma activities of hepatic enzymes is not a common consequence of hypoglycaemia.

PubMed

Jones, R G; Grant, P J; Brown, D; Stickland, M; Wiles, P G

1988-04-01

Eight otherwise healthy insulin-dependent diabetic patients were subjected to controlled, symptomatic hypoglycaemia for 20 min (median glucose concentration 1.7 mmol/l, range 1.0-2.6 mmol/l). Concentrations of plasma adrenaline and plasma vasopressin were significantly increased, indicating normal counter-regulatory responses for these hormones. Plasma activities of the hepatic enzymes AST, ALT, LDH, GGT, and CK did not increase during or following the period of hypoglycaemia. Thus, abnormal plasma enzyme activities noted after clinical hypoglycaemia should be fully investigated, and not disregarded as due to the hypoglycaemic episode.
Hepatic lipase deficiency in a Middle-Eastern-Arabic male

PubMed Central

Al Riyami, Nafila; Al-Ali, Abdullah M; Al-Sarraf, Ahmad J; Hill, John; Sachs-Barrable, Kristina; Hegele, Robert; Wasan, Kishor M; Frohlich, Jiri

2010-01-01

Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles. PMID:22798447
Hepatic lipase deficiency in a Middle-Eastern-Arabic male.

PubMed

Al Riyami, Nafila; Al-Ali, Abdullah M; Al-Sarraf, Ahmad J; Hill, John; Sachs-Barrable, Kristina; Hegele, Robert; Wasan, Kishor M; Frohlich, Jiri

2010-11-12

Hepatic lipase (HL) deficiency is a rare genetic disorder that has been associated with premature atherosclerosis despite high plasma high-density lipoprotein (HDL) cholesterol concentrations in the affected individuals. The authors describe the clinical and biochemical features of HL deficiency in a young male of Middle-Eastern-Arabic origin. This is the first report of cholesterol ester transfer protein (CETP) activity and mass in HL deficiency in a patient from this ethnic group. While the CETP mass was high, its activity was low, a discrepancy likely due to the abnormal composition of patient's HDL particles.
Subclinical seizures as a pitfall in 18F-FDG PET imaging of temporal lobe epilepsy.

PubMed

Tafti, Bashir Akhavan; Mandelkern, Mark; Berenji, Gholam Reza

2014-09-01

A 61-year-old man with history of heroin abuse, hepatitis B, hepatitis C, and hypertension was evaluated for seizures. MRI findings were concerning for temporal epilepsy. A brain 18F-FDG PET study showed a hypermetabolic focus in the left temporal lobe, although the patient was asymptomatic during the scan. Later review of electroencephalography recordings revealed a subclinical seizure during imaging. A whole-body 18F-FDG PET scan performed 4 days later for cancer screening purposes, during which the electroencephalography tracings were normal, showed no abnormal metabolic activity in the brain.
Hepatitis B X-interacting protein promotes cisplatin resistance and regulates CD147 via Sp1 in ovarian cancer.

PubMed

Zou, Wei; Ma, Xiangdong; Yang, Hong; Hua, Wei; Chen, Biliang; Cai, Guoqing

2017-03-01

Ovarian cancer is the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure in malignant tumors. Hepatitis B X-interacting protein acts as an oncoprotein, regulates cell proliferation, and migration in breast cancer. We aimed to investigate the effects and mechanisms of hepatitis B X-interacting protein on resistance to cisplatin in human ovarian cancer cell lines. The mRNA and protein levels of hepatitis B X-interacting protein were detected using RT-PCR and Western blotting in cisplatin-resistant and cisplatin-sensitive tissues, cisplatin-resistant cell lines A2780/CP and SKOV3/CP, and cisplatin-sensitive cell lines A2780 and SKOV3. Cell viability and apoptosis were measured to evaluate cellular sensitivity to cisplatin in A2780/CP cells. Luciferase reporter gene assay was used to determine the relationship between hepatitis B X-interacting protein and CD147. The in vivo function of hepatitis B X-interacting protein on tumor burden was assessed in cisplatin-resistant xenograft models. The results showed that hepatitis B X-interacting protein was highly expressed in ovarian cancer of cisplatin-resistant tissues and cells. Notably, knockdown of hepatitis B X-interacting protein significantly reduced cell viability in A2780/CP compared with cisplatin treatment alone. Hepatitis B X-interacting protein and cisplatin cooperated to induce apoptosis and increase the expression of c-caspase 3 as well as the Bax/Bcl-2 ratio. We confirmed that hepatitis B X-interacting protein up-regulated CD147 at the protein expression and transcriptional levels. Moreover, we found that hepatitis B X-interacting protein was able to activate the CD147 promoter through Sp1. In vivo, depletion of hepatitis B X-interacting protein decreased the tumor volume and weight induced by cisplatin. Taken together, these results indicate that hepatitis B X-interacting protein promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines. Impact statement We found that hepatitis B X-interacting protein (HBXIP) was able to activate the CD147 promoter through Sp1. In vivo, depletion of HBXIP decreased the tumor volume and weight induced by CP. Taken together, these results indicate that HBXIP promotes cisplatin resistance and regulated CD147 via Sp1 in ovarian cancer cell lines.
Role of necroptosis in autophagy signaling during hepatic ischemia and reperfusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Jeong-Min; Kim, Seok-Joo; Lee, Sun-Mee, E-ma

Ischemia and reperfusion (I/R) is a complex phenomenon involving massive inflammation and cell death. Necroptosis refers to a newly described cell death as “programmed necrosis” that is controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, which is involved in the pathogenesis of several inflammatory diseases. Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli and involves crosstalk between different modes of cell death and inflammation. In this study, we investigated pattern changes in necroptosis and its role in autophagy signaling during hepatic I/R. Male C57BL/6 mice were subjected to 60 min of ischemiamore » followed by 3 h reperfusion. Necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.65 mg/kg) was administered intraperitoneally 5 min before reperfusion. Hepatic I/R significantly increased the level of RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome formation, which were attenuated by Nec-1. I/R also significantly increased serum levels of alanine aminotransferase, tumor necrosis factor-α, and interleukin-6, which were attenuated by Nec-1. Meanwhile, hepatic I/R activated autophagy and mitophagy, as evidenced by increased LC3-II, PINK1, and Parkin, and decreased sequestosome 1/p62 protein expression. Nec-1 attenuated these changes and attenuated the increased levels of autophagy-related protein (ATG) 3, ATG7, Rab7, and cathepsin B protein expression during hepatic I/R. Moreover, hepatic I/R activated the extracellular signal-regulated kinase (ERK) pathway, and Nec-1 attenuated this increase. Taken together, our findings suggest that necroptosis contributes to hepatic damage during I/R, which induces autophagy via ERK activation. - Highlights: • Hepatic I/R induces RIP1/RIP3-dependent necroptosis. • Necroptosis contributes to hepatic I/R injury. • Necroptosis activates autophagic flux via ERK activation during hepatic I/R.« less
Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring

PubMed Central

Clayton, Zoe E.; Vickers, Mark H.; Bernal, Angelica; Yap, Cassandra; Sloboda, Deborah M.

2015-01-01

Aim Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Methods Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Results Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Conclusions Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may point to impaired immune sensing. PMID:26562417
Acute liver failure during treatment of interferon alpha 2a chronic hepatitis B and coinfection of parvovirus B19

PubMed

Sobala-Szczygieł, Barbara; Boroń-Kaczmarska, Anna; Kępa, Lucjan; Oczko-Grzesik, Barbara; Piotrowski, Damian; Stolarz, Wojciech

Parvovirus B19 infection is associated with a broad spectrum of clinical manifestations among which some are well known but others remain controversial. The role of this infection as a cause of acute hepatitis or exacerbation of chronic liver disease requires discussion regarding its significance in a strategy of prevention and treatment of patients with chronic hepatitis. Clinical importance of this infection in patients with chronic hepatitis B treated with pegylated interferon alpha 2a is still unclear but exactly in this population significant complications during treatment may arise. Parvovirus B19 infection is not rare among persons with chronic hepatitis B, therefore searching for co-infection should be placed in standard diagnostic procedures especially in case of exacerbation of chronic hepatitis, pancytopaenia or anaemia of unknown origin. Pegylated interferon alpha 2a still remains a gold standard of therapy of patients with chronic hepatitis B according to European (EASL) and Polish guidelines. We present a case of 35 years old woman treated with pegylated interferon alpha 2a who developed acute liver failure in 23rd week of chronic hepatitis B therapy. An exacerbation of hepatitis with encephalopathy and pancytopaenia have been observed. Parvovirus B19 and HBV co-infection does not increase the frequency of liver function abnormalities in patients with chronic hepatitis B. Further investigations should be done to describe the natural course of co-infection with parvovirus B19 and HBV and to establish possible association between parvovirus B19 infection and chronic hepatitis B and also the influence of interferon alpha 2a on the infections course.
Impaired adipogenesis in adipose tissue associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet.

PubMed

Yang, Shumin; Zhang, Wenlong; Zhen, Qianna; Gao, Rufei; Du, Tingting; Xiao, Xiaoqiu; Wang, Zhihong; Ge, Qian; Hu, Jinbo; Ye, Peng; Zhu, Qibo; Li, Qifu

2015-09-15

Chronic inflammation might be associated with hepatic lipid deposition independent of overnutrition. However, the mechanism is not fully understood. In this study, we investigate if impaired adipogenesis in adipose tissue is associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet. Casein injection in C57BL/6J mice was given every other day to induce chronic inflammation. All mice were sacrificed after 18weeks of injections. The serum, liver and adipose tissue were collected for analysis. Real-time polymerase chain reaction and western blotting were used to examine the gene and protein expressions of molecules involved in hepatic lipid metabolism and adipose adipogenesis. Casein injection elevated serum levels of insulin, free fatty acid (FFA) and proinflammatory factors. The gene expression of proinflammatory factors of adipose tissue and the liver also increased in the casein group as compared with the control group. Chronic inflammation up-regulated the hepatic expression of fatty acid translocase (CD36) and down-regulated microsomal triacylglycerol transfer protein (MTP), carnitine palmitoyltransferase 1a (CPT1a) and acyl-coenzyme a oxidase 1 (ACOX1). Meanwhile, chronic inflammation not only diminished the size of adipocytes, but also down-regulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding proteinα (C/EBPα), both indicating an impaired adipogenesis. Besides disturbed lipid metabolism in the liver per se, impaired adipogenesis in the adipose tissue might also be associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet. Copyright © 2015 Elsevier Inc. All rights reserved.
Pro-Inflammatory Activated Kupffer Cells by Lipids Induce Hepatic NKT Cells Deficiency through Activation-Induced Cell Death

PubMed Central

Tang, Tongfang; Sui, Yongheng; Lian, Min; Li, Zhiping; Hua, Jing

2013-01-01

Background Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response. Aims The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. Methods Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. Results High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. Conclusion High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD. PMID:24312613
STAT5A and STAT5B have opposite correlations with drug response gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamba, V., E-mail: vlamba@ufl.edu; Jia, B.; Liang, F.

Introduction: STAT5A and STAT5B are important transcription factors that play a key role in regulation of several important physiological processes including proliferation, survival, mediation of responses to cytokines and in regulating gender differences in drug response genes such as the hepatic cytochrome P450s (CYPs) that are responsible for a large majority of drug metabolism reactions in the human body. STAT5A and STAT5b have a high degree of sequence homology and have been reported to have largely similar functions. Recent studies have, however, indicated that they can also often have distinct and unique roles in regulating gene expression. Objective: In thismore » study, we evaluated the association of STAT5A and STAT5B mRNA expression levels with those of several key hepatic cytochrome P450s (CYPs) and hepatic transcription factors (TFs) and evaluated the potential roles of STAT5A and 5b in mediating gender differences in these CYPs and TFs. Methods: Expression profiling for major hepatic CYP isoforms and transcription factors was performed using RNA sequencing (RNA-seq) in 102 human liver samples (57 female, 45 male). Real time PCR gene expression data for selected CYPs and TFs was available on a subset of 50 human liver samples (25 female, 25 male) and was used to validate the RNA-seq findings. Results: While STAT5A demonstrated significant negative correlation with expression levels of multiple hepatic transcription factors (including NR1I2 and HNF4A) and DMEs such as CYP3A4 and CYP2C19, STAT5B expression was observed to demonstrate positive associations with several CYPs and TFs analyzed. As STAT5A and STAT5B have been shown to be important in regulation of gender differences in CYPs, we also analyzed STAT5A and 5b associations with CYPs and TFs separately in males and females and observed gender dependent differential associations of STATs with several CYPs and TFs. Results from the real time PCR validation largely supported our RNA-seq findings. Conclusions: Using both RNA sequencing and real time PCR, we examined the association of STAT5A and STAT5B mRNA expression with CYP and TF gene expression. While STAT5A demonstrated significant negative correlations with expression levels of multiple hepatic TFs (including NR1I2 and HNF4α) and CYPs (eg. CYP3A4, CYP2C19), STAT5B expression was observed to demonstrate positive association with most of the CYPs/TFs analyzed suggesting that STAT5A and STAT5b have potentially different and distinct roles in regulating expression of hepatic drug response genes. Further studies are needed to elucidate the potential roles of STAT5A and 5b in regulation of CYPs/TFs and the potential implications of these findings.« less
A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

PubMed

Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

2012-08-27

The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.
A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione

PubMed Central

Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

2012-01-01

The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients. PMID:22993667
Hepatic encephalopathy: cause and possible management with botanicals.

PubMed

Tripathi, Suyash; Tripathi, Yamini B

2014-01-01

Hepatic encephalopathy is a brain functional disorder, characterized by neuropsychiatric abnormalities with liver failure. High blood ammonia, causing glutamate neurotoxicity is the basic cause, finally leading to low-grade cerebral edema. Its manifestation is more likely in patients of sepsis, oxidative stress, generalized inflammation, gut mal-functioning, amoebiaesis, viral hepatitis, nervous imbalance, etc. Thus, the therapeutic goals primarily include the maintenance of proper blood supply and prevention of hypoxic condition in liver, along with management of factors responsible for high blood ammonia, oxidative stress, inflammation, and high GI- serotonin. The drugs in clinical practice include lactulose, sodium benzoate, flumazenil and rifaximin, supplementation of zinc, branched chain amino acids (BCAA), l-ornithine-l aspartate, antioxidants and iNOS inhibitors. However, herbal formulations would be of great importance as it shows multi-targeted action because it possesses a natural cocktail of secondary metabolites. It can collectively act as an antioxidant, anti-inflammatory, prebiotic, hepatoprotective and neuron-protective agents. We have briefly outlined some of these plants and also recent patents useful in the management of hepatic encephalopathy.
Diagnostic value of Doppler assessment of the hepatic and portal vessels and ultrasound of the spleen in liver disease.

PubMed

O'Donohue, John; Ng, Chaan; Catnach, Susan; Farrant, Patricia; Williams, Roger

2004-02-01

To investigate the clinical utility and the intra-observer and inter-observer variability of Doppler ultrasound assessment of the hepatic and portal vessels along with measurement of spleen size in the diagnosis of chronic liver disease and cirrhosis. Ultrasound measurements of portal vein diameter (PVD), portal vein velocity (PVV), hepatic arterial resistance index (HARI), hepatic vein profile (HVP), and spleen size were obtained in 49 controls and 45 patients with liver disease (23 with primary biliary cirrhosis, 22 with hepatitis C) by two experienced observers, who each performed three blinded measurements of each variable. Control values were derived from normal hospital workers. Percutaneous liver biopsies in 41 of the patients showed cirrhosis (14 patients), moderate/severe fibrosis (13 patients), and early disease (14 patients). Seventy-one percent of cirrhotic patients had splenomegaly (> 13.6 cm). The spleen size was significantly larger in cirrhotics (16.0 cm) than in non-cirrhotics (13.0 cm, P < 0.009) and healthy controls (10.7 cm, P < 0.00005), and was the only independent predictor of cirrhosis, with a threshold of 15 cm predicting cirrhosis with a specificity of 98%, positive predictive value of 93%, sensitivity of 57% and negative predictive value of 80%. HVP was abnormal in 76.9% of cirrhotics, 57.7% of non-cirrhotics and 2.1% of controls (P < 0.04). However, the mean PVV, PVD and HARI were no different between controls and patients or between cirrhotic and non-cirrhotic liver disease. There was significant inter-observer variability for PVV, but intra-observer and inter-observer variability was acceptable for the other measurements. Splenomegaly size and abnormal HVP are useful predictors of chronic liver disease and cirrhosis, and both can be measured reliably and reproducibly. However, Doppler measurements of PVV, PVD and HARI are not useful in distinguishing patients with chronic liver disease from normal controls.
Differentiation of umbilical cord derived mesenchymal stem cells to hepatocyte cells by transfection of miR-106a, miR-574-3p, and miR-451.

PubMed

Khosravi, Maryam; Azarpira, Negar; Shamdani, Sara; Hojjat-Assari, Suzzan; Naserian, Sina; Karimi, Mohammad Hossein

2018-08-15

Studying the profile of micro RNAs (miRs) elucidated the highest expressed miRs in hepatic differentiation. In this study, we investigated to clarify the role of three embryonic overexpressed miRs (miR-106a, miR-574-3p and miR-451) during hepatic differentiation of human umbilical cord derived mesenchymal stem cells (UC-MSCs). We furthermore, aimed to explore whether overexpression of any of these miRs alone is sufficient to induce the differentiation of the UC-MSCs into hepatocyte-like cells. UC-MSCs were transfected either alone or together with miR-106a, miR-574-3p and miR-451 and their potential hepatic differentiation and alteration in gene expression profile, morphological changes and albumin secretion ability were investigated. We found that up-regulation of any of these three miRs alone cannot induce expression of all hepatic specific genes. Transfection of each miR alone, led to Sox17, FoxA2 expression that are related to initiation step of hepatic differentiation. However, concurrent ectopic overexpression of three miRs together can induce UC-MSCs differentiation into functionally mature hepatocytes. These results show that miRs have the capability to directly convert UC-MSCs to a hepatocyte phenotype in vitro. Copyright © 2018. Published by Elsevier B.V.
Effects of strain and age on hepatic gene expression profiles in murine models of HFE-associated hereditary hemochromatosis.

PubMed

Lee, Seung-Min; Loguinov, Alexandre; Fleming, Robert E; Vulpe, Christopher D

2015-01-01

Hereditary hemochromatosis is an iron overload disorder most commonly caused by a defect in the HFE gene. While the genetic defect is highly prevalent, the majority of individuals do not develop clinically significant iron overload, suggesting the importance of genetic modifiers. Murine hfe knockout models have demonstrated that strain background has a strong effect on the severity of iron loading. We noted that hepatic iron loading in hfe-/- mice occurs primarily over the first postnatal weeks (loading phase) followed by a timeframe of relatively static iron concentrations (plateau phase). We thus evaluated the effects of background strain and of age on hepatic gene expression in Hfe knockout mice (hfe-/-). Hepatic gene expression profiles were examined using cDNA microarrays in 4- and 8-week-old hfe-/- and wild-type mice on two different genetic backgrounds, C57BL/6J (C57) and AKR/J (AKR). Genes differentially regulated in all hfe-/- mice groups, compared with wild-type mice, including those involved in cell survival, stress and damage responses and lipid metabolism. AKR strain-specific changes in lipid metabolism genes and C57 strain-specific changes in cell adhesion and extracellular matrix protein genes were detected in hfe-/- mice. Mouse strain and age are each significantly associated with hepatic gene expression profiles in hfe-/- mice. These affects may underlie or reflect differences in iron loading in these mice.

CRACC-CRACC Interaction between Kupffer and NK Cells Contributes to Poly I:C/D-GalN Induced Hepatitis

PubMed Central

Li, Yangxi; Cao, Guoshuai; Zheng, Xiaodong; Wang, Jun; Wei, Haiming; Tian, Zhigang; Sun, Rui

2013-01-01

CD2-like receptor activating cytotoxic cells (CRACC) is known as a critical activating receptor of natural killer (NK) cells. We have previously reported that NK cells contribute to Poly I:C/D-galactosamine (D-GalN)-induced fulminant hepatitis. Since natural killer group 2, member D (NKG2D) is considered critical but not the only activating receptor for NK cells, we investigated the role of CRACC in this model. We found that CRACC was abundant on hepatic NK cells but with low expression levels on Kupffer cells under normal conditions. Expression of CRACC on NK cells and Kupffer cells was remarkably upregulated after poly I:C injection. Hepatic CRACC mRNA levels were also upregulated in Poly I:C/D-GalN-treated mice, and correlated positively with the serum alanine aminotransferase (ALT) levels. CRACC expression on Kupffer cells was specifically silenced by nano-particle encapsulated siRNA in vivo, which significantly reduced Poly I:C/D-GalN-induced liver injury. In co-culture experiments, it was further verified that silencing CRACC expression or blockade of CRACC activation by mAb reduced the production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Collectively, our findings suggest that CRACC-CRACC interaction between NK cells and resident Kupffer cells contributes to Poly I:C/D-GalN-induced fulminant hepatitis. PMID:24098802
Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

NASA Astrophysics Data System (ADS)

Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

2016-01-01

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.
Transforming growth factor beta1 gene variation Leu10Pro affects secretion and function in hepatic cells.

PubMed

Gu, Xing; Ji, Xin; Shi, Le-Hua; Yi, Chang-Hong; Zhao, Yun-Peng; Wang, Ai-Hua; Lu, Lun-Gen; Yu, Wen-Bo; Gao, Chun-Fang

2012-11-01

Our previous work revealed transforming growth factor beta1 (TGFβ1) gene polymorphisms are associated with susceptibility to hepatocellular carcinoma and liver cirrhosis. However, no further study of functional substitution in hepatic cells has yet been reported. This study was designed to uncover the functional mechanisms of TGFβ1 gene polymorphisms in the pathogenesis of liver diseases. Two recombinant TGFβ1 expression plasmids containing TGFβ1 codon 10 Leu/Pro variation were constructed with CMV promoter and transfected into human hepatoma cell lines (HepG2 and SMMU 7721), hepatic stellate cells (LX-2), and immortalized hepatocytes (L02). The secretion capacities of TGFβ1 protein in the transfected cells were determined by ELISA. Apoptosis, proliferative activity, and expression of CD 105, CD83, and CD80 were also measured by use of flow cytometry. The ELISA results showed that cells transfected with CMV-Pro10 were more capable of TGFβ1 secretion than those transfected with CMV-Leu10. Functionally, CMV-Pro10 was more apoptosis-protective and induced more proliferation than CMV-Leu10 in transfected hepatic cells. Pro10 up-regulated expression of CD105 and down-regulated expression of CD83. TGFβ1 gene Leu10Pro variation in signal peptide has significant effects on TGFβ1 secretion and functions in hepatic cells.
A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver.

PubMed

Takaya, Junji; Iharada, Anna; Okihana, Hiroyuki; Kaneko, Kazunari

2013-11-01

Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring. © 2013.
The effect of isorhamnetin glycosides extracted from Opuntia ficus-indica in a mouse model of diet induced obesity.

PubMed

Rodríguez-Rodríguez, César; Torres, Nimbe; Gutiérrez-Uribe, Janet A; Noriega, Lilia G; Torre-Villalvazo, Iván; Leal-Díaz, Ana M; Antunes-Ricardo, Marilena; Márquez-Mota, Claudia; Ordaz, Guillermo; Chavez-Santoscoy, Rocío A; Serna-Saldivar, Sergio O; Tovar, Armando R

2015-03-01

A diet rich in polyphenols can ameliorate some metabolic alterations associated with obesity and type 2 diabetes. Opuntia ficus-indica (OFI) is a plant rich in isorhamnetin glycosides and is highly consumed in Mexico. The purpose of this research was to determine the metabolic effect of an OFI extract on a mouse model of diet-induced obesity and in isolated pancreatic islets. OFI extract was added to a high fat (HF) diet at a low (0.3%) or high (0.6%) dose and administered to C57BL/6 mice for 12 weeks. Mice fed the HF diet supplemented with the OFI extract gained less body weight and exhibited significantly lower circulating total cholesterol, LDL cholesterol and HDL cholesterol compared to those fed the HF diet alone. The HF-OFI diet fed mice presented lower glucose and insulin concentration than the HF diet fed mice. However, the HF-OFI diet fed mice tended to have higher insulin concentration than control mice. The OFI extract stimulated insulin secretion in vitro, associated with increased glucose transporter 2 (GLUT2) and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA content. Furthermore, the OFI extract improved glucose tolerance, and additionally increased energy expenditure. These metabolic improvements were associated with reduced adipocyte size, increased hepatic IRS1 tyr-608 and S6 K thr-389 phosphorylation. OFI isorhamnetin glycosides also diminished the hepatic lipid content associated with reduced mRNA expression of the endoplasmic reticulum stress markers and lipogenic enzymes and increased mRNA expression of genes related to fatty acid oxidation. Overall, the OFI extract prevented the development of metabolic abnormalities associated with diet-induced obesity.
Abnormal Chloride Homeostasis in the Substancia Nigra Pars Reticulata Contributes to Locomotor Deficiency in a Model of Acute Liver Injury

PubMed Central

Wei, Yan-Yan; Chen, Jing; Dou, Ke-Feng; Wang, Ya-Yun

2013-01-01

Background Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. Methods Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. Results In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. Conclusion Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure. PMID:23741482
Gonadal development and transcript profiling of steroidogenic enzymes in response to 17α-methyltestosterone in the rare minnow Gobiocypris rarus.

PubMed

Liu, Shaozhen; Wang, Lihong; Qin, Fang; Zheng, Yao; Li, Meng; Zhang, Yingying; Yuan, Cong; Wang, Zaizhao

2014-09-01

It is well known that natural and anthropogenic chemicals interfere with the hormonal system of vertebrate and invertebrate organisms. How these chemicals regulate gonadal steroidogenesis remains to be determined. The main objective of this study was to evaluate the effects of 17α-methyltestosterone (MT), a synthetic model androgen, on gene expression profiles of six key steroidogenic genes in adult rare minnow. The full-length cDNA encoding 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) was firstly isolated and characterized by RT-PCR and RACE methods. The gonadal transcript changes of StAR, cyp11a1, 3β-HSD, cyp17a1, 11β-HSD2 and cyp19a1a in 6-month adult Gobiocypris rarus exposed to MT and 17α-ethinylestradiol (EE2) for 7, 14 and 21 days were detected by qRT-PCR. To make an effort to connect the transcriptional changes of steroidogenic enzymes with effects on higher levels of biological organization and on VTG, one remarkable sensitive target of steroids, body and gonad weights, histology of gonads, and hepatic vtg mRNA level were measured. MT caused varying degree of abnormalities in ovaries and testes. The hepatic vtg mRNA level was highly inhibited in females and slightly altered in males by MT. Transcripts of several steroidogenic genes including StAR, cyp17a1, and cyp11a1 showed high responsiveness to MT exposure in G. rarus. The gene expression profiles of these steroidogenic genes in MT-treated groups were much distinct with the EE2-treated group. Copyright © 2014 Elsevier Ltd. All rights reserved.
Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.

PubMed

Prakash, Prem; Singh, Vishal; Jain, Manish; Rana, Minakshi; Khanna, Vivek; Barthwal, Manoj Kumar; Dikshit, Madhu

2014-03-15

High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. Copyright © 2014 Elsevier B.V. All rights reserved.
Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

PubMed

Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

2016-01-01

Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.
Trivalent chromium alleviates oleic acid induced steatosis in SMMC-7721 cells by decreasing fatty acid uptake and triglyceride synthesis.

PubMed

Wang, Song; Wang, Jian; Zhang, Xiaonan; Hu, Linlin; Fang, Zhijia; Huang, Zhiwei; Shi, Ping

2016-10-01

Trivalent chromium [Cr(III)] has been shown as an essential trace element for human health. Previous studies depict that Cr(III) plays important roles in maintaining normal glucose and lipid metabolism, whereas its effect on the hepatic lipid metabolism is still unknown. In the present study, we investigated the effects and underlying mechanisms of Cr on hepatic steatosis induced by oleic acid (OA) in human hepatoma SMMC-7721 cells. Hepatic steatosis model was co-administered with Cr. Indexes of lipid accumulation were determined and associated genes expression were analyzed. The data showed that OA could induce lipid accumulation and triglyceride (TG) content in SMMC-7721 cells, and significantly increase the expression of cluster of differentiation 36 (CD36) and diacylglycerol acyltransferase 2 (DGAT2). This steatosis effect of OA was ameliorated by Cr. The TG accumulation and up-regulation of CD36 and DGAT2 genes followed steatosis induction were inhibited by Cr. After the treatment of Cr, excessive intracellular OA content was also attenuated. Furthermore, Cr still performed inhibitory effect of DGAT2 expression at the presence of DGAT2 agonist or inhibitor, which indicated that the inhibitory effect of Cr on lipogenesis is associated with the downregulation of DGAT2 expression. These findings demonstrate that Cr alleviates hepatic steatosis via suppressing CD36 expression to prevent fatty acid uptake, as well as suppressing DGAT2 expression to inhibit TG synthesis. It suggests that CD36 and DGAT2 might become the novel drug targets for their properties in hepatic steatosis. Most importantly, Cr may be a potential anti-steatosis candidate to offer protective effects against liver damage.
Graft reconditioning with nitric oxide gas in rat liver transplantation from cardiac death donors.

PubMed

Kageyama, Shoichi; Yagi, Shintaro; Tanaka, Hirokazu; Saito, Shunichi; Nagai, Kazuyuki; Hata, Koichiro; Fujimoto, Yasuhiro; Ogura, Yasuhiro; Tolba, Rene; Shinji, Uemoto

2014-03-27

Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor. We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group). Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01). These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.
A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice.

PubMed

Yan, Caifeng; Chen, Jinfeng; Li, Min; Xuan, Wenying; Su, Dongming; You, Hui; Huang, Yujie; Chen, Nuoqi; Liang, Xiubin

2016-07-01

MicroRNA-9 (miR-9) is involved in the regulation of pancreatic beta cell function. However, its role in gluconeogenesis is still unclear. Our objective was to investigate the role of miR-9 in hepatic glucose production (HGP). MiR-9 expression was measured in livers of high-fat diet (HFD) mice and ob/ob mice. The methylation status of the miR-9-3 promoter regions in hepatocytes was determined by the methylation-specific PCR procedure. The binding activity of DNA methyltransferase (DNMT)1, DNMT3a and DNMT3b on the miR-9-3 promoter was detected by chromatin immunoprecipitation (ChIP) and quantitative real-time PCR assays. HGP was evaluated in vitro and in vivo. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were also performed. Reduced miR-9 expression and hypermethylation of the miR-9-3 promoter were observed in the livers of obese mice. Further study showed that the binding of DNMT1, but not of DNMT3a and DNMT3b, to the miR-9-3 promoter was increased in hepatocytes from ob/ob mice. Knockdown of DNMT1 alleviated the decrease in hepatic miR-9 expression in vivo and in vitro. Overexpression of hepatic miR-9 improved insulin sensitivity in obese mice and inhibited HGP. In addition, deletion of hepatic miR-9 led to an increase in random and fasting blood glucose levels in lean mice. Importantly, silenced forkhead box O1 (FOXO1) expression reversed the gluconeogenesis and glucose production in hepatocytes induced by miR-9 deletion. Our observations suggest that the decrease in miR-9 expression contributes to an inappropriately activated gluconeogenesis in obese mice.
Alterations of Hepatic Metabolism in Chronic Kidney Disease via D-box-binding Protein Aggravate the Renal Dysfunction.

PubMed

Hamamura, Kengo; Matsunaga, Naoya; Ikeda, Eriko; Kondo, Hideaki; Ikeyama, Hisako; Tokushige, Kazutaka; Itcho, Kazufumi; Furuichi, Yoko; Yoshida, Yuya; Matsuda, Masaki; Yasuda, Kaori; Doi, Atsushi; Yokota, Yoshifumi; Amamoto, Toshiaki; Aramaki, Hironori; Irino, Yasuhiro; Koyanagi, Satoru; Ohdo, Shigehiro

2016-03-04

Chronic kidney disease (CKD) is associated with an increase in serum retinol; however, the underlying mechanisms of this disorder are poorly characterized. Here, we found that the alteration of hepatic metabolism induced the accumulation of serum retinol in 5/6 nephrectomy (5/6Nx) mice. The liver is the major organ responsible for retinol metabolism; accordingly, microarray analysis revealed that the hepatic expression of most CYP genes was changed in 5/6Nx mice. In addition, D-box-binding protein (DBP), which controls the expression of several CYP genes, was significantly decreased in these mice. Cyp3a11 and Cyp26a1, encoding key proteins in retinol metabolism, showed the greatest decrease in expression in 5/6Nx mice, a process mediated by the decreased expression of DBP. Furthermore, an increase of plasma transforming growth factor-β1 (TGF-β1) in 5/6Nx mice led to the decreased expression of the Dbp gene. Consistent with these findings, the alterations of retinol metabolism and renal dysfunction in 5/6Nx mice were ameliorated by administration of an anti-TGF-β1 antibody. We also show that the accumulation of serum retinol induced renal apoptosis in 5/6Nx mice fed a normal diet, whereas renal dysfunction was reduced in mice fed a retinol-free diet. These findings indicate that constitutive Dbp expression plays an important role in mediating hepatic dysfunction under CKD. Thus, the aggravation of renal dysfunction in patients with CKD might be prevented by a recovery of hepatic function, potentially through therapies targeting DBP and retinol. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Expression and function of the atypical cadherin FAT1 in chronic liver disease.

PubMed

Valletta, Daniela; Czech, Barbara; Thasler, Wolfgang E; Müller, Martina; Bosserhoff, Anja-Katrin; Hellerbrand, Claus

2012-09-28

Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during in vitro activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease. Copyright © 2012 Elsevier Inc. All rights reserved.
A hepatic amino acid/mTOR/S6K-dependent signalling pathway modulates systemic lipid metabolism via neuronal signals.

PubMed

Uno, Kenji; Yamada, Tetsuya; Ishigaki, Yasushi; Imai, Junta; Hasegawa, Yutaka; Sawada, Shojiro; Kaneko, Keizo; Ono, Hiraku; Asano, Tomoichiro; Oka, Yoshitomo; Katagiri, Hideki

2015-08-13

Metabolism is coordinated among tissues and organs via neuronal signals. Levels of circulating amino acids (AAs), which are elevated in obesity, activate the intracellular target of rapamycin complex-1 (mTORC1)/S6kinase (S6K) pathway in the liver. Here we demonstrate that hepatic AA/mTORC1/S6K signalling modulates systemic lipid metabolism via a mechanism involving neuronal inter-tissue communication. Hepatic expression of an AA transporter, SNAT2, activates the mTORC1/S6K pathway, and markedly elevates serum triglycerides (TGs), while downregulating adipose lipoprotein lipase (LPL). Hepatic Rheb or active-S6K expression have similar metabolic effects, whereas hepatic expression of dominant-negative-S6K inhibits TG elevation in SNAT2 mice. Denervation, pharmacological deafferentation and β-blocker administration suppress obesity-related hypertriglyceridemia with adipose LPL upregulation, suggesting that signals are transduced between liver and adipose tissue via a neuronal pathway consisting of afferent vagal and efferent sympathetic nerves. Thus, the neuronal mechanism uncovered here serves to coordinate amino acid and lipid levels and contributes to the development of obesity-related hypertriglyceridemia.
Oral MSG administration alters hepatic expression of genes for lipid and nitrogen metabolism in suckling piglets.

PubMed

Chen, Gang; Zhang, Jun; Zhang, Yuzhe; Liao, Peng; Li, Tiejun; Chen, Lixiang; Yin, Yulong; Wang, Jinquan; Wu, Guoyao

2014-01-01

This experiment was conducted to investigate the effects of oral administration of monosodium glutamate (MSG) on expression of genes for hepatic lipid and nitrogen metabolism in piglets. A total of 24 newborn pigs were assigned randomly into one of four treatments (n = 6/group). The doses of oral MSG administration, given at 8:00 and 18:00 to sow-reared piglets between 0 and 21 days of age, were 0 (control), 0.06 (low dose), 0.5 (intermediate dose), and 1 (high dose) g/kg body weight/day. At the end of the 3-week treatment, serum concentrations of total protein and high-density lipoprotein cholesterol in the intermediate dose group were elevated than those in the control group (P < 0.05). Hepatic mRNA levels for fatty acid synthase, acetyl-coA carboxylase, insulin-like growth factor-1, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were higher in the middle-dose group (P < 0.05), compared with the control group. MSG administration did not affect hepatic mRNA levels for hormone-sensitive lipase or carnitine palmitoyl transferase-1. We conclude that oral MSG administration alters hepatic expression of certain genes for lipid and nitrogen metabolism in suckling piglets.
Effects of Lactobacillus fermented soymilk and soy yogurt on hepatic lipid accumulation in rats fed a cholesterol-free diet.

PubMed

Kitawaki, Ryoko; Nishimura, Yuko; Takagi, Naohiro; Iwasaki, Mitsuhiro; Tsuzuki, Kimiko; Fukuda, Mitsuru

2009-07-01

We examined the effects of lactic acid fermented soymilk, in which part of the soymilk was replaced with okara (soy yogurt), on plasma and hepatic lipid profiles in rats fed a cholesterol-free diet. Additionally, we investigated the effects of soy yogurt on hepatic gene expression in rats using DNA microarray analysis. Male Sprague-Dawley rats aged 5 weeks (n=5/group) were fed a control diet (AIN-93) or a test diet in which 20% of the diet was replaced by soy yogurt for 7 weeks. Soy yogurt consumption did not affect body weight or adipose tissue weight as compared with control diet. In the soy yogurt group, the liver weight and hepatic triglyceride content were significantly lower than the control group, and the level of plasma cholesterol was also lower. Furthermore, DNA microarray analysis indicated that soy yogurt ingestion down-regulated the expression of the SREBP-1 gene and enzymes related to lipogenesis in the rat liver, while expression of beta-oxidation-related genes was up-regulated. These results suggest that soy yogurt is beneficial in preventing hepatic lipid accumulation in rats.
Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: Novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease.

PubMed

Lin, Yi; Ding, Dongxiao; Huang, Qiansheng; Liu, Qiong; Lu, Haoyang; Lu, Yanyang; Chi, Yulang; Sun, Xia; Ye, Guozhu; Zhu, Huimin; Wei, Jie; Dong, Sijun

2017-09-01

Exposure to Bisphenol A (BPA) has been associated with the development of nonalcoholic fatty liver disease (NAFLD) but the underlying mechanism remains unclear. Given that microRNA (miRNA) is recognized as a key regulator of lipid metabolism and a potential mediator of environmental cues, this study was designed to explore whether exposure to BPA-triggered abnormal steatosis and lipid accumulation in the liver could be modulated by miR-192. We showed that male post-weaning C57BL/6 mice exposed to 50μg/kg/day of BPA by oral gavage for 90days displayed a NAFLD-like phenotype. In addition, we found in mouse liver and human HepG2 cells that BPA-induced hepatic steatosis and lipid accumulation were associated with decreased expression of miR-192, upregulation of SREBF1 and a series of genes involved in de novo lipogenesis. Downregulation of miR-192 in BPA-exposed hepatocytes could be due to defective pre-miR-192 processing by DROSHA. Using HepG2 cells, we further confirmed that miR-192 directly acted on the 3'UTR of SREBF1, contributing to dysregulation of lipid homeostasis in hepatocytes. MiR-192 mimic and lentivirus-mediated overexpression of miR-192 improved BPA-induced hepatic steatosis by suppressing SREBF1. Lastly, we noted that lipid accumulation was not a strict requirement for developing insulin resistance in mice after BPA treatment. In conclusion, this study demonstrated a novel mechanism in which NAFLD associated with BPA exposure arose from alterations in the miR-192-SREBF1 axis. Copyright © 2017 Elsevier B.V. All rights reserved.
Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strakovsky, Rita S.; Wang, Huan; Engeseth, Nicki J.

Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate the potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague–Dawley rats were dosed with vehicle (oil) or BPA (100 μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C,more » and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglyceride (TG) and free fatty acid (FFA) compositions in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet. - Highlights: • Developmental BPA exposure exacerbates HF-diet induced steatosis in adult males. • Gestational BPA exposure increases hepatic lipid accumulation in neonatal males. • BPA decreases Cpt1a and other hepatic β-oxidation genes in neonatal males. • BPA alters neonatal male Cpt1a DNA methylation, histones, and transcription factors.« less
Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J., E-mail: Thomas.Weber@pnl.gov

Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional programmore » encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.« less

Knockout of the aryl hydrocarbon receptor results in distinct hepatic and renal phenotypes in rats and mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harrill, Joshua A.; Hukkanen, Renee R.; Lawson, Marie

2013-10-15

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor which plays a role in the development of multiple tissues and is activated by a large number of ligands, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In order to examine the roles of the AHR in both normal biological development and response to environmental chemicals, an AHR knockout (AHR-KO) rat model was created and compared with an existing AHR-KO mouse. AHR-KO rats harboring either 2-bp or 29-bp deletion mutation in exon 2 of the AHR were created on the Sprague–Dawley genetic background using zinc-finger nuclease (ZFN) technology. Rats harboring either mutation type lacked expressionmore » of AHR protein in the liver. AHR-KO rats were also insensitive to thymic involution, increased hepatic weight and the induction of AHR-responsive genes (Cyp1a1, Cyp1a2, Cyp1b1, Ahrr) following acute exposure to 25 μg/kg TCDD. AHR-KO rats had lower basal expression of transcripts for these genes and also accumulated ∼ 30–45-fold less TCDD in the liver at 7 days post-exposure. In untreated animals, AHR-KO mice, but not AHR-KO rats, had alterations in serum analytes indicative of compromised hepatic function, patent ductus venosus of the liver and persistent hyaloid arteries in the eye. AHR-KO rats, but not AHR-KO mice, displayed pathological alterations to the urinary tract: bilateral renal dilation (hydronephrosis), secondary medullary tubular and uroepithelial degenerative changes and bilateral ureter dilation (hydroureter). The present data indicate that the AHR may play significantly different roles in tissue development and homeostasis and toxicity across rodent species. - Highlights: • An AHR knockout rat was generated on a Sprague–Dawley outbred background. • AHR-KO rats lack expression of AHR protein. • AHR-KO rats are insensitive to TCDD-mediated effects. • Data suggests difference in the role of AHR in tissue development of rats and mice. • Abnormalities in vascular development are observed in AHR-KO mouse, but not rat. • Renal pathology is observed in AHR-KO rat, but not mouse.« less
Genomic Methylation Inhibits Expression of Hepatitis B Virus Envelope Protein in Transgenic Mice: A Non-Infectious Mouse Model to Study Silencing of HBV Surface Antigen Genes.

PubMed

Graumann, Franziska; Churin, Yuri; Tschuschner, Annette; Reifenberg, Kurt; Glebe, Dieter; Roderfeld, Martin; Roeb, Elke

2015-01-01

The Hepatitis B virus genome persists in the nucleus of virus infected hepatocytes where it serves as template for viral mRNA synthesis. Epigenetic modifications, including methylation of the CpG islands contribute to the regulation of viral gene expression. The present study investigates the effects of spontaneous age dependent loss of hepatitis B surface protein- (HBs) expression due to HBV-genome specific methylation as well as its proximate positive effects in HBs transgenic mice. Liver and serum of HBs transgenic mice aged 5-33 weeks were analyzed by Western blot, immunohistochemistry, serum analysis, PCR, and qRT-PCR. From the third month of age hepatic loss of HBs was observed in 20% of transgenic mice. The size of HBs-free area and the relative number of animals with these effects increased with age and struck about 55% of animals aged 33 weeks. Loss of HBs-expression was strongly correlated with amelioration of serum parameters ALT and AST. In addition lower HBs-expression went on with decreased ER-stress. The loss of surface protein expression started on transcriptional level and appeared to be regulated epigenetically by DNA methylation. The amount of the HBs-expression correlated negatively with methylation of HBV DNA in the mouse genome. Our data suggest that methylation of specific CpG sites controls gene expression even in HBs-transgenic mice with truncated HBV genome. More important, the loss of HBs expression and intracellular aggregation ameliorated cell stress and liver integrity. Thus, targeted modulation of HBs expression may offer new therapeutic approaches. Furthermore, HBs-transgenic mice depict a non-infectious mouse model to study one possible mechanism of HBs gene silencing by hypermethylation.
Isoform-specific regulation of cytochrome P450 expression and activity by estradiol in female rats

PubMed Central

Choi, Su-Young; Fischer, Liam; Yang, Kyunghee; Chung, Hyejin; Jeong, Hyunyoung

2011-01-01

Estradiol (E2) is the major endogenous estrogen, and its plasma concentration increases up to 100-fold during pregnancy in humans. Accumulating evidence suggests that an elevated level of E2 may influence hepatic drug metabolism, potentially being responsible for altered drug metabolism during pregnancy. We characterized effects of E2 on expression and activities of cytochrome P450 enzymes (CYPs) in an in vivo system using rats. To this end, female rats were treated with estradiol benzoate (EB) or known CYP inducers. Liver tissues were obtained after 5 days of treatment, and mRNA and protein expression levels as well as activities of major hepatic CYPs were determined by qRT-PCR, immunoblot, and microsomal assay. E2 increased CYP1A2 expression and activity to a smaller extent than β-naphthoflavone did. E2 also enhanced CYP2C expression (CYP2C6, CYP2C7, and CYP2C12) to levels comparable to those observed by phenobarbital. E2 upregulated CYP3A9 expression, while expression of CYP3A1 was downregulated. Expression of hepatic nuclear receptors (PXR and CAR) and the obligate redox partner of CYPs (POR) was downregulated in EB-treated rats, suggesting their potential involvement in regulation of CYP expression and activity by E2. In summary, in female rats E2 regulates expression of hepatic CYPs in a CYP isoform-specific manner although the directional changes are different from those clinically observed during human pregnancy. Further study is warranted to determine whether the changes in drug metabolism during human pregnancy are attributable to involvement of hormones other than E2. PMID:21219883
Abrogating Monoacylglycerol Acyltransferase Activity in Liver Improves Glucose Tolerance and Hepatic Insulin Signaling in Obese Mice

PubMed Central

Soufi, Nisreen; Chambers, Kari T.; Chen, Zhouji; Schweitzer, George G.; McCommis, Kyle S.; Erion, Derek M.; Graham, Mark J.; Su, Xiong; Finck, Brian N.

2014-01-01

Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol (DAG), a lipid that has been linked to the development of hepatic insulin resistance through activation of protein kinase C (PKC). The expression of genes that encode MGAT enzymes is induced in the livers of insulin-resistant human subjects with nonalcoholic fatty liver disease, but whether MGAT activation is causal of hepatic steatosis or insulin resistance is unknown. We show that the expression of Mogat1, which encodes MGAT1, and MGAT activity are also increased in diet-induced obese (DIO) and ob/obmice. To probe the metabolic effects of MGAT1 in the livers of obese mice, we administered antisense oligonucleotides (ASOs) against Mogat1 to DIO and ob/ob mice for 3 weeks. Knockdown of Mogat1 in liver, which reduced hepatic MGAT activity, did not affect hepatic triacylglycerol content and unexpectedly increased total DAG content. Mogat1 inhibition also increased both membrane and cytosolic compartment DAG levels. However, Mogat1 ASO treatment significantly improved glucose tolerance and hepatic insulin signaling in obese mice. In summary, inactivation of hepatic MGAT activity, which is markedly increased in obese mice, improved glucose tolerance and hepatic insulin signaling independent of changes in body weight, intrahepatic DAG and TAG content, and PKC signaling. PMID:24595352
Hepatic differentiation potential of commercially available human mesenchymal stem cells.

PubMed

Ong, Shin-Yeu; Dai, Hui; Leong, Kam W

2006-12-01

The ready availability and low immunogenicity of commercially available mesenchymal stem cells (MSC) render them a potential cell source for the development of therapeutic products. With cell source a major bottleneck in hepatic tissue engineering, we investigated whether commercially available human MSC (hMSC) can transdifferentiate into the hepatic lineage. Based on previous studies that find rapid gain of hepatic genes in bone marrow-derived stem cells cocultured with liver tissue, we used a similar approach to drive hepatic differentiation by coculturing the hMSC with rat livers treated or untreated with gadolinium chloride (GdCl(3)). After a 24-hour coculture period with liver tissue injured by GdCl(3) in a Transwell configuration, approximately 34% of the cells differentiated into albumin-expressing cells. Cocultured cells were subsequently maintained with growth factors to complete the hepatic differentiation. Cocultured cells expressed more hepatic gene markers, and had higher metabolic functions and P450 activity than cells that were only differentiated with growth factors. In conclusion, commercially available hMSC do show hepatic differentiation potential, and a liver microenvironment in culture can provide potent cues to accelerate and deepen the differentiation. The ability to generate hepatocyte-like cells from a commercially available cell source would find interesting applications in liver tissue engineering.
Hepatic NPC1L1 overexpression ameliorates glucose metabolism in diabetic mice via suppression of gluconeogenesis.

PubMed

Kurano, Makoto; Hara, Masumi; Satoh, Hiroaki; Tsukamoto, Kazuhisa

2015-05-01

Inhibition of intestinal NPC1L1 by ezetimibe has been demonstrated to improve glucose metabolism in rodent models; however, the role of hepatic NPC1L1 in glucose metabolism has not been elucidated. In this study, we analyzed the effects of hepatic NPC1L1 on glucose metabolism. We overexpressed NPC1L1 in the livers of lean wild type mice, diet-induced obesity mice and db/db mice with adenoviral gene transfer. We found that in all three mouse models, hepatic NPC1L1 overexpression lowered fasting blood glucose levels as well as blood glucose levels on ad libitum; in db/db mice, hepatic NPC1L1 overexpression improved blood glucose levels to almost the same as those found in lean wild type mice. A pyruvate tolerance test revealed that gluconeogenesis was suppressed by hepatic NPC1L1 overexpression. Further analyses revealed that hepatic NPC1L1 overexpression decreased the expression of FoxO1, resulting in the reduced expression of G6Pase and PEPCK, key enzymes in gluconeogenesis. These results indicate that hepatic NPC1L1 might have distinct properties of suppressing gluconeogenesis via inhibition of FoxO1 pathways. Copyright © 2015 Elsevier Inc. All rights reserved.
A Combination of Flaxseed Oil and Astaxanthin Improves Hepatic Lipid Accumulation and Reduces Oxidative Stress in High Fat-Diet Fed Rats

PubMed Central

Xu, Jiqu; Rong, Shuang; Gao, Hui; Chen, Chang; Yang, Wei; Deng, Qianchun; Huang, Qingde; Xiao, Lingyun; Huang, Fenghong

2017-01-01

Hepatic lipid accumulation and oxidative stress are crucial pathophysiological mechanisms for non-alcoholic fatty liver disease (NAFLD). Thus, we examined the effect of a combination of flaxseed oil (FO) and astaxanthin (ASX) on hepatic lipid accumulation and oxidative stress in rats fed a high-fat diet. ASX was dissolved in flaxseed oil (1 g/kg; FO + ASX). Animals were fed diets containing 20% fat, where the source was lard, or 75% lard and 25% FO + ASX, or 50% lard and 50% FO + ASX, or FO + ASX, for 10 weeks. Substitution of lard with FO + ASX reduced steatosis and reduced hepatic triacylglycerol and cholesterol. The combination of FO and ASX significantly decreased hepatic sterol regulatory element-binding transcription factor 1 and 3-hydroxy-3-methylglutaryl-CoA reductase but increased peroxisome proliferator activated receptor expression. FO + ASX significantly suppressed fatty acid synthase and acetyl CoA carboxylase but induced carnitine palmitoyl transferase-1 and acyl CoA oxidase expression. FO + ASX also significantly elevated hepatic SOD, CAT and GPx activity and GSH, and markedly reduced hepatic lipid peroxidation. Thus, FO and ASX may reduce NAFLD by reversing hepatic steatosis and reducing lipid accumulation and oxidative stress. PMID:28335388
Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

PubMed

Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

2017-04-01

For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.
Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.

PubMed

Kelly, Daniel M; Nettleship, Joanne E; Akhtar, Samia; Muraleedharan, Vakkat; Sellers, Donna J; Brooke, Jonathan C; McLaren, David S; Channer, Kevin S; Jones, T Hugh

2014-07-30

Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis. Copyright © 2014 Elsevier Inc. All rights reserved.
Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

PubMed

Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

2016-01-01

Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.
Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease

PubMed Central

Ji, Guixiang; Xu, Cheng; Sun, Haidong; Liu, Qian; Hu, Hai; Gu, Aihua; Jiang, Zhao-Yan

2016-01-01

Background Organochlorine pesticides (OCPs) are one kind of persistent organic pollutants. Although they are reported to be associated with metabolic disorders, the underlying mechanism is unclear. We explored the association of OCPs with gallstone disease and its influence on hepatic lipid metabolism. Materials and Methods OCPs levels in omentum adipose tissues from patients with and without gallstone disease between 2008 and 2011 were measured by GC-MS. Differences of gene expression involved in hepatic lipid metabolism and hepatic lipids content were compared in liver biopsies between groups with high and low level of OCPs. Using HepG2 cell lines, the influence on hepatic lipid metabolism by individual OCP was evaluated in vitro. Results In all patients who were from non-occupational population, there were high levels of β-hexachlorocyclohexane (β-HCH) and p',p'-dichloroethylene (p',p'-DDE) accumulated in adipose tissues. Both β-HCH and p', p'-DDE levels were significantly higher in adipose tissues from patients with gallstone disease (294.3± 313.5 and 2222± 2279 ng/g of lipid) than gallstone-free controls (282.7± 449.0 and 2025±2664 ng/g of lipid, P< 0.01) and they were strongly related with gallstone disease (P for trend = 0.0004 and 0.0138). Furthermore, higher OCPs in adipose tissue led to increase in the expression of hepatic cholesterol transporters ABCG5 and G8 (+34% and +27%, P< 0.01) and higher cholesterol saturation index in gallbladder bile, and induced hepatic fatty acids synthesis, which was further confirmed in HepG2 cells. Conclusion OCPs might enhance hepatic secretion of cholesterol into bile via ABCG5/G8 which promoting gallstone disease as well as lipogenesis. PMID:27203212
Hepatic nuclear sterol regulatory binding element protein 2 abundance is decreased and that of ABCG5 increased in male hamsters fed plant sterols.

PubMed

Harding, Scott V; Rideout, Todd C; Jones, Peter J H

2010-07-01

The effect of dietary plant sterols on cholesterol homeostasis has been well characterized in the intestine, but how plant sterols affect lipid metabolism in other lipid-rich tissues is not known. Changes in hepatic cholesterol homeostasis in response to high dietary intakes of plant sterols were determined in male golden Syrian hamsters fed hypercholesterolemia-inducing diets with and without 2% plant sterols (wt:wt; Reducol, Forbes Meditech) for 28 d. Plasma and hepatic cholesterol concentrations, cholesterol biosynthesis and absorption, and changes in the expression of sterol response element binding protein 2 (SREBP2) and liver X receptor-beta (LXRbeta) and their target genes were measured. Plant sterol feeding reduced plasma total cholesterol, non-HDL cholesterol, and HDL cholesterol concentrations 43% (P < 0.0001), 60% (P < 0.0001), and 21% (P = 0.001), respectively, compared with controls. Furthermore, there was a 93% reduction (P < 0.0001) in hepatic total cholesterol and >6-fold (P = 0.029) and >2-fold (P < 0.0001) increases in hepatic beta-sitosterol and campesterol concentrations, respectively, in plant sterol-fed hamsters compared with controls. Plant sterol feeding also increased fractional cholesterol synthesis >2-fold (P < 0.03) and decreased cholesterol absorption 83% (P < 0.0001) compared with controls. Plant sterol feeding increased hepatic protein expression of cytosolic (inactive) SREBP2, decreased nuclear (active) SREBP2, and tended to increase LXRbeta (P = 0.06) and ATP binding cassette transporter G5, indicating a differential modulation of the expression of proteins central to cholesterol metabolism. In conclusion, high-dose plant sterol feeding of hamsters changes hepatic protein abundance in favor of cholesterol excretion despite lower hepatic cholesterol concentrations and higher cholesterol fractional synthesis.
Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats.

PubMed

Lee, Tzung-Yan; Wang, Guei-Jane; Chiu, Jen-Hwey; Lin, Han-Chieh

2003-11-01

Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4-induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg(-1) twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-beta1, tissue inhibitor of metalloproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4-induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis.
Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non-alcoholic steatohepatitis in rats.

PubMed

Kanamori, Hiroyuki; Nakade, Yukiomi; Yamauchi, Taeko; Sakamoto, Kazumasa; Inoue, Tadahisa; Yamamoto, Takaya; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sumida, Yoshio; Nakao, Haruhisa; Fukuzawa, Yoshitaka; Yoneda, Masashi

2017-01-01

Nicotine, a major compound in cigarette smoke, decreases food intake and body weight gain in mammals; however, the influence of nicotine on the progression of non-alcoholic steatohepatitis (NASH) remains controversial. This study aimed to investigate the effect of nicotine on NASH in rat models. Male Wistar rats were fed choline-deficient, l-amino acid-defined (CDAA) diet and treated with nicotine or saline. Food intake, body weight gain, presence of hepatic steatosis, inflammation, and fibrosis were assessed 6 weeks after the rats were fed CDAA diet. Hepatic branch vagotomy was performed to elucidate the mechanism through which nicotine affected steatohepatitis. CDAA diet induced hepatic steatosis, inflammation, and fibrosis, as well as increased the expression of inflammation-related genes. Conversely, nicotine significantly attenuated food intake, body weight gain, and inhibited the CDAA-diet-induced hepatic steatosis, inflammation, and fibrosis, together with increased expression of inflammation-related genes. Hepatic branch vagotomy by itself decreased food intake, body weight gain, and attenuated the CDAA-diet-induced hepatic steatosis, but not inflammation. However, nicotine did not change the food intake, body weight gain, and CDAA diet-induced hepatic steatosis and inflammation in vagotomized rats. These results suggest that nicotine attenuates the CDAA-diet-induced hepatic steatosis and inflammation through the hepatic branch of the vagus nerve in rats.
A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma.

PubMed

Siegel, Abby B; Narayan, Rupa; Rodriguez, Rosa; Goyal, Abhishek; Jacobson, Judith S; Kelly, Kara; Ladas, Elena; Lunghofer, Paul J; Hansen, Ryan J; Gustafson, Daniel L; Flaig, Thomas W; Tsai, Wei Yann; Wu, David P H; Lee, Valerie; Greenlee, Heather

2014-01-01

To determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction. Patients with advanced HCC not eligible for other therapies based on poor hepatic function were enrolled in a phase I study of silybin phosphatidylcholine. A standard phase I design was used with 4 planned cohorts, dose escalating from 2, 4, 8, to 12 g per day in divided doses for 12 weeks. Three participants enrolled in this single institution trial. All enrolled subjects consumed 2 g per day of study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all 3 patients, liver function abnormalities and tumor marker α-fetoprotein progressed, but after day 56 the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All 3 participants died within 23 to 69 days of enrolling into the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly due to the study drug. Short-term administration of silybin phosphatidylcholine in patients with advanced HCC resulted in detectable increases in silibinin and its metabolite, silibinin glucuronide. The maximum tolerated dose could not be established. Since patients died soon after enrollment, this patient population may have been too ill to benefit from an intervention designed to improve liver function tests.
IL-32γ promotes integrin αvβ6 expression through the activation of NF-κB in HSCs

PubMed Central

Liu, Hongcan; Pan, Xingfei; Cao, Hong; Shu, Xin; Sun, Haixia; Lu, Jianxi; Liang, Jiayin; Zhang, Ka; Zhu, Fengqin; Li, Gang; Zhang, Qi

2017-01-01

Hepatic stellate cell (HSC) activation is important in the pathogenesis of liver fibrosis. However, the molecular mechanism of HSC activation is not completely understood. In the present study, it was demonstrated that interleukin-32γ (IL-32γ) is capable of enhancing intefgrin αvβ6 expression by inducing integrin αvβ6 promoter activity in a dose-dependent manner in HSCs. Furthermore, it was determined that nuclear factor κB (NF-κB) activation is required for IL-32γ-induced integrin αvβ6 expression. Increased integrin αvβ6 expression is then able to activate HSCs. These results indicate that NF-κB activation is required for IL-32γ to induce integrin αvβ6 expression and consequently promote HSC activation. Therefore, IL-32γ activates HSCs and therefore may be associated with hepatic fibrogenesis. These results may enable the development of novel effective strategies to treat hepatic fibrosis. PMID:29042996
Fat Quantification in the Abdomen.

PubMed

Hong, Cheng William; Fazeli Dehkordy, Soudabeh; Hooker, Jonathan C; Hamilton, Gavin; Sirlin, Claude B

2017-12-01

Fatty liver disease is characterized histologically by hepatic steatosis, the abnormal accumulation of lipid in hepatocytes. It is classified into alcoholic fatty liver disease and nonalcoholic fatty liver disease, and is an increasingly important cause of chronic liver disease and cirrhosis. Assessing the severity of hepatic steatosis in these conditions is important for diagnostic and prognostic purposes, as hepatic steatosis is potentially reversible if diagnosed early. The criterion standard for assessing hepatic steatosis is liver biopsy, which is limited by sampling error, its invasive nature, and associated morbidity. As such, noninvasive imaging-based methods of assessing hepatic steatosis are needed. Ultrasound and computed tomography are able to suggest the presence of hepatic steatosis based on imaging features, but are unable to accurately quantify hepatic fat content. Since Dixon's seminal work in 1984, magnetic resonance imaging has been used to compute the signal fat fraction from chemical shift-encoded imaging, commonly implemented as out-of-phase and in-phase imaging. However, signal fat fraction is confounded by several factors that limit its accuracy and reproducibility. Recently, advanced chemical shift-encoded magnetic resonance imaging methods have been developed that address these confounders and are able to measure the proton density fat fraction, a standardized, accurate, and reproducible biomarker of fat content. The use of these methods in the liver, as well as in other abdominal organs such as the pancreas, adrenal glands, and adipose tissue will be discussed in this review.
White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice

PubMed Central

Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

2016-01-01

Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism. PMID:26914024
Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection.

PubMed

Song, L-W; Liu, P-G; Liu, C-J; Zhang, T-Y; Cheng, X-D; Wu, H-L; Yang, H-C; Hao, X-K; Yuan, Q; Zhang, J; Kao, J-H; Chen, D-S; Chen, P-J; Xia, N-S

2015-02-01

We previously demonstrated that pretreatment quantitative anti-hepatitis B core protein (qAnti-HBc) levels can predict the treatment response for both interferon and nucleoside analogue therapy, but the characteristics of qAnti-HBc during chronic hepatitis B virus (HBV) infection remain poorly understood. To understand this issue, the qAnti-HBc levels were evaluated in individuals with past HBV infection, occult HBV infection and chronic HBV infection in the immune tolerance phase, immune clearance phase, low-replicative phase and hepatitis B e antigen (HBeAg)-negative hepatitis phase. Individuals with hepatitis B surface antigen (n = 598, 3.74 ± 0.90 log10 IU/mL) had significantly higher (p < 0.001, approximately 1000-fold) serum qAnti-HBc levels than those who had occult HBV, and serum qAnti-HBc levels were significantly higher in the occult HBV group than in the past HBV infection group (p < 0.001). qAnti-HBc levels were positively correlated with alanine aminotransferase levels (R = 0.663, p < 0.001), and subjects with an abnormal alanine aminotransferase level had a higher qAnti-HBc level (p < 0.001). Serum qAnti-HBc level varied in different phases of HBV infection, as determined by host immune status. Serum qAnti-HBc level is strongly associated with hepatitis activity in subjects with chronic HBV infection. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
IGF-1 modulates gene expression of proteins involved in inflammation, cytoskeleton, and liver architecture.

PubMed

Lara-Diaz, V J; Castilla-Cortazar, I; Martín-Estal, I; García-Magariño, M; Aguirre, G A; Puche, J E; de la Garza, R G; Morales, L A; Muñoz, U

2017-05-01

Even though the liver synthesizes most of circulating IGF-1, it lacks its receptor under physiological conditions. However, according to previous studies, a damaged liver expresses the receptor. For this reason, herein, we examine hepatic histology and expression of genes encoding proteins of the cytoskeleton, extracellular matrix, and cell-cell molecules and inflammation-related proteins. A partial IGF-1 deficiency murine model was used to investigate IGF-1's effects on liver by comparing wild-type controls, heterozygous igf1 +/- , and heterozygous mice treated with IGF-1 for 10 days. Histology, microarray for mRNA gene expression, RT-qPCR, and lipid peroxidation were assessed. Microarray analyses revealed significant underexpression of igf1 in heterozygous mice compared to control mice, restoring normal liver expression after treatment, which then normalized its circulating levels. IGF-1 receptor mRNA was overexpressed in Hz mice liver, while treated mice displayed a similar expression to that of the controls. Heterozygous mice showed overexpression of several genes encoding proteins related to inflammatory and acute-phase proteins and underexpression or overexpression of genes which coded for extracellular matrix, cytoskeleton, and cell junction components. Histology revealed an altered hepatic architecture. In addition, liver oxidative damage was found increased in the heterozygous group. The mere IGF-1 partial deficiency is associated with relevant alterations of the hepatic architecture and expression of genes involved in cytoskeleton, hepatocyte polarity, cell junctions, and extracellular matrix proteins. Moreover, it induces hepatic expression of the IGF-1 receptor and elevated acute-phase and inflammation mediators, which all resulted in liver oxidative damage.

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