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Sample records for affects hepatic metabolism

  1. Perinephric and epididymal fat affect hepatic metabolism in rats.

    PubMed

    Ben-Shlomo, Shani; Einstein, Francine H; Zvibel, Isabel; Atias, Dikla; Shlomai, Amir; Halpern, Zamir; Barzilai, Nir; Fishman, Sigal

    2012-01-01

    The present study examined whether the perinephric and epididymal visceral fat (PEVF) depot under short-term excess nutrient protected the liver by trapping nutrient-derived nonesterified free fatty acids (NEFAs) or had deleterious effects on hepatic triglycerides (TGs) accumulation and insulin resistance due to adipokine secretion. Young rats pre-emptively underwent surgical PEVF removal or sham operations and were fed with either high-fat diet (HFD) (PEVF-HFD) or regular chow (RC) (PEVF-RC) for 3 days. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Liver TG, serum NEFA, and fat-derived adipokines were assessed. Insulin and lipogenesis signaling were assessed by western blots. Pre-emptive PEVF removal significantly decreases insulin-induced suppression of hepatic glucose production (HGP) both in RC and in HFD-fed rats. In accordance with the clamp results, hepatic TG accumulation is also significantly reduced by PEVF excision both in RC and HFD-fed rats. These results are further validated by insulin signaling results, which show that pre-emptive PEVF removal increases phosphorylation of hepatic Akt, irrespective of diet. Notably, high levels of serum leptin induced by HFD are significantly reduced by pre-emptive PEVF excision. Additionally, expression of lipogenic enzyme p-acetyl-CoA-carboxylase, denoting reduced lipogenesis, is increased in the PEVF-HFD rats. In conclusion, PEVF has a deleterious effect on the liver as a source of insulin resistance-inducing adipokines irrespective of diet, and does not serve as a buffer for excess nutrients. PMID:21818154

  2. In Ovo injection of betaine affects hepatic cholesterol metabolism through epigenetic gene regulation in newly hatched chicks.

    PubMed

    Hu, Yun; Sun, Qinwei; Li, Xiaoliang; Wang, Min; Cai, Demin; Li, Xi; Zhao, Ruqian

    2015-01-01

    Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P < 0.05) and the hepatic content (P < 0.01) of cholesterol. Accordingly, the cholesterol biosynthetic enzyme HMGCR was up-regulated (P < 0.05 for both mRNA and protein), while CYP7A1 which converts cholesterol to bile acids was down-regulated (P < 0.05 for mRNA and P = 0.07 for protein). Moreover, hepatic protein content of the sterol-regulatory element binding protein 1 which regulates cholesterol and lipid biosynthesis, and the mRNA abundance of ATP binding cassette sub-family A member 1 (ABCA1) which mediates cholesterol counter transport were significantly (P < 0.05) increased in betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P < 0.05), which was associated with global genomic DNA hypermethylation (P < 0.05) and diminished gene repression mark histone H3 lysine 27 trimethylation (P < 0.05). Furthermore, CpG methylation level on gene promoters was found to be increased (P < 0.05) for CYP7A1 yet decreased (P < 0.05) for ABCA1. These results indicate that in ovo betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations. PMID:25860502

  3. In Ovo Injection of Betaine Affects Hepatic Cholesterol Metabolism through Epigenetic Gene Regulation in Newly Hatched Chicks

    PubMed Central

    Hu, Yun; Sun, Qinwei; Li, Xiaoliang; Wang, Min; Cai, Demin; Li, Xi; Zhao, Ruqian

    2015-01-01

    Betaine is reported to regulate hepatic cholesterol metabolism in mammals. Chicken eggs contain considerable amount of betaine, yet it remains unknown whether and how betaine in the egg affects hepatic cholesterol metabolism in chicks. In this study, eggs were injected with betaine at 2.5 mg/egg and the hepatic cholesterol metabolism was investigated in newly hatched chicks. Betaine did not affect body weight or liver weight, but significantly increased the serum concentration (P < 0.05) and the hepatic content (P < 0.01) of cholesterol. Accordingly, the cholesterol biosynthetic enzyme HMGCR was up-regulated (P < 0.05 for both mRNA and protein), while CYP7A1 which converts cholesterol to bile acids was down-regulated (P < 0.05 for mRNA and P = 0.07 for protein). Moreover, hepatic protein content of the sterol-regulatory element binding protein 1 which regulates cholesterol and lipid biosynthesis, and the mRNA abundance of ATP binding cassette sub-family A member 1 (ABCA1) which mediates cholesterol counter transport were significantly (P < 0.05) increased in betaine-treated chicks. Meanwhile, hepatic protein contents of DNA methyltransferases 1 and adenosylhomocysteinase-like 1 were increased (P < 0.05), which was associated with global genomic DNA hypermethylation (P < 0.05) and diminished gene repression mark histone H3 lysine 27 trimethylation (P < 0.05). Furthermore, CpG methylation level on gene promoters was found to be increased (P < 0.05) for CYP7A1 yet decreased (P < 0.05) for ABCA1. These results indicate that in ovo betaine injection regulates hepatic cholesterol metabolism in chicks through epigenetic mechanisms including DNA and histone methylations. PMID:25860502

  4. METABOLISM Wnt Signaling Regulates Hepatic Metabolism

    PubMed Central

    Liu, Hongjun; Fergusson, Maria M.; Wu, J. Julie; Rovira, Ilsa I.; Liu, Jie; Gavrilova, Oksana; Lu, Teng; Bao, Jianjun; Han, Donghe; Sack, Michael N.; Finkel, Toren

    2011-01-01

    The contribution of the Wnt pathway has been extensively characterized in embryogenesis, differentiation, and stem cell biology but not in mammalian metabolism. Here, using in vivo gain- and loss-of-function models, we demonstrate an important role for Wnt signaling in hepatic metabolism. In particular, β-Catenin, the downstream mediator of canonical Wnt signaling, altered serum glucose concentrations and regulated hepatic glucose production. β-catenin also modulated hepatic insulin signaling. Furthermore, β-catenin interacted with the transcription factor FoxO1 in livers from mice under starved conditions. The interaction of FoxO1 with β-catenin regulated the transcriptional activation of the genes encoding glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), the two rate-limiting enzymes in hepatic gluconeogenesis. Moreover, starvation induced the hepatic expression of mRNAs encoding different Wnt isoforms. In addition, nutrient deprivation appeared to favor the association of β-catenin with FoxO family members, rather than with members of the T cell factor of transcriptional activators. Notably, in a model of diet-induced obesity, hepatic deletion of β-catenin improved overall metabolic homeostasis. These observations implicate Wnt signaling in the modulation of hepatic metabolism and raise the possibility that Wnt signaling may play a similar role in the metabolic regulation of other tissues. PMID:21285411

  5. Body condition score at calving affects systemic and hepatic transcriptome indicators of inflammation and nutrient metabolism in grazing dairy cows.

    PubMed

    Akbar, H; Grala, T M; Vailati Riboni, M; Cardoso, F C; Verkerk, G; McGowan, J; Macdonald, K; Webster, J; Schutz, K; Meier, S; Matthews, L; Roche, J R; Loor, J J

    2015-02-01

    Calving body condition score (BCS) is an important determinant of early-lactation dry matter intake, milk yield, and disease incidence. The current study investigated the metabolic and molecular changes induced by the change in BCS. A group of cows of mixed age and breed were managed from the second half of the previous lactation to achieve mean group BCS (10-point scale) that were high (HBCS, 5.5; n=20), medium (MBCS, 4.5; n=18), or low (LBCS, 3.5; n=19). Blood was sampled at wk -4, -3, -2, 1, 3, 5, and 6 relative to parturition to measure biomarkers of energy balance, inflammation, and liver function. Liver was biopsied on wk 1, 3, and 5 relative to parturition, and 10 cows per BCS group were used for transcript profiling via quantitative PCR. Cows in HBCS and MBCS produced more milk and had greater concentrations of nonesterified fatty acids and β-hydroxybutyrate postpartum than LBCS. Peak concentrations of nonesterified fatty acids and β-hydroxybutyrate and greater hepatic triacylglycerol concentrations were recorded in HBCS at wk 3. Consistent with blood biomarkers, HBCS and MBCS had greater expression of genes associated with fatty acid oxidation (CPT1A, ACOX1), ketogenesis (HMGCS2), and hepatokines (FGF21, ANGPTL4), whereas HBCS had the lowest expression of APOB (lipoprotein transport). Greater expression during early lactation of BBOX1 in MBCS and LBCS suggested greater de novo carnitine synthesis. The greater BCS was associated with lower expression of growth hormone/insulin-like growth factor-1 signaling axis genes (GHR1A, IGF1, and IGFALS) and greater expression of gluconeogenic genes. These likely contributed to the higher milk production and greater gluconeogenesis. Despite greater serum haptoglobin around calving, cows in HBCS and MBCS had greater blood albumin. Cows in MBCS, however, had a higher albumin:globulin ratio, probably indicating a less pronounced inflammatory status and better liver function. The marked decrease in expression of NFKB1

  6. Hepatic drug metabolism and adverse hepatic drug reactions.

    PubMed

    Schaffner, F

    1975-01-01

    Drugs and other chemicals are usually metabolized in the liver in the drug-metabolizing enzyme system. The metabolites sometimes bind with cellular macromolecules and injure the cell directly or serve as new antigens to create immunologic injury in a delayed fashion. The immediate or toxic injury is dose-dependent, predictable and zonal in the liver lobule, usually in the central region. Carbon tetrachloride intoxication and acetaminophen overdose are examples of injury resulting from microsomal metabolism. Other injuries related to microsomal metabolism are those produced by vinyl chloride in polymerization plant workers and by methotrexate in psoriatics or leukemic children. Most adverse drug reactions affecting the liver and producing jaundice are unpredictable, delayed in onset, and only hypothetically related to microsomal metabolism in some instances. The two main types are cholestasis and viral-hepatitis-like. The former may be in a pure form, in which case it may be partly dose-dependent, or in a form mixed with hepatitis. Many drugs produce cholestasis in a small percentage of persons, and because the reaction is benign, albeit prolonged at times, such drugs continue to be used. The viral-hepatitis-like reaction involves few drugs and affects few persons, but can be fatal. The recognition that chronic hepatitis can be caused by drugs such as oxyphenisatin, alpha-methyldopa, and isoniazid has added a new dimension to the clinical problem of adverse drug reactions, which may extend to widely used and commonly available agents like aspirin. PMID:171822

  7. Increasing levels of dietary crystalline methionine affect plasma methionine profiles, ammonia excretion, and the expression of genes related to the hepatic intermediary metabolism in rainbow trout (Oncorhynchus mykiss).

    PubMed

    Rolland, Marine; Skov, Peter V; Larsen, Bodil K; Holm, Jørgen; Gómez-Requeni, Pedro; Dalsgaard, Johanne

    2016-08-01

    Strictly carnivorous fish with high requirements for dietary protein, such as rainbow trout (Oncorhynchus mykiss) are interesting models for studying the role of amino acids as key regulators of intermediary metabolism. Methionine is an essential amino acid for rainbow trout, and works as a signalling factor in different metabolic pathways. The study investigated the effect of increasing dietary methionine intake on the intermediary metabolism in the liver of juvenile rainbow trout. For this purpose, five diets were formulated with increasing methionine levels from 0.60 to 1.29% dry matter. The diets were fed in excess for six weeks before three sampling campaigns carried out successively to elucidate (i) the hepatic expression of selected genes involved in lipid, glucose and amino acid metabolism; (ii) the postprandial ammonia excretion; and (iii) the postprandial plasma methionine concentrations. The transcript levels of enzymes involved in lipid metabolism (fatty acid synthase, glucose 6 phosphate dehydrogenase and carnitine palmitoyl transferase 1 a), gluconeogenesis (fructose-1,6-biphosphatase) and amino acid catabolism (alanine amino transferase and glutamate dehydrogenase) were significantly affected by the increase in dietary methionine. Changes in gene expression reflected to some extent the decrease in ammonia excretion (P=0.022) and in the hepatosomatic index (HSI; P<0.001) when dietary methionine increased. Postprandial plasma methionine concentrations correlated positively with the dietary level (P<0.001) at the different sampling points. The study shows that the expression of several genes related to the hepatic intermediary metabolism in rainbow trout responded in a dose-dependent manner to increasing levels of dietary methionine. PMID:27105833

  8. Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats.

    PubMed

    Kim, J; Lee, K S; Kwon, D-H; Bong, J J; Jeong, J Y; Nam, Y S; Lee, M S; Liu, X; Baik, M

    2014-02-01

    Dietary lysine restriction may differentially affect body growth and lipid and nitrogen metabolism, depending on the degree of lysine restriction. This study was conducted to examine the effect of dietary lysine restriction on growth and lipid and nitrogen metabolism with two different degree of lysine restriction. Isocaloric amino acid-defined diets containing 1.4% lysine (adequate), 0.70% lysine (50% moderate lysine restriction) and 0.35% lysine (75% severe lysine restriction) were fed from the age of 52 to 77 days for 25 days in male Sprague-Dawley rats. The 75% severe lysine restriction increased (p < 0.05) food intake, but retarded (p < 0.05) growth, increased (p < 0.05) liver and muscle lipid contents and abdominal fat accumulation, increased (p < 0.05) blood urea nitrogen levels and mRNA levels of the serine-synthesizing 3-phosphoglycerate dehydrogenase gene, but decreased (p < 0.05) urea cycle arginase gene mRNA levels. In contrast, the 50% lysine restriction did not significantly (p > 0.05) affect body growth and lipid and nitrogen metabolism. Our results demonstrate that severe 75% lysine restriction has detrimental effects on body growth and deregulate lipid and nitrogen metabolism. PMID:23441935

  9. Drugs affecting glycosaminoglycan metabolism.

    PubMed

    Ghiselli, Giancarlo; Maccarana, Marco

    2016-07-01

    Glycosaminoglycans (GAGs) are charged polysaccharides ubiquitously present at the cell surface and in the extracellular matrix. GAGs are crucial for cellular homeostasis, and their metabolism is altered during pathological processes. However, little consideration has been given to the regulation of the GAG milieu through pharmacological interventions. In this review, we provide a classification of small molecules affecting GAG metabolism based on their mechanism of action. Furthermore, we present evidence to show that clinically approved drugs affect GAG metabolism and that this could contribute to their therapeutic benefit. PMID:27217160

  10. Triglyceride Metabolism and Hepatic Diseases.

    PubMed

    Fernandez-Mejia, Emptyyn Y

    2013-09-11

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplasticcells. One of the main medical concerns vis-à-vishepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis. PMID:24032513

  11. Hepatic iron metabolism.

    PubMed

    Anderson, Gregory J; Frazer, David M

    2005-11-01

    The liver performs three main functions in iron homeostasis. It is the major site of iron storage, it regulates iron traffic into and around the body through its production of the peptide hepcidin, and it is the site of synthesis of major proteins of iron metabolism such as transferrin and ceruloplasmin. Most of the iron that enters the liver is derived from plasma transferrin under normal circumstances, and transferrin receptors 1 and 2 play important roles in this process. In pathological situations, non-transferrin-bound iron, ferritin, and hemoglobin/haptoglobin and heme/hemopexin complexes assume greater importance in iron delivery to the organ. Iron is stored in the liver as ferritin and, with heavy iron loading, as hemosiderin. The liver can divest itself of iron through the plasma membrane iron exporter ferroportin 1, a process that also requires ceruloplasmin. Hepcidin can regulate this iron release through its interaction with ferroportin. PMID:16315136

  12. Hepatic Metabolism Affects the Atropselective Disposition of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) in Mice

    PubMed Central

    2015-01-01

    To understand the role of hepatic vs extrahepatic metabolism in the disposition of chiral PCBs, we studied the disposition of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) and its hydroxylated metabolites (HO-PCBs) in mice with defective hepatic metabolism due to the liver-specific deletion of cytochrome P450 oxidoreductase (KO mice). Female KO and congenic wild type (WT) mice were treated with racemic PCB 136, and levels and chiral signatures of PCB 136 and HO-PCBs were determined in tissues and excreta 3 days after PCB administration. PCB 136 tissue levels were higher in KO compared to WT mice. Feces was a major route of PCB metabolite excretion, with 2,2′,3,3′,6,6′-hexachlorobiphenyl-5-ol being the major metabolite recovered from feces. (+)-PCB 136, the second eluting PCB 136 atropisomers, was enriched in all tissues and excreta. The second eluting atropisomers of the HO-PCBs metabolites were enriched in blood and liver; 2,2′,3,3′,6,6′-hexachlorobiphenyl-5-ol in blood was an exception and displayed an enrichment of the first eluting atropisomers. Fecal HO-PCB levels and chiral signatures changed with time and differed between KO and WT mice, with larger HO-PCB enantiomeric fractions in WT compared to KO mice. Our results demonstrate that hepatic and, possibly, extrahepatic cytochrome P450 (P450) enzymes play a role in the disposition of PCBs. PMID:25420130

  13. Hepatic glucose and lipid metabolism.

    PubMed

    Jones, John G

    2016-06-01

    The liver has a central role in the regulation of systemic glucose and lipid fluxes during feeding and fasting and also relies on these substrates for its own energy needs. These parallel requirements are met by coordinated control of carbohydrate and lipid fluxes into and out of the Krebs cycle, which is highly tuned to nutrient availability and heavily regulated by insulin and glucagon. During progression of type 2 diabetes, hepatic carbohydrate and lipid biosynthesis fluxes become elevated, thus contributing to hyperglycaemia and hypertriacylglycerolaemia. Over this interval there are also significant fluctuations in hepatic energy state. To date, it is not known to what extent abnormal glucose and lipid fluxes are causally linked to altered energy states. Recent evidence that the glucose-lowering effects of metformin appear to be mediated by attenuation of hepatic energy generation places an additional spotlight on the interdependence of hepatic biosynthetic and oxidative fluxes. The transition from fasting to feeding results in a significant re-direction of hepatic glucose and lipid fluxes and may also incur a temporary hepatic energy deficit. At present, it is not known to what extent these variables are additionally modified by type 2 diabetes and/or non-alcoholic fatty liver disease. Thus, there is a compelling need to measure fluxes through oxidative, gluconeogenic and lipogenic pathways and determine their relationship with hepatic energy state in both fasting and fed conditions. New magnetic resonance-based technologies allow these variables to be non-invasively studied in animal models and humans. This review summarises a presentation given at the symposium entitled 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1 ) and a commentary by the Session Chair, Michael

  14. Hepatic diseases related to triglyceride metabolism.

    PubMed

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis. PMID:24059726

  15. Exercise and the Regulation of Hepatic Metabolism

    PubMed Central

    Trefts, Elijah; Williams, Ashley S.; Wasserman, David H.

    2016-01-01

    The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the hepatic response, sustained exercise would be impossible. The liver stores, releases, and recycles potential energy. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from adipose tissue. Adaptations immediately following exercise facilitate the replenishment of glycogen stores. Pancreatic glucagon and insulin responses orchestrate the hepatic response during and immediately following exercise. Like skeletal muscle and other physiological systems, liver adapts to repeated demands of exercise by increasing its capacity to produce energy by oxidizing fat. The ability of regular physical activity to increase fat oxidation is protective and can reverse fatty liver disease. Engaging in regular physical exercise has broad ranging positive health implications including those that improve the metabolic health of the liver. PMID:26477916

  16. Leucine metabolism in patients with Hepatic Encephalopathy

    SciTech Connect

    McGhee, A.S.; Kassouny, M.E.; Matthews, D.E.; Millikan, W.

    1986-03-01

    A primed continuous infusion of (/sup 15/N, 1-/sup 13/C)leucine was used to determine whether increased oxidation and/or protein synthesis of leucine occurs in patients with cirrhosis. Five controls and patients were equilibrated on a metabolic balance diet (0.6 g protein per kg ideal body weight (IBW)). An additional four patients were equilibrated in the same manner with the same type of diet with a protein level of 0.75 g per kg IBW. Plasma leucine and breath CO/sub 2/ enrichments were measured by mass spectrometry. Protein synthesis and leucine metabolism were identical in controls and patients when both were fed a diet with 0.6 g protein/kg IBW. Results indicate that systemic derangements of leucine metabolism are not the cause of Hepatic Encephalopathy.

  17. [Pathogenetic correction of metabolic disturbances in chronic liver affections].

    PubMed

    Romantsov, M G; Petrov, A Iu; Aleksandrova, L N; Sukhanov, D S; Kovalenko, A L

    2012-01-01

    The available drugs for the treatment of chronic liver affections (the adequate model is chronic hepatitis C) include agents of metabolic therapy, whose efficacy is not always enough, that required the search for original mitochondrial substrates on the basis of succinate. Such agents were composed as a pharmaceutical group named "Substrates of Energetic Metabolism" or "Substrate Antihypoxants". The review presents the description of the pharmacological effects of remaxole and cytoflavin, evident from lower levels of active metabolites of oxygen that increases the clinical efficacy of the therapy. Their role in the metabolic reactions in chronic liver affections is exclusive and rather actual. PMID:23700935

  18. Hepatitis C Virus Hijacks Host Lipid Metabolism

    PubMed Central

    Syed, Gulam H; Amako, Yutaka; Siddiqui, Aleem

    2009-01-01

    Hepatitis C virus (HCV) modulates cellular lipid metabolism to enhance its replication. HCV circulates in the blood in association with lipoproteins. HCV infection is associated with enhanced lipogenesis, reduced secretion and β-oxidation of lipids. HCV-induced imbalance in lipid homeostasis leads to steatosis. Many lipids are crucial for viral life cycle, and inhibitors of cholesterol/fatty acid biosynthetic pathways inhibit viral replication, maturation and secretion. HCV negatively modulates the synthesis and secretion of very low-density lipoproteins (VLDL). The components involved in VLDL assembly are also required for HCV morphogenesis/secretion, suggesting that HCV coopts the VLDL secretory pathway for its own secretion. This review highlights HCV-altered lipid metabolic events that aid in the viral life cycle and ultimately promote liver disease pathogenesis. PMID:19854061

  19. Glucagon: acute actions on hepatic metabolism.

    PubMed

    Miller, Russell A; Birnbaum, Morris J

    2016-07-01

    Type 2 diabetes mellitus is the result of impaired systemic control of glucose homeostasis, in part through the dysregulation of the hormone glucagon. Glucagon acts on the liver to increase glucose production through alterations in hepatic metabolism, and reducing the elevated glucagon signalling in diabetic patients is an attractive strategy for the treatment of hyperglycaemia. Here we review the actions of the hormone in the liver, focusing on the acute alterations of metabolic pathways. This review summarises a presentation given at the 'Novel data on glucagon' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Mona Abraham and Tony Lam, DOI: 10.1007/s00125-016-3950-3 , and by Young Lee and colleagues, DOI: 10.1007/s00125-016-3965-9 ) and an overview by the Session Chair, Isabel Valverde (DOI: 10.1007/s00125-016-3946-z ). PMID:27115415

  20. Regulation of hepatic energy metabolism by the nuclear receptor PXR.

    PubMed

    Hakkola, Jukka; Rysä, Jaana; Hukkanen, Janne

    2016-09-01

    The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR was originally identified to regulate drug-metabolizing enzymes and transporters. During the last ten years it has become clear that PXR harbors broader functions. Evidence obtained both in experimental animals and humans indicate that ligand-activated PXR regulates hepatic glucose and lipid metabolism and affects whole body metabolic homeostasis. Currently, the consequences of PXR activation on overall metabolic health are not yet fully understood and varying results on the effect of PXR activation or knockout on metabolic disorders and weight gain have been published in mouse models. Rifampicin and St. John's wort, the prototypical human PXR agonists, impair glucose tolerance in healthy volunteers. Chronic exposure to PXR agonists could potentially represent a risk factor for diabetes and metabolic syndrome. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:27041449

  1. Ethanol impairs post-prandial hepatic protein metabolism.

    PubMed Central

    De Feo, P; Volpi, E; Lucidi, P; Cruciani, G; Monacchia, F; Reboldi, G; Santeusanio, F; Bolli, G B; Brunetti, P

    1995-01-01

    The effects of acute ethanol ingestion on whole body and hepatic protein metabolism in humans are not known. To simulate social drinking, we compared the effects of the association of a mixed meal (632 kcal, 17% amino acids, 50% glucose, 33% lipids) with a bottle of either table wine (ethanol content 71 g) or water on the estimates ([1-14C]-leucine infusion) of whole body protein breakdown, oxidation, and synthesis, and on the intravascular fractional secretory rates (FSR) of hepatically (albumin, fibrinogen) and extrahepatically (IgG) synthesized plasma proteins in two randomized groups (ethanol n = 7, water n = 7) of healthy nonalcoholic volunteers. Each study was carried out for 8 h. Protein kinetics were measured in the overnight post-absorptive state, over the first 4 h, and during a meal infusion (via a nasogastric feeding tube at constant rate) combined with the oral ingestion of wine or water, over the last 4 h. When compared with water, wine ingestion during the meal reduced (P < 0.03) by 24% the rate of leucine oxidation, did not modify the estimates of whole body protein breakdown and synthesis, reduced (P < 0.01) by approximately 30% the FSR of albumin and fibrinogen, but did not affect IgG FSR. In conclusion, 70 g of ethanol, an amount usual among social drinkers, impairs hepatic protein metabolism. The habitual consumption of such amounts by reducing the synthesis and/or secretion of hepatic proteins might lead to the progressive development of liver injury and to hypoalbuminemia also in the absence of protein malnutrition. PMID:7706451

  2. Sirtuin 1 Deacetylase: A Key Regulator of Hepatic Lipid Metabolism

    PubMed Central

    Kemper, Jongsook Kim; Choi, SungE; Kim, Dong Hyun

    2016-01-01

    Summary Obesity is a serious medical problem worldwide and disruption of metabolic/energy homeostasis plays a pivotal role in this global epidemic. In obese people, fatty liver (steatosis) develops, which increases the risk for diabetes, cardiovascular disease, and even, liver cancer. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that functions as a key metabolic/energy sensor and mediates homeostatic responses to nutrient availability. Accumulating evidence indicates that SIRT1 is a master regulator of the transcriptional networks that control hepatic lipid metabolism. During energy-deprived conditions, SIRT1 deacetylates and alters the expression and activities of key transcriptional regulators involved in hepatic lipogenesis, fatty acid β-oxidation, and cholesterol/bile acid metabolism. This review will discuss the latest advances in this field, focusing on beneficial roles of SIRT1 in hepatic lipid metabolism including its potential as a therapeutic target for treatment of steatosis and other obesity-related metabolic diseases. PMID:23374725

  3. Hepatic ACAT2 Knock Down Increases ABCA1 and Modifies HDL Metabolism in Mice

    PubMed Central

    Degirolamo, Chiara; Gomaraschi, Monica; Graham, Mark; Ossoli, Alice; Larsson, Lilian; Calabresi, Laura; Gustafsson, Jan-Åke; Steffensen, Knut R.; Eriksson, Mats; Parini, Paolo

    2014-01-01

    Objectives ACAT2 is the exclusive cholesterol-esterifying enzyme in hepatocytes and enterocytes. Hepatic ABCA1 transfers unesterified cholesterol (UC) to apoAI, thus generating HDL. By changing the hepatic UC pool available for ABCA1, ACAT2 may affect HDL metabolism. The aim of this study was to reveal whether hepatic ACAT2 influences HDL metabolism. Design WT and LXRα/β double knockout (DOKO) mice were fed a western-type diet for 8 weeks. Animals were i.p. injected with an antisense oligonucleotide targeted to hepatic ACAT2 (ASO6), or with an ASO control. Injections started 4 weeks after, or concomitantly with, the beginning of the diet. Results ASO6 reduced liver cholesteryl esters, while not inducing UC accumulation. ASO6 increased hepatic ABCA1 protein independently of the diet conditions. ASO6 affected HDL lipids (increased UC) only in DOKO, while it increased apoE-containing HDL in both genotypes. In WT mice ASO6 led to the appearance of large HDL enriched in apoAI and apoE. Conclusions The use of ASO6 revealed a new pathway by which the liver may contribute to HDL metabolism in mice. ACAT2 seems to be a hepatic player affecting the cholesterol fluxes fated to VLDL or to HDL, the latter via up-regulation of ABCA1. PMID:24695360

  4. Metabolic control of hepatic gluconeogenesis during exercise.

    PubMed Central

    Dohm, G L; Newsholme, E A

    1983-01-01

    Prolonged exercise increased the concentrations of the hexose phosphates and phosphoenolpyruvate and depressed those of fructose 1,6-bisphosphate, triose phosphates and pyruvate in the liver of the rat. Since exercise increases gluconeogenic flux, these changes in metabolite concentrations suggest that metabolic control is exerted, at least, at the fructose 6-phosphate/fructose 1,6-bisphosphate and phosphoenolpyruvate/pyruvate substrate cycles. Exercise increased the maximal activities of glucose 6-phosphatase, fructose 1,6-bisphosphatase, pyruvate kinase and pyruvate carboxylase in the liver, but there were no changes in those of glucokinase, 6-phosphofructokinase and phosphoenolpyruvate carboxykinase. Exercise changed the concentrations of several allosteric effectors of the glycolytic or gluconeogenic enzymes in liver; the concentrations of acetyl-CoA, ADP and AMP were increased, whereas those of ATP, fructose 1,6-bisphosphate and fructose 2,6-bisphosphate were decreased. The effect of exercise on the phosphorylation-dephosphorylation state of pyruvate kinase was investigated by measuring the activities under conditions of saturating and subsaturating concentrations of substrate. The submaximal activity of pyruvate kinase (0.5 mM-phosphoenolpyruvate), expressed as percentage of Vmax., decreased in the exercised animals to less than half that found in the controls. These changes suggest that hepatic pyruvate kinase is less active during exercise, possibly owing to phosphorylation of the enzyme, and this may play a role in increasing the rate of gluconeogenesis. PMID:6224482

  5. Hepatic metabolism in patients with alcoholic cirrhosis.

    PubMed

    Reichle, F A; Owen, O E; Golsorkhi, M; Kreulen, T

    1978-07-01

    Fuel homeostasis was studied in 15 patients with hepatic cirrhosis who previously had sustained upper gastrointestinal hemorrhage secondary to portal hypertension. By combining substrate arteriovenous concentration differences with measured hepatic blood flow rates, the exchange rates of metabolites across the liver was calculated. Hepatic extraction of acetoacetate, beta-hydroxybutyrate, lactate, pyruvate, analine, and glycerol was studied. After an overnight fast, splanchnic glucose production in 15 cirrhotic patients was diminished markedly. Despite reduced total glucose production, there was no decrease in hepatic gluconeogenesis; instead, there was increased glucose formation from amino acids, glycerol, lactate, and pyruvate. In patients with hepatic cirrhosis, the liver does not produce as much glucose as does a normal liver; the failing cirrhotic liver is capable of maintaining fuel homeostasis by increased ketone-body production. PMID:663824

  6. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans.

    PubMed

    Gancheva, Sofiya; Koliaki, Chrysi; Bierwagen, Alessandra; Nowotny, Peter; Heni, Martin; Fritsche, Andreas; Häring, Hans-Ulrich; Szendroedi, Julia; Roden, Michael

    2015-06-01

    Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery have provided conflicting results. In this randomized controlled crossover trial, we investigated the effects of intranasal insulin on hepatic insulin sensitivity (HIS) and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCLs), ATP, and inorganic phosphate concentrations with (1)H/(31)P magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin levels followed by a gradual lowering of blood glucose in CON only. Fasting HIS index was not affected by intranasal insulin in CON and patients. HCLs decreased by 35% in CON only, whereas absolute hepatic ATP concentration increased by 18% after 3 h. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCLs without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes. PMID:25576060

  7. IFNL4 affects clearance of hepatitis C virus

    Cancer.gov

    Scientists have discovered a new human interferon gene, Interferon Lambda 4 (IFNL4), that affects clearance of the hepatitis C virus. They also identified an inherited genetic variant within IFNL4 that predicts how people respond to treatment for hepatit

  8. Metabolism of bupropion by baboon hepatic and placental microsomes

    PubMed Central

    Wang, Xiaoming; Abdelrahman, Doaa R.; Fokina, Valentina M.; Hankins, Gary D.V.; Ahmed, Mahmoud S.; Nanovskaya, Tatiana N.

    2011-01-01

    The aim of this investigation was to determine the biotransformation of bupropion by baboon hepatic and placental microsomes, identify the enzyme(s) catalyzing the reaction(s) and determine its kinetics. Bupropion was metabolized by baboon hepatic and placental microsomes to hydroxybupropion (OH-BUP), threo- (TB) and erythrohydrobupropion (EB). OH-bupropion was the major metabolite formed by hepatic microsomes (Km 36 ± 6 µM, Vmax 258 ± 32 pmol mg protein−1 min−1), however the formation of OH-BUP by placental microsomes was below the limit of quantification. The apparent Km values of bupropion for the formation of TB and EB by hepatic and placental microsomes were similar. The selective inhibitors of CYP2B6 (ticlopidine and phencyclidine) and monoclonal antibodies raised against human CYP2B6 isozyme caused 80% inhibition of OH-BUP formation by baboon hepatic microsomes. The chemical inhibitors of aldo-keto reductases (flufenamic acid), carbonyl reductases (menadione), and 11β-hydroxysteroid dehydrogenases (18β-glycyrrhetinic acid) significantly decreased the formation of TB and EB by hepatic and placental microsomes. Data indicate that CYP2B of baboon hepatic microsomes is responsible for biotransformation of bupropion to OH-BUP, while hepatic and placental short chain dehydrogenases/reductases and to a lesser extent aldo-keto reductases are responsible for the reduction of bupropion to TB and EB. PMID:21570381

  9. Metabolic alterations and hepatitis C: From bench to bedside

    PubMed Central

    Chang, Ming-Ling

    2016-01-01

    In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight. PMID:26819514

  10. Metabolic alterations and hepatitis C: From bench to bedside.

    PubMed

    Chang, Ming-Ling

    2016-01-28

    In addition to causing cirrhosis and hepatocellular carcinoma, hepatitis C virus (HCV) is thought to cause hypolipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, and diabetes. The viral life cycle of HCV depends on cholesterol metabolism in host cells. HCV core protein and nonstructural protein 5A perturb crucial lipid and glucose pathways, such as the sterol regulatory element-binding protein pathway and the protein kinase B/mammalian target of rapamycin/S6 kinase 1 pathway. Although several lines of transgenic mice expressing core or full HCV proteins exhibit hepatic steatosis and/or dyslipidemia, whether they completely reflect the metabolic alterations in humans with HCV infection remains unknown. Many cross-sectional studies have demonstrated increased prevalences of metabolic alterations and cardiovascular events in patients with chronic hepatitis C (CHC); however, conflicting results exist, primarily due to unavoidable individual variations. Utilizing anti-HCV therapy, most longitudinal cohort studies of CHC patients have demonstrated the favorable effects of viral clearance in attenuating metabolic alterations and cardiovascular risks. To determine the risks of HCV-associated metabolic alterations and associated complications in patients with CHC, it is necessary to adjust for crucial confounders, such as HCV genotype and host baseline glucose metabolism, for a long follow-up period after anti-HCV treatment. Adipose tissue is an important endocrine organ due to its release of adipocytokines, which regulate lipid and glucose metabolism. However, most data on HCV infection and adipocytokine alteration are inconclusive. A comprehensive overview of HCV-associated metabolic and adipocytokine alterations, from bench to bedside, is presented in this topic highlight. PMID:26819514

  11. Hepatic Steatosis as a Marker of Metabolic Dysfunction

    PubMed Central

    Fabbrini, Elisa; Magkos, Faidon

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID:26102213

  12. β-Catenin Links Hepatic Metabolic Zonation with Lipid Metabolism and Diet-Induced Obesity in Mice

    PubMed Central

    Behari, Jaideep; Li, Huanan; Liu, Shiguang; Stefanovic-Racic, Maja; Alonso, Laura; O'Donnell, Christopher P.; Shiva, Sruti; Singamsetty, Srikanth; Watanabe, Yoshio; Singh, Vijay P.; Liu, Qing

    2015-01-01

    β-catenin regulates the establishment of hepatic metabolic zonation. To elucidate the functional significance of liver metabolic zonation in the chronically overfed state in vivo, we fed a high-fat diet (HFD) to hepatocyte-specific β-catenin transgenic (TG) and knockout (KO) mice. Chow-fed TG and KO mice had normal liver histologic findings and body weight. However, HFD-fed TG mice developed prominent perivenous steatosis with periportal sparing. In contrast, HFD-fed KO mice had increased lobular inflammation and hepatocyte apoptosis. HFD-fed TG mice rapidly developed diet-induced obesity and systemic insulin resistance, but KO mice were resistant to diet-induced obesity. However, β-catenin did not directly affect hepatic insulin signaling, suggesting that the metabolic effects of β-catenin occurred via a parallel pathway. Hepatic expression of key glycolytic and lipogenic genes was higher in HFD-fed TG and lower in KO mice compared with wild-type mice. KO mice also exhibited defective hepatic fatty acid oxidation and fasting ketogenesis. Hepatic levels of hypoxia inducible factor-1α, an oxygen-sensitive transcriptional regulator of glycolysis and a known β-catenin binding partner, were higher in HFD-fed TG and lower in KO mice. KO mice had attenuated perivenous hypoxia, suggesting disruption of the normal sinusoidal oxygen gradient, a major determinant of liver carbohydrate and liver metabolism. Canonical Wnt signaling in hepatocytes is essential for the development of diet-induced fatty liver and obesity. PMID:25300578

  13. The Effects of Physiological and Environmental Factors on Hepatic Perfusion and First-Pass Metabolism.

    NASA Astrophysics Data System (ADS)

    Modi, Marlene Woodruff

    The interaction of three important parameters; hepatic blood flow (Q_{rm H} ), plasma protein binding (f), and hepatic intrinsic clearance (CL_{rm int}) determines the disposition of agents undergoing extensive first-pass metabolism. This collection of studies focuses on the interaction of these parameters in man and the rat in the presence and absence of a given physiological and environmental perturbation. Potential mechanisms implicated in the "Food Effect" phenomenon whereby concomitant food intake increases the bioavailability a basic lipophilic drug are examined. These investigations provide insight as to the physiological response of the liver in the face of nutritional, pharmacological and physiological perturbations. The measurement of hepatic blood flow is a necessary endeavor before and understanding of the hepatic circulation or hepatic clearance concepts can be realized. Preliminary studies were performed to improve our understanding of the factors affecting the interpretation of hepatic blood flow estimates. It has been postulated that this food effect is caused at least in part by a transient increase in Q _{rm H} with its associated decrease in hepatic first-pass metabolism. Posture was manipulated in such a manner as to simulate the hepatic blood flow pattern observed in postprandial subjects. Although transient changes in Q_{rm H } comparable in magnitude and duration to those encountered after food consumption were observed, the AUC _{rm oral} for propanolol was not affected. It is important to assess the free concentration being presented to the organ which is highly extracting the drug. Single macronutrient feedings of glucose and vitamin-free casein to male Sprague-Dawley rats did not produce significant changes in the serum protein binding of a model basic lipophilic drug (quinidine) in systemic or hepatic blood. It has been postulated that food intake may have a greater influence on the bioavailability of metoprolol (a high clearance drug

  14. Hepatitis

    MedlinePlus

    ... has been associated with drinking contaminated water. Hepatitis Viruses Type Transmission Prognosis A Fecal-oral (stool to ... risk for severe disease. Others A variety of viruses can affect the liver Signs and Symptoms Hepatitis ...

  15. Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats.

    PubMed

    Klieverik, Lars P; Sauerwein, Hans P; Ackermans, Mariëtte T; Boelen, Anita; Kalsbeek, Andries; Fliers, Eric

    2008-03-01

    Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition. PMID:18182466

  16. Hepatitis B virus infection and metabolic syndrome: fact or fiction?

    PubMed

    Wang, Chia-Chi; Tseng, Tai-Chung; Kao, Jia-Horng

    2015-01-01

    Although hepatitis C virus infection is known to be linked with insulin resistance, dyslipidemia, and hepatic steatosis, the relationship between hepatitis B virus (HBV) infection and metabolic factors remains unclear. HBV infection is a health problem worldwide, especially in endemic regions such as Asia and Africa. It induces liver decompensation, cirrhosis, hepatocellualr carcinoma, and premature mortality. The prevalence of metabolic syndrome continues to increase in parallel with the epidemic of obesity, which is closely associated with the development of diabetes, cardiovascular disease, or even cancer. The systemic review shows that chronic HBV infection protects against instead of promotes fatty liver. The mechanism is possibly due to a lower frequency of dyslipidemia profile in patients with chronic HBV infection. The association of HBV with metabolic syndrome, insulin resistance, and the risk of arteriosclerosis is still inconclusive. In addition, obesity, diabetes, and metabolic syndrome may accelerate the progression of liver disease in patients with chronic HBV infection and synergistically induce cirrhosis or even hepatocellualr carcinoma development. PMID:25092429

  17. 'Micro-managers' of hepatic lipid metabolism and NAFLD.

    PubMed

    Liu, Wei; Cao, Hongchao; Yan, Jun; Huang, Ruimin; Ying, Hao

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is tightly associated with insulin resistance, type 2 diabetes, and obesity. As the defining feature of NAFLD, hepatic steatosis develops as a consequence of metabolic dysregulation of de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and triglycerides (TG) export. MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, play critical roles in various biological processes through regulating gene expression at post-transcriptional level. A growing body of evidence suggests that miRNAs not only maintain hepatic TG homeostasis under physiological condition, but also participate in the pathogenesis of NAFLD. In this review, we focus on the current knowledge of the hepatic miRNAs associated with the development of liver steatosis and the regulatory mechanisms involved, which might be helpful to further understand the nature of NAFLD and provide a sound scientific basis for the drug development. PMID:26198708

  18. Affective Disorders, Bone Metabolism, and Osteoporosis

    PubMed Central

    2013-01-01

    The nature of the relationship between affective disorders, bone mineral density (BMD), and bone metabolism is unresolved, although there is growing evidence that many medications used to treat affective disorders are associated with low BMD or alterations in neuroendocrine systems that influence bone turnover. The objective of this review is to describe the current evidence regarding the association of unipolar and bipolar depression with BMD and indicators of bone metabolism, and to explore potential mediating and confounding influences of those relationships. The majority of studies of unipolar depression and BMD indicate that depressive symptoms are associated with low BMD. In contrast, evidence regarding the relationship between bipolar depression and BMD is inconsistent. There is limited but suggestive evidence to support an association between affective disorders and some markers of bone turnover. Many medications used to treat affective disorders have effects on physiologic systems that influence bone metabolism, and these conditions are also associated with a range of health behaviors that can influence osteoporosis risk. Future research should focus on disentangling the pathways linking psychotropic medications and their clinical indications with BMD and fracture risk. PMID:23874147

  19. Hepatic metabolism of carcinogenic β-asarone.

    PubMed

    Cartus, Alexander T; Stegmüller, Simone; Simson, Nadine; Wahl, Andrea; Neef, Sylvia; Kelm, Harald; Schrenk, Dieter

    2015-09-21

    β-Asarone (1) belongs to the group of naturally occurring phenylpropenes like eugenol or anethole. Compound 1 is found in several plants, e.g., Acorus calamus or Asarum europaeum. Compound 1-containing plant materials and essential oils thereof are used to flavor foods and alcoholic beverages and as ingredients of many drugs in traditional phytomedicines. Although 1 has been claimed to have several positive pharmacological effects, it was found to be genotoxic and carcinogenic in rodents (liver and small intestine). The mechanism of action of carcinogenic allylic phenylpropenes consists of the metabolic activation via cytochrome P450 enzymes and sulfotransferases. In vivo experiments suggested that this pathway does not play a major role in the carcinogenicity of the propenylic compound 1 as is the case for other propenylic compounds, e.g., anethole. Since the metabolic pathways of 1 have not been investigated and its carcinogenic mode of action is unknown, we investigated the metabolism of 1 in liver microsomes of rats, bovines, porcines, and humans using (1)H NMR, HPLC-DAD, and LC-ESI-MS/MS techniques. We synthesized the majority of identified metabolites which were used as reference compounds for the quantification and final verification of metabolites. Microsomal epoxidation of the side chain of 1 presumably yielded (Z)-asarone-1',2'-epoxide (8a) which instantly was hydrolyzed to the corresponding erythro- and threo-configurated diols (9b, 9a) and the ketone 2,4,5-trimethoxyphenylacetone (13). This was the main metabolic pathway in the metabolism of 1 in all investigated liver microsomes. Hydroxylation of the side chain of 1 led to the formation of three alcohols at total yields of less than 30%: 1'-hydroxyasarone (2), (E)- and (Z)-3'-hydroxyasarone (4 and 6), with 6 being the mainly formed alcohol and 2 being detectable only in liver microsomes of Aroclor 1254-pretreated rats. Small amounts of 4 and 6 were further oxidized to the corresponding carbonyl

  20. Integrative Metabolic Signatures for Hepatic Radiation Injury

    PubMed Central

    Su, Gang; Meng, Fan; Liu, Laibin; Mohney, Robert; Kulkarni, Shilpa; Guha, Chandan

    2015-01-01

    Background Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice. Methods Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry. Results Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine). Conclusions We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney. PMID:26046990

  1. Liver Fat Content in Type 2 Diabetes: Relationship With Hepatic Perfusion and Substrate Metabolism

    PubMed Central

    Rijzewijk, Luuk J.; van der Meer, Rutger W.; Lubberink, Mark; Lamb, Hildo J.; Romijn, Johannes A.; de Roos, Albert; Twisk, Jos W.; Heine, Robert J.; Lammertsma, Adriaan A.; Smit, Johannes W.A.; Diamant, Michaela

    2010-01-01

    OBJECTIVE Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content. RESEARCH DESIGN AND METHODS Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%. RESULTS Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = −0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = −0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = −0.329, P = 0.004). CONCLUSIONS In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat

  2. Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism.

    PubMed

    Madiraju, Anila K; Alves, Tiago; Zhao, Xiaojian; Cline, Gary W; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T; Kibbey, Richard G; Shulman, Gerald I

    2016-06-14

    A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism. PMID:27247419

  3. Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism

    PubMed Central

    Madiraju, Anila K.; Alves, Tiago; Zhao, Xiaojian; Cline, Gary W.; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T.; Kibbey, Richard G.; Shulman, Gerald I.

    2016-01-01

    A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepatic ASS1 expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism. PMID:27247419

  4. Metabolism of C-peptide in the dog. In vivo demonstration of the absence of hepatic extraction.

    PubMed Central

    Polonsky, K; Jaspan, J; Pugh, W; Cohen, D; Schneider, M; Schwartz, T; Moossa, A R; Tager, H; Rubenstein, A H

    1983-01-01

    The in vivo hepatic metabolism of connecting peptide (C-peptide) in relation to that of insulin has not been adequately characterized. A radioimmunoassay for dog C-peptide was therefore developed and its metabolism studied in conscious mongrel dogs, with sampling catheters chronically implanted in their portal and hepatic veins and femoral artery. The hepatic extraction of endogenous C-peptide under basal conditions was negligible (4.3 +/- 4.5%) and was similar to the hepatic extraction of C-peptide measured during the constant exogenous infusion of C-peptide isolated from dog pancreas. Simultaneously measured hepatic extraction of endogenous and exogenously infused insulin were 43.8 +/- 7.6 and 47.5 +/- 4.4%, respectively. The metabolic clearance rate of infused C-peptide was 11.5 +/- 0.8 ml/kg per min and was constant over the concentration range usually encountered under physiological conditions. In additional experiments, the effect of parenteral glucose administration on the hepatic extraction of C-peptide and insulin was investigated. The hepatic extraction of C-peptide (6.2 +/- 4.0%) was again negligible in comparison with that of insulin (46.7 +/- 3.4%). Parenteral glucose administration did not affect the hepatic extraction of either peptide irrespective of whether it was infused peripherally, intraportally, or together with an intraportal infusion of gastrointestinal inhibitory polypeptide. The fasting C-peptide insulin molar ratio in both the portal vein (1.2 +/- 0.1) and femoral artery (2.1 +/- 0.3) was also unaffected by the glucose stimulus. These results therefore indicate that, since the hepatic extraction of C-peptide is negligible and its clearance kinetics linear, the peripheral C-peptide concentration should accurately reflect the rate of insulin secretion. New approaches to the quantitation of hepatic extraction and secretion of insulin by noninvasive techniques are now feasible. PMID:6350363

  5. 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. PMID:24221354

  6. Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

    PubMed Central

    Gish, Robert G.

    2016-01-01

    Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality. PMID:27499712

  7. Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection.

    PubMed

    Wong, Robert J; Gish, Robert G

    2016-05-01

    Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality. PMID:27499712

  8. How dietary arachidonic- and docosahexaenoic- acid rich oils differentially affect the murine hepatic transcriptome

    PubMed Central

    Berger, Alvin; Roberts, Matthew A; Hoff, Bruce

    2006-01-01

    Introduction Herein, we expand our previous work on the effects of long chain polyunsaturated fatty acids (LC-PUFA) on the murine hepatic transcriptome using novel statistical and bioinformatic approaches for evaluating microarray data. The analyses focuses on key differences in the transcriptomic response that will influence metabolism following consumption of FUNG (rich in 20:4n6), FISH (rich in 20:5n3, 22:5n3, and 22:6n3) and COMB, the combination of the two. Results Using a variance-stabilized F-statistic, 371 probe sets (out of 13 K probe sets in the Affymetrix Mu11K chip set) were changed by dietary treatment (P < 0.001). Relative to other groups, COMB had unique affects on murine hepatic transcripts involved in cytoskeletal and carbohydrate metabolism; whereas FUNG affected amino acid metabolism via CTNB1 signaling. All three diets affected transcripts linked to apoptosis and cell proliferation, with evidence FISH may have increased apoptosis and decreased cell proliferation via various transcription factors, kinases, and phosphatases. The three diets affected lipid transport, lipoprotein metabolism, and bile acid metabolism through diverse pathways. Relative to other groups, FISH activated cyps that form hydroxylated fatty acids known to affect vascular tone and ion channel activity. FA synthesis and delta 9 desaturation were down regulated by COMB relative to other groups, implying that a FA mixture of 20:4n6, 20:5n3, and 22:6n3 is most effective at down regulating synthesis, via INS1, SREBP, PPAR alpha, and TNF signaling. Heme synthesis and the utilization of heme for hemoglobin production were likely affected by FUNG and FISH. Finally, relative to other groups, FISH increased numerous transcripts linked to combating oxidative such as peroxidases, an aldehyde dehydrogenase, and heat shock proteins, consistent with the major LC-PUFA in FISH (20:5n3, 22:5n3, 22:6n3) being more oxidizable than the major fatty acids in FUNG (20:4n6). Conclusion Distinct

  9. Hypolipidemic effect of dietary pea proteins: Impact on genes regulating hepatic lipid metabolism.

    PubMed

    Rigamonti, Elena; Parolini, Cinzia; Marchesi, Marta; Diani, Erika; Brambilla, Stefano; Sirtori, Cesare R; Chiesa, Giulia

    2010-05-01

    Controversial data on the lipid-lowering effect of dietary pea proteins have been provided and the mechanisms behind this effect are not completely understood. The aim of the study was to evaluate a possible hypolipidemic activity of a pea protein isolate and to determine whether pea proteins could affect the hepatic lipid metabolism through regulation of genes involved in cholesterol and fatty acid homeostasis. Rats were fed Nath's hypercholesterolemic diets for 28 days, the protein sources being casein or a pea protein isolate from Pisum sativum. After 14 and 28 days of dietary treatment, rats fed pea proteins had markedly lower plasma cholesterol and triglyceride levels than rats fed casein (p<0.05). Pea protein-fed rats displayed higher hepatic mRNA levels of LDL receptor versus those fed casein (p<0.05). Hepatic mRNA concentration of genes involved in fatty acids synthesis, such as fatty acid synthase and stearoyl-CoA desaturase, was lower in pea protein-fed rats than in rats fed casein (p<0.05). In conclusion, the present study demonstrates a marked cholesterol and triglyceride-lowering activity of pea proteins in rats. Moreover, pea proteins appear to affect cellular lipid homeostasis by upregulating genes involved in hepatic cholesterol uptake and by downregulating fatty acid synthesis genes. PMID:20077421

  10. Exposure to a northern contaminant mixture (NCM) alters hepatic energy and lipid metabolism exacerbating hepatic steatosis in obese JCR rats.

    PubMed

    Mailloux, Ryan J; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to 10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co

  11. Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

    PubMed Central

    Mailloux, Ryan J.; Florian, Maria; Chen, Qixuan; Yan, Jin; Petrov, Ivan; Coughlan, Melanie C.; Laziyan, Mahemuti; Caldwell, Don; Lalande, Michelle; Patry, Dominique; Gagnon, Claude; Sarafin, Kurtis; Truong, Jocelyn; Chan, Hing Man; Ratnayake, Nimal; Li, Nanqin; Willmore, William G.; Jin, Xiaolei

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co

  12. Chronic hepatitis C virus infection and lipoprotein metabolism

    PubMed Central

    Aizawa, Yoshio; Seki, Nobuyoshi; Nagano, Tomohisa; Abe, Hiroshi

    2015-01-01

    Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins. PMID:26420957

  13. Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment

    SciTech Connect

    Taguchi, Kazuaki; Miyasato, Mayumi; Ujihira, Hayato; Watanabe, Hiroshi; Kadowaki, Daisuke; Sakai, Hiromi; Tsuchida, Eishun; Horinouchi, Hirohisa; Kobayashi, Koichi; Maruyama, Toru; Otagiri, Masaki

    2010-11-01

    The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings.

  14. HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.

    PubMed

    Zhang, Yuxiang; Fang, Bin; Damle, Manashree; Guan, Dongyin; Li, Zhenghui; Kim, Yong Hoon; Gannon, Maureen; Lazar, Mitchell A

    2016-07-15

    Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver. PMID:27445394

  15. Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes.

    PubMed

    Liu, Yan; Pu, Qiang-Hong; Wu, Ming-Jun; Yu, Chao

    2016-10-01

    1. Our objective is to investigate the alterations of hepatic drug transporters and metabolizing enzymes in hypercholesterolemia. Male Sprague-Dawley rats were fed high-cholesterol chows for 8 weeks to induce hypercholesterolemia. Protein levels of hepatic drug transporters and metabolizing enzymes were analyzed by iTRAQ labeling coupled with LC TRIPLE-TOF. 2. Total 239 differentially expressed proteins were identified using proteomic analysis. Among those, protein levels of hepatic drug transporters (MRP2, ABCD3, OAT2, SLC25A12, SCL38A3, SLC2A2 and SLC25A5) and metabolizing enzymes (CYP2B3, CYP2C7, CYP2C11, CYP2C13, CYP4A2 and UGT2B) were markedly reduced, but the levels of CYP2C6 and CYP2E1 were increased in hypercholesterolemia group compared to control. Decreased expressions of drug transporters MRP2 and OAT2 were further confirmed by real time quantitative PCR (RT-qPCR) and western blot. 3. Ingenuity pathway analysis revealed that these differentially expressed proteins were regulated by various signaling pathways including nuclear receptors and inflammatory cytokines. One of the nuclear receptor candidates, liver X receptor alpha (LXRα), was further validated by RT-qPCR and western blot. Additionally, LXRα agonist T0901317 rescued the reduced expressions of MRP2 and OAT2 in HepG2 cells in hypercholesterolemic serum treatment. 4. Our present results indicated that hypercholesterolemia affected the expressions of various drug transporters and metabolizing enzymes in liver via nuclear receptors pathway. Especially, decreased function of LXRα contributes to the reduced expressions of MRP2 and OAT2. PMID:26887802

  16. Pharmacological basis for hepatic drug metabolism in sheep.

    PubMed

    Galtier, P; Alvinerie, M

    1996-01-01

    Age-related changes in hepatic drug metabolizing activities of Lacaune ewes were determined in foetal, neonatal, growing, pregnant and adult animals. The ontogenic evolution of cytochrome P450 was compared to those of microsomal monooxygenases and some microsomal and cytosolic transferases. The involvement of two purified izoenzymes P4502B and P4503A was determined in the N-demethylation of various substrates and the hydroxylations of progesterone. An experimental fascioliasis, provoked by the oral administration of 150 metacercariae of Fasciola hepatica to sheep, was proposed as a pathological model. Its effect was measured on the pharmacokinetics of various hepatic tracers and veterinary drugs. The mean residence times of antipyrine, pentobarbital, albendazole and mebendazole were increased in infected lambs with consequences on the urinary excretion of 4-hydroxyantipyrine, prolongation of pentobarbital-induced sleeping time, elimination of albendazole sulfone and reduced mebendazole. The characteristic decrease in liver cytochrome P450 could be responsible for most of the pharmacokinetic and pharmacodynamic changes observed in fluke-infected ruminants. PMID:8822607

  17. Mapping Metabolic Brain Activity in Three Models of Hepatic Encephalopathy

    PubMed Central

    Méndez, Marta; Fidalgo, Camino; Aller, María Ángeles; Arias, Jaime; Arias, Jorge L.

    2013-01-01

    Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups. PMID:23573412

  18. Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.

    PubMed

    Caesar, Robert; Nygren, Heli; Orešič, Matej; Bäckhed, Fredrik

    2016-03-01

    The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition. PMID:26783361

  19. Immunologic, metabolic and genetic factors in hepatitis C virus infection.

    PubMed

    Fierro, Nora A; Gonzalez-Aldaco, Karina; Torres-Valadez, Rafael; Martinez-Lopez, Erika; Roman, Sonia; Panduro, Arturo

    2014-04-01

    The mechanisms that regulate disease progression during hepatitis C virus (HCV) infection and the response to treatment are not clearly identified. Numerous studies have demonstrated that a strong host immune response against HCV favors HCV clearance. In addition, genetic factors and metabolic machinery, particularly cholesterol modulation, are involved in HCV infection. It is likely that the interplay between all of these factors contributes to the outcome of HCV infection. In recent years, the world has experienced its largest epidemic of obesity. Mexico and the United States are the leading sufferers from this epidemic at the global level. Obesity is associated with the development of numerous pathologies including hypercholesterolemia which is one of the eight most important risk factors for mortality in Mexico. This may be related to the course of HCV infection in this population. Here, we focus on the urgent need to study the progression of HCV infection in relation to ethnic characteristics. Discoveries are discussed that hold promise in identifying immune, metabolic and genetic factors that, in conjunction, could be therapeutic targets or predictors of the progression of HCV infection. PMID:24707127

  20. Leptin: a possible metabolic signal affecting reproduction.

    PubMed

    Spicer, L J

    2001-11-01

    Since its discovery in 1994, leptin, a protein hormone synthesized and secreted by adipose tissue, has been shown to regulate feed intake in several species including sheep and pigs. Although a nimiety of information exists regarding the physiological role of leptin in rodents and humans, the regulation and action of leptin in domestic animals is less certain. Emerging evidence in several species indicates that leptin may also affect the hypothalamo-pituitary-gonadal axis. Leptin receptor mRNA is present in the anterior pituitary and hypothalamus of several species, including sheep. In rats, effects of leptin on GnRH, LH and FSH secretion have been inconsistent, with leptin exhibiting both stimulatory and inhibitory action in vivo and in vitro. Evidence to support direct action of leptin at the level of the gonad indicates that the leptin receptor and its mRNA are present in ovarian tissue of several species, including cattle. These leptin receptors are functional, since leptin inhibits insulin-induced steroidogenesis of both granulosa and thecal cells of cattle in vitro. Leptin receptor mRNA is also found in the testes of rodents. As with the ovary, these receptors are functional, at least in rats, since leptin inhibits hCG-induced testosterone secretion by Leydig cells in vitro. During pregnancy, placental production of leptin may be a major contributor to the increase in maternal leptin in primates but not rodents. However, in both primates and rodents, leptin receptors exist in placental tissues and may regulate metabolism of the fetal-placental unit. As specific leptin immunoassays are developed for domestic animals, in vivo associations may then be made among leptin, body energy stores, dietary energy intake and reproductive function. This may lead to a more definitive role of leptin in domestic animal reproduction. PMID:11872320

  1. The Role of Gastrointestinal Hormones in Hepatic Lipid Metabolism

    PubMed Central

    Mells, Jamie Eugene; Anania, Frank A.

    2014-01-01

    Hepatocellular accumulation of free fatty acids (FFAs) in the form of triglycerides constitutes the metabolic basis for the development of nonalcoholic fatty liver disease (NAFLD). Recent data demonstrate that excess FFA hepatocyte storage is likely to lead to lipotoxicity and hepatocyte apoptosis. Hence, FFA-mediated hepatocyte injury is a key contributor to the pathogenesis of nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis, obesity, type 2 diabetes, essential hypertension, and other common medical problems together comprise metabolic syndrome. Evidence suggests that peptide hormones from the L cells of the distal small intestine, which comprise the core of the enteroendocrine system (EES), play two key roles, serving either as incretins, or as mediators of appetite and satiety in the central nervous system. Recent data related to glucagon-like peptide-1 (GLP-1) and other known L-cell hormones have accumulated due to the increasing frequency of bariatric surgery, which increase delivery of bile salts to the hindgut. Bile acids are a key stimulus for the TGR5 receptor of the L cells. Enhanced bile-salt flow and subsequent EES stimulation may be central to elimination of hepatic steatosis following bariatric surgery. Although GLP-1 is a clinically relevant pharmacological analogue that drives pancreatic β-cell insulin output, GLP-1 analogues also have independent benefits via their effects on hepatocellular FFA metabolism. The authors also discuss recent data regarding the role of the major peptides released by the EES, which promote satiety and modulate energy homeostasis and utilization, as well as those that control fat absorption and intestinal permeability. Taken together, elucidating novel functions for EES-related peptides and pharmacologic development of peptide analogues offer potential far-ranging treatment for obesity-related human disease. PMID:24222092

  2. Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice.

    PubMed

    Tsuneki, Hiroshi; Nagata, Takashi; Fujita, Mikio; Kon, Kanta; Wu, Naizhen; Takatsuki, Mayumi; Yamaguchi, Kaoru; Wada, Tsutomu; Nishijo, Hisao; Yanagisawa, Masashi; Sakurai, Takeshi; Sasaoka, Toshiyasu

    2016-01-01

    Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems. PMID:26492471

  3. The role of hepatic mitochondria in the regulation of glucose metabolism in BHE rats

    SciTech Connect

    Kim, M.J.C.

    1988-01-01

    The interacting effects of dietary fat source and thyroxine treatment on the hepatic mitochondrial function and glucose metabolism were studied. In the first study, three different sources of dietary fatty acids and thyroxine treatment were used to investigate the hepatic mitochondrial thermotropic behavior in two strains of rat. The NIDDM BHE and Sprague-Dawley rats were used. Feeding coconut oil increased serum T{sub 4} levels and T{sub 4} treatment increased serum T{sub 3} levels in the BHE rats. In the mitochondria from BHE rats fed coconut oil and treated with T{sub 4}, the transition temperature disappeared due to a decoupling of succinate supported respiration. This was not observed in the Sprague-Dawley rats. In the second study, two different sources of dietary fat and T{sub 4} treatment were used to investigate hepatic mitochondrial function. Coconut oil feeding increased Ca{sup ++}Mg{sup ++}ATPase and Mg{sup ++}ATPase. T{sub 4} treatment had potentiated this effect. T{sub 4} increased the malate-aspartate shuttle and {alpha}-glycerophosphate shuttle activities. In the third study, the glucose turnover rate from D-({sup 14}C-U)/(6-{sup 3}H)-glucose and gluconeogeneis from L-({sup 14}C-U)-alanine was examined. Dietary fat or T{sub 4} did not affect the glucose mass. T{sub 4} increased the irreversible fractional glucose turnover rate.

  4. Hepatitis C virus mutation affects proteasomal epitope processing

    PubMed Central

    Seifert, Ulrike; Liermann, Heike; Racanelli, Vito; Halenius, Anne; Wiese, Manfred; Wedemeyer, Heiner; Ruppert, Thomas; Rispeter, Kay; Henklein, Peter; Sijts, Alice; Hengel, Hartmut; Kloetzel, Peter-M.; Rehermann, Barbara

    2004-01-01

    The high incidence of hepatitis C virus (HCV) persistence raises the question of how HCV interferes with host immune responses. Studying a single-source HCV outbreak, we identified an HCV mutation that impaired correct carboxyterminal cleavage of an immunodominant HLA-A2–restricted CD8 cell epitope that is frequently recognized by recovered patients. The mutation, a conservative HCV nonstructural protein 3 (NS3) tyrosine to phenylalanine substitution, was absent in 54 clones of the infectious source, but present in 15/21 (71%) HLA-A2–positive and in 11/24 (46%) HLA-A2–negative patients with chronic hepatitis C. In order to analyze whether the mutation affected the processing of the HLA-A2–restricted CD8 cell epitope, mutant and wild-type NS3 polypeptides were digested in vitro with 20S constitutive proteasomes and with immunoproteasomes. The presence of the mutation resulted in impaired carboxyterminal cleavage of the epitope. In order to analyze whether impaired epitope processing affected T cell priming in vivo, HLA-A2–transgenic mice were infected with vaccinia viruses encoding either wild-type or mutant HCV NS3. The mutant induced fewer epitope-specific, IFN-γ;–producing and fewer tetramer+ cells than the wild type. These data demonstrate how a conservative mutation in the flanking region of an HCV epitope impairs the induction of epitope-specific CD8+ T cells and reveal a mechanism that may contribute to viral sequence evolution in infected patients. PMID:15254592

  5. Factors affecting metabolic syndrome by lifestyle

    PubMed Central

    Ki, Nam-Kyun; Lee, Hae-Kag; Cho, Jae-Hwan; Kim, Seon-Chil; Kim, Nak-Sang

    2016-01-01

    [Purpose] The aim of this study was to explore lifestyle factors in relation to metabolic syndrome so as to be able to utilize the results as baseline data for the furtherance of health-care and medical treatment. [Subjects and Methods] This study was conducted with patients who visited a health care center located in Seoul and had abdominal ultrasonography between 2 March 2013 and 28 February, 2014. Heights, weights, and blood pressures were measured by automatic devices. Three radiologists examined the patients using abdominal ultrasonography for gallstone diagnosis. The statuses of patients with regard to smoking, alcohol, coffee, and physical activities were explored for the lifestyle investigation. For investigating baseline demographics, we first used descriptive statistics. We then used the χ2 test to analyze lifestyles and gallstone prevalence with regard to the presence of metabolic syndrome. Lastly, logistic regression analysis was conducted to discover the risk factors of metabolic syndrome. [Results] For men, body mass index, maximum gallstone size, and waist circumference were revealed as risk factors for metabolic syndrome, in descending order of the degree of risk. For females, gallstone presence was the most significant risk factor, followed by waist circumference. [Conclusion] Metabolic disease mainly presents itself along with obesity, and we should become more focused on preventing and treating this disease. A large-scale prospective study is needed in the future, as the cause of nonalcoholic steatohepatitis remained unclear in this study. PMID:26957725

  6. Hepatic autophagy contributes to the metabolic response to dietary protein restriction.

    PubMed

    Henagan, Tara M; Laeger, Thomas; Navard, Alexandra M; Albarado, Diana; Noland, Robert C; Stadler, Krisztian; Elks, Carrie M; Burk, David; Morrison, Christopher D

    2016-06-01

    Autophagy is an essential cellular response which acts to release stored cellular substrates during nutrient restriction, and particularly plays a key role in the cellular response to amino acid restriction. However, there has been limited work testing whether the induction of autophagy is required for adaptive metabolic responses to dietary protein restriction in the whole animal. Here, we found that moderate dietary protein restriction led to a series of metabolic changes in rats, including increases in food intake and energy expenditure, the downregulation of hepatic fatty acid synthesis gene expression and reduced markers of hepatic mitochondrial number. Importantly, these effects were also associated with an induction of hepatic autophagy. To determine if the induction of autophagy contributes to these metabolic effects, we tested the metabolic response to dietary protein restriction in BCL2-AAA mice, which bear a genetic mutation that impairs autophagy induction. Interestingly, BCL2-AAA mice exhibit exaggerated responses in terms of both food intake and energy expenditure, whereas the effects of protein restriction on hepatic metabolism were significantly blunted. These data demonstrate that restriction of dietary protein is sufficient to trigger hepatic autophagy, and that disruption of autophagy significantly alters both hepatic and whole animal metabolic response to dietary protein restriction. PMID:27173459

  7. Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice.

    PubMed

    Soufi, Nisreen; Hall, Angela M; Chen, Zhouji; Yoshino, Jun; Collier, Sara L; Mathews, James C; Brunt, Elizabeth M; Albert, Carolyn J; Graham, Mark J; Ford, David A; Finck, Brian N

    2014-10-24

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  8. Inhibiting Monoacylglycerol Acyltransferase 1 Ameliorates Hepatic Metabolic Abnormalities but Not Inflammation and Injury in Mice*

    PubMed Central

    Soufi, Nisreen; Hall, Angela M.; Chen, Zhouji; Yoshino, Jun; Collier, Sara L.; Mathews, James C.; Brunt, Elizabeth M.; Albert, Carolyn J.; Graham, Mark J.; Ford, David A.; Finck, Brian N.

    2014-01-01

    Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury. PMID:25213859

  9. A model for the extended studies of hepatic hemodynamics and metabolism in swine.

    PubMed

    Drougas, J G; Barnard, S E; Wright, J K; Sika, M; Lopez, R R; Stokes, K A; Williams, P E; Pinson, C W

    1996-12-01

    To our knowledge postoperative hepatic hemodynamics and hepatic metabolism have not been fully studied on a long-term basis. Our goal was to develop a large animal model that would permit the measurement of hepatic blood flow (BF), perihepatic pressures (P), and hepatic metabolism in a long-term setting. Catheters were inserted into the jugular vein, carotid artery, pulmonary artery, hepatic vein, and portal vein (PV) of 27 commercially bred pigs; ultrasonic transit time flowmeter probes were placed around the hepatic artery and PV. Daily postoperative measurements of jugular vein P, carotid artery P, pulmonary artery P, hepatic vein P, and PVP, as well as hepatic artery BF and PVBF, were recorded for 20 days. Hepatic carbohydrate metabolism was assessed by arteriovenous difference techniques. Jugular vein P, pulmonary artery P, hepatic vein P, PVP, and heart rate reached steady-state values during the first week, with a mean +/- SEM of 1.0 +/- 0.3 mm Hg for jugular vein P, 21.4 +/- 2.1 mm Hg for pulmonary artery P, 4.3 +/- 0.4 mm Hg for HVP, 7.8 +/- 0.5 mm Hg for PVP, and 116 +/- 4 beats per minute for heart rate. Mean carotid artery P increased from 65 +/- 3 mm Hg during surgery to 94 +/- 2 mm Hg on postoperative day 1 (P < 0.001) and to a mean 101 +/- 2 mm Hg thereafter. Total hepatic BF reached a steady-state value of 1,132 +/- 187 ml/min by postoperative day 7 (P = 0.19). Over week 1 hepatic artery BF measured as a percentage of total hepatic BF decreased from 35.0 +/- 3.0% to 15.5 +/- 2.7%, and PVBF increased from 65.0 +/- 3.0% to 84.5 +/- 2.7% (P < 0.005); both variables were steady thereafter. In the hemodynamic steady state the net hepatic balances of glucose, lactate, glycerol, and alanine in 5 pigs were 9.9 +/- 4.0, -4.2 +/- 0.4, -2.3 +/- 1.1, and -0.68 +/- 0.22 micromol/kg per min respectively. The net gut (portal-drained viscera) balances of glucose, lactate, alanine, and glycerol were -2.0 +/- 2.5, 1.1 +/- 0.5, 0.73 +/- 0.18, and -0.69 +/- 0

  10. Association Between Metabolic Syndrome and Its Individual Components with Viral Hepatitis B

    PubMed Central

    Jinjuvadia, Raxitkumar; Liangpunsakul, Suthat

    2013-01-01

    Background The association between hepatitis B and metabolic syndrome (MetS) has not been well described. Overall epidemiologic evidences for this association have suggested conflicting results. The aim of our study is to determine the association between hepatitis B infection and MetS using large U.S. population database, the Third National Health and Nutrition Examination Survey (NHANES III). Methods Individuals with age ≥ 18 years were included in this study. MetS was defined according to NCEP/ATP III guideline. The chronic hepatitis B was defined as presence of hepatitis B surface antigen. The presence of hepatitis B core antibody with/without surface antibody, in absence of surface antigen was considered as past exposure to hepatitis B. To represent national estimates, weighted frequencies for chronic hepatitis B and past exposure to hepatitis B are reported. Multivariate logistic regression analysis accounting for age, gender, race, smoking and alcohol status was conducted to identify the independent predictor(s) of MetS. Results Our study cohort consisted of population total of 593,594 with chronic hepatitis B and 7,280,620 with past exposure to hepatitis B. Prevalence of MetS among included study cohort was 25.7%. Inverse association was observed between MetS and chronic hepatitis B (aOR: 0.32, 95% CI 0.12–0.84). Among individual components of MetS, waist circumference was inversely associated with chronic hepatitis B (aOR: 0.31, 95% CI 0.14–0.71). No significant association noted between past exposure to hepatitis B and MetS or its individuals components. Conclusion In this study, we noted significant inverse association between MetS and chronic hepatitis B. PMID:23514672

  11. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism

    PubMed Central

    Kim, Kyung Eun; Jung, Youngae; Min, Soonki; Nam, Miso; Heo, Rok Won; Jeon, Byeong Tak; Song, Dae Hyun; Yi, Chin-ok; Jeong, Eun Ae; Kim, Hwajin; Kim, Jeonghyun; Jeong, Seon-Yong; Kwak, Woori; Ryu, Do Hyun; Horvath, Tamas L.; Roh, Gu Seob; Hwang, Geum-Sook

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. 1H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications. PMID:27439777

  12. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism.

    PubMed

    Kim, Kyung Eun; Jung, Youngae; Min, Soonki; Nam, Miso; Heo, Rok Won; Jeon, Byeong Tak; Song, Dae Hyun; Yi, Chin-Ok; Jeong, Eun Ae; Kim, Hwajin; Kim, Jeonghyun; Jeong, Seon-Yong; Kwak, Woori; Ryu, Do Hyun; Horvath, Tamas L; Roh, Gu Seob; Hwang, Geum-Sook

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. (1)H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications. PMID:27439777

  13. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism.

    PubMed

    Abruzzese, Giselle Adriana; Heber, Maria Florencia; Ferreira, Silvana Rocio; Velez, Leandro Martin; Reynoso, Roxana; Pignataro, Omar Pedro; Motta, Alicia Beatriz

    2016-07-01

    Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis. PMID:27179108

  14. Gene Expression Variability in Human Hepatic Drug Metabolizing Enzymes and Transporters

    PubMed Central

    Yang, Lun; Price, Elvin T.; Chang, Ching-Wei; Li, Yan; Huang, Ying; Guo, Li-Wu; Guo, Yongli; Kaput, Jim; Shi, Leming; Ning, Baitang

    2013-01-01

    Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications. PMID:23637747

  15. Regulation of Hepatic Phase II Metabolism in Pregnant Mice

    PubMed Central

    Wen, Xia; Donepudi, Ajay C.; Thomas, Paul E.; Slitt, Angela L.; King, Roberta S.

    2013-01-01

    Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo- and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARα, and PXR and their target genes were downregulated, whereas ERα mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARα, PXR, and ERα signaling pathways may be candidate signaling pathways responsible for these changes. PMID:23055538

  16. Fasting and postabsorptive hepatic glucose and insulin metabolism in hyperthyroidism.

    PubMed

    Raboudi, N; Arem, R; Jones, R H; Chap, Z; Pena, J; Chou, J; Field, J B

    1989-01-01

    The effect of thyroid hormone excess on hepatic glucose balances and fractional hepatic extraction of insulin and glucagon was examined in six conscious dogs with catheters in the portal vein, hepatic vein, and femoral artery and Doppler flow probes on the portal vein and hepatic artery. An oral glucose tolerance test was performed before and after the animals were made hyperthyroid by intramuscular thyroxine administration (100 micrograms.kg-1.day-1) for 10 days. In the basal state and after oral glucose, insulin and glucagon levels in the three vessels and the basal fractional hepatic extraction of insulin and glucagon were not significantly modified by thyroid hormone. These results suggest that in short-term thyrotoxicosis insulin secretion is not impaired, and the rise in fasting plasma glucose and increased hepatic glucose production could reflect hepatic insulin resistance, increased availability of precursors for gluconeogenesis, or increased glycogenolysis. Hyperthyroidism significantly increased basal flows in the portal vein (14.7 +/- 0.6 vs. 12.9 +/- 0.5 ml.kg-1.min-1), the hepatic artery (4.8 +/- 0.3 vs. 3.9 +/- 0.2 ml.kg-1.min-1) and vein (19.6 +/- 0.7 vs. 16.9 +/- 0.4 ml.kg-1.min-1), the fasting plasma glucose concentration (104 +/- 3 vs. 92 +/- 2 mg/dl), and basal hepatic glucose output (2.1 +/- 0.2 vs. 1.5 +/- 0.2 mg.kg-1.min-1). It did not alter the nonhepatic splanchnic uptake of glucose, the percent of orally administered glucose that appeared in the portal vein (47 +/- 2 vs. 45 +/- 11%), the percent of hepatic uptake of glucose (59 +/- 11 vs. 74 +/- 22%), or the shape of the glucose tolerance test. PMID:2643338

  17. Effects of a farnesoid X receptor antagonist on hepatic lipid metabolism in primates.

    PubMed

    Amano, Yuichiro; Shimada, Mitsuyuki; Miura, Shotaro; Adachi, Ryutaro; Tozawa, Ryuichi

    2014-01-15

    We aimed to elucidate the mechanism underlying the anti-dyslipidemic effect of compound-T3, a farnesoid X receptor antagonist, by investigating its effects on hepatic lipid metabolism in non-human primates. We administered lipid-lowering drugs for 7 days to cynomolgus monkeys receiving a high-fat diet, and subsequently measured the levels of lipid parameters in plasma, feces, and hepatic tissue fluids. Compound-T3 (0.3 and 3mg/kg p.o.) significantly decreased the plasma levels of non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B in a dose-dependent manner. It also decreased the mRNA levels of hepatic small heterodimer partner-1, induced the mRNA expression of hepatic cholesterol 7α-hydroxylase, reduced hepatic cholesterol and triglyceride levels, increased fecal bile acid excretion, and upregulated the expression of hepatic low-density lipoprotein (LDL) receptor. Furthermore, compound-T3 significantly increased plasma HDL cholesterol and apolipoprotein A-I levels. The mRNA expression levels of hepatic apolipoprotein A-I tended to increase after compound-T3 treatment. Compound-T3 also induced accumulation of hepatic bile acids and decreased the mRNA expression levels of the hepatic bile acid export pump. The effects of cholestyramine (300mg/kg p.o.) on the plasma and hepatic lipid parameters were similar to those of compound-T3, and it increased fecal bile acid levels without causing accumulation of hepatic bile acids. These findings suggest that LDL receptor-mediated hepatic LDL incorporation due to cholesterol catabolism catalyzed by cholesterol 7α-hydroxylase decreases plasma non-HDL cholesterol levels. Upregulation of hepatic apolipoprotein A-I mRNA expression may partially contribute to the increase in HDL cholesterol levels mediated by compound-T3. PMID:24361308

  18. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease

    PubMed Central

    Pacana, Tommy; Cazanave, Sophie; Verdianelli, Aurora; Patel, Vaishali; Min, Hae-Ki; Mirshahi, Faridoddin; Quinlivan, Eoin; Sanyal, Arun J.

    2015-01-01

    Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA

  19. Comprehensive insights into microcystin-LR effects on hepatic lipid metabolism using cross-omics technologies.

    PubMed

    Zhang, Zongyao; Zhang, Xu-Xiang; Wu, Bing; Yin, Jinbao; Yu, Yunjiang; Yang, Liuyan

    2016-09-01

    Microcystin-LR (MC-LR) can induce hepatic tissue damages and molecular toxicities, but its effects on lipid metabolism remain unknown. This study investigated the effects of MC-LR exposure on mice lipid metabolism and uncovered the underlying mechanism through metabonomic, transcriptomic and metagenomic analyses after administration of mice with MC-LR by gavage for 28 d. Increased liver weight and abdominal fat weight, and evident hepatic lipid vacuoles accumulation were observed in the mice fed with 0.2mg/kg/d MC-LR. Serum nuclear magnetic resonance analysis showed that MC-LR treatment altered the levels of serum metabolites including triglyceride, unsaturated fatty acid (UFA) and very low density lipoprotein. Digital Gene Expression technology was used to reveal differential expression of hepatic transcriptomes, demonstrating that MC-LR treatment disturbed hepatic UFA biosynthesis and activated peroxisome proliferator-activated receptor (PPAR) signaling pathways via Pparγ, Fabp1 and Fabp2 over-expression. Metagenomic analyses of gut microbiota revealed that MC-LR exposure also increased abundant ratio of Firmicutes vs. Bacteroidetes in gut and altered biosynthetic pathways of various microbial metabolic and pro-inflammatory molecules. In conclusion, oral MC-LR exposure can induce hepatic lipid metabolism disorder mediated by UFA biosynthesis and PPAR activation, and gut microbial community shift may play an important role in the metabolic disturbance. PMID:27208774

  20. Gut microbiome phenotypes driven by host genetics affect arsenic metabolism.

    PubMed

    Lu, Kun; Mahbub, Ridwan; Cable, Peter Hans; Ru, Hongyu; Parry, Nicola M A; Bodnar, Wanda M; Wishnok, John S; Styblo, Miroslav; Swenberg, James A; Fox, James G; Tannenbaum, Steven R

    2014-02-17

    Large individual differences in susceptibility to arsenic-induced diseases are well-documented and frequently associated with different patterns of arsenic metabolism. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that gut microbiome phenotypes affect the spectrum of metabolized arsenic species. However, it remains unclear how host genetics and the gut microbiome interact to affect the biotransformation of arsenic. Using an integrated approach combining 16S rRNA gene sequencing and HPLC-ICP-MS arsenic speciation, we demonstrate that IL-10 gene knockout leads to a significant taxonomic change of the gut microbiome, which in turn substantially affects arsenic metabolism. PMID:24490651

  1. Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling.

    PubMed

    Li, Zhi-Qin; Gu, Xin-Yu; Hu, Jin-Xing; Ping, Yu; Li, Hua; Yan, Jing-Ya; Li, Juan; Sun, Ran; Yu, Zu-Jing; Zhang, Yi

    2016-07-01

    It has been suggested that Hepatitis C virus (HCV) core protein is associated with metabolic disorders of liver cell. However, the precise mechanism is still unclear. The aim of the present study was to explore the impact of HCV core protein on hepatocyte metabolism by HepG2 and the possible involvement of long non-coding (lnc) RNAs in this process. The effect of HCV core protein on lncRNAs expression was examined with quantitative RT-PCR (qRT-PCR). Manipulation of HVC core protein and lncRNA HOTAIR was to evaluate the role of interaction between them on cell metabolism-related gene expression and cellular metabolism. The potential downstream Sirt1 signal was examined by western blotting and qRT-PCR. Our data suggested that suppression of HOTAIR abrogates HCV core protein-induced reduction in Sirt1 and differential expression of glucose- and lipid-metabolism-related genes. Also it benefits for metabolic homoeostasis of hepatocyte indicated by restoration of cellular reactive oxygen species (ROS) level and NAD/NADH ratio. By manipulation of HOTAIR, we concluded that HOTAIR negatively regulates Sirt1 expression through affecting its promotor methylation. Moreover, overexpression of Sirt1 reverses pcDNA-HOTAIR-induced glucose- and lipid-metabolism-related gene expression. Our study suggests that HCV core protein causes dysfunction of glucose and lipid metabolism in liver cells through HOTAIR-Sirt1 signalling pathway. PMID:27129296

  2. The role of feeding regimens in regulating metabolism of sexually mature broiler breeders: hepatic lipid metabolism, plasma hormones and metabolites

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A trial was conducted to determine the effects of different rearing feed regimens on plasma hormone and metabolite levels and hepatic lipid metabolism on sexually mature broiler breeders. A flock of Cobb 500 birds was divided into two groups at 35 days of age and fed either everyday (ED) or skip-a-d...

  3. Gender and Species-Mediated Differences in the In Vitro Metabolism of Triadimefon by Rodent Hepatic Microsomes

    EPA Science Inventory

    Understanding how metabolism kinetics differ between genders and species is important in developing informative pharmacokinetic models and accurately assessing risk. Metabolism of the conazole fungicide Triadimefon (TDN) was studied in hepatic microsomes of SD rats and CD-1 mice...

  4. Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

    PubMed Central

    Correia, Jorge C.; Massart, Julie; de Boer, Jan Freark; Porsmyr-Palmertz, Margareta; Martínez-Redondo, Vicente; Agudelo, Leandro Z.; Sinha, Indranil; Meierhofer, David; Ribeiro, Vera; Björnholm, Marie; Sauer, Sascha; Dahlman-Wright, Karin; Zierath, Juleen R.; Groen, Albert K.; Ruas, Jorge L.

    2015-01-01

    Objective Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. Methods We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr−/− mouse liver was performed to evaluate their role in vivo. The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXRα2 expression in Fxr−/− mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Conclusions Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists. PMID:26909306

  5. Organization of hepatic nitrogen metabolism and its relation to acid-base homeostasis.

    PubMed

    Häussinger, D

    1990-11-16

    Hepatic and renal nitrogen metabolism are linked by an interorgan glutamine flux, coupling both renal ammoniagenesis and hepatic ureogenesis to systemic acid base regulation. This is because protein breakdown produces equimolar amounts of NH4+ and HCO3-. A hepatic role in this interorgan team effort is based upon the tissue-specific presence of urea synthesis, which represents a major irreversible pathway for removal of metabolically generated bicarbonate. A sensitive and complex control of bicarbonate disposal via ureogenesis by the extracellular acid-base status creates a feed-back control loop between the acid-base status and the rate of bicarbonate elimination. This bicarbonate-homeostatic mechanism operates without threat of hyperammonemia, because a sophisticated structural and functional organisation of ammonia-metabolizing pathways in the liver acinus uncouples urea synthesis from the vital need to eliminate potentially toxic ammonia. PMID:2126308

  6. Sexual Dimorphic Metabolic Alterations in Hepatitis C Virus-infected Patients: A Community-Based Study in a Hepatitis B/Hepatitis C Virus Hyperendemic Area.

    PubMed

    Hu, Jing-Hong; Chen, Mei-Yen; Yeh, Chau-Ting; Lin, Huang-Shen; Lin, Ming-Shyan; Huang, Tung-Jung; Chang, Ming-Ling

    2016-05-01

    The impact of sex on metabolic alterations in individuals with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection remains elusive.A community-based study was performed to assess sex, age, body mass index, the lipid profile, blood pressure, glucose, alanine aminotransferase, HBV surface antigen (HBsAg), and HCV antibody levels, smoking and alcohol drinking habits, and cardiometabolic diseases, including diabetes, hypertension, cardiovascular events, and renal diseases. The HCV-RNA level and genotype were further assessed in HCV antibody-positive subjects, and the hepatitis B e antigen and HBV-DNA levels were further examined in HBsAg-positive subjects.Among the 10,959 adults enrolled, 1949 (17.8%) and 1536 (14.0%) were HBV and HCV-infected, respectively. Univariate and multivariate analyses showed that the lipid profile and hypertension were independently associated with HCV infection (95% confidence intervals of odds ratios [OR 95% CI]: total cholesterol [TC] = 0.508-0.677; triglycerides = 0.496-0.728; hypertension = 0.669-0.937), but not with HBV infection. Consistently, HCV, but not HBV infection, was negatively associated with the TC and triglyceride levels (OR 95% CI for TC: 0.450-0.601; triglycerides: 0.443-0.671). Generalized linear models revealed that HCV infection, sex, and age interactively affected the lipid profile (OR 95% CI TC = 1.189-1.385; triglycerides = 1.172-5.289). Age-stratification analysis showed that the lipid levels were lower in both the HCV-positive females aged ≥49 years (TC, P < 0.001; triglycerides, P = 0.001) and males of all ages (TC, P < 0.001; triglycerides, P < 0.001) compared with their sex and age-matched HCV-negative counterparts. HCV infection was associated with a higher body mass index (≥49 years, β = 0.405, P = 0.002) and increased rates of cardiovascular events (<49 years, OR 95% CI 1.23-9.566), diabetes (≥49 years, OR 95% CI 1.114-1.932), and renal diseases (

  7. Three conazoles increase hepatic microsomal retinoic acid metabolism and decrease mouse hepatic retinoic acid levels in vivo

    SciTech Connect

    Chen, P.-J.; Padgett, William T.; Moore, Tanya; Winnik, Witold; Lambert, Guy R.; Thai, Sheau-Fung; Hester, Susan D.; Nesnow, Stephen

    2009-01-15

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with cancer-preventative properties (Ward et al., Toxicol. Pathol. 2006; 34:863-78). The goals of this study were to examine effects of propiconazole, triadimefon, and myclobutanil, three triazole-containing conazoles, on the microsomal metabolism of atRA, the associated hepatic cytochrome P450 (P450) enzyme(s) involved in atRA metabolism, and their effects on hepatic atRA levels in vivo. The in vitro metabolism of atRA was quantitatively measured in liver microsomes from male CD-1 mice following four daily intraperitoneal injections of propiconazole (210 mg/kg/d), triadimefon (257 mg/kg/d) or myclobutanil (270 mg/kg/d). The formation of both 4-hydroxy-atRA and 4-oxo-atRA were significantly increased by all three conazoles. Propiconazole-induced microsomes possessed slightly greater metabolizing activities compared to myclobutanil-induced microsomes. Both propiconazole and triadimefon treatment induced greater formation of 4-hydroxy-atRA compared to myclobutanil treatment. Chemical and immuno-inhibition metabolism studies suggested that Cyp26a1, Cyp2b, and Cyp3a, but not Cyp1a1 proteins were involved in atRA metabolism. Cyp2b10/20 and Cyp3a11 genes were significantly over-expressed in the livers of both triadimefon- and propiconazole-treated mice while Cyp26a1, Cyp2c65 and Cyp1a2 genes were over-expressed in the livers of either triadimefon- or propiconazole-treated mice, and Cyp2b10/20 and Cyp3a13 genes were over-expressed in the livers of myclobutanil-treated mice. Western blot analyses indicated conazole induced-increases in Cyp2b and Cyp3a proteins. All three conazoles decreased hepatic atRA tissue levels ranging from 45-67%. The possible implications of these changes in hepatic atRA levels

  8. Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

    PubMed Central

    Schröder, Torsten; Kucharczyk, David; Bär, Florian; Pagel, René; Derer, Stefanie; Jendrek, Sebastian Torben; Sünderhauf, Annika; Brethack, Ann-Kathrin; Hirose, Misa; Möller, Steffen; Künstner, Axel; Bischof, Julia; Weyers, Imke; Heeren, Jörg; Koczan, Dirk; Schmid, Sebastian Michael; Divanovic, Senad; Giles, Daniel Aaron; Adamski, Jerzy; Fellermann, Klaus; Lehnert, Hendrik; Köhl, Jörg; Ibrahim, Saleh; Sina, Christian

    2016-01-01

    Objective Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH). However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T) of the mitochondrial ATP synthase protein 8 (mt-ATP8). Results At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS). Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a

  9. Hepatitis

    MedlinePlus

    ... Got Homework? Here's Help White House Lunch Recipes Hepatitis KidsHealth > For Kids > Hepatitis Print A A A ... an important digestive liquid called bile . What Is Hepatitis? Hepatitis is an inflammation (say: in-fluh-MAY- ...

  10. Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans.

    PubMed

    Clore, John N; Stillman, Julie S; Li, Jing; O'Keefe, Stephen J D; Levy, James R

    2004-08-01

    Prolonged infusions of lipid and heparin that achieve high physiological free fatty acid (FFA) concentrations inhibit hepatic (and peripheral) insulin sensitivity in humans. These infusions are composed largely of polyunsaturated fatty acids (PUFA; linoleic and linolenic). It is not known whether fatty acid composition per se affects hepatic glucose metabolism in humans. To address this issue, we examined the impact of enteral infusions of either palm oil (48% palmitic, 35% oleic, and 8% linoleic acids) or safflower oil (6% palmitic, 12% oleic, 74% linoleic acids) in 14 obese nondiabetic subjects. (2)H(2)O was administered to determine the contribution of gluconeogenesis to endogenous glucose production (EGP), and a primed continuous infusion of [6,6-(2)H]glucose was administered to assess glucose appearance. As a result of the lipid infusions, plasma FFA concentrations increased significantly in both the palm oil (507.5 +/- 47.4 to 939.3 +/- 61.3 micromol/l, P < 0.01) and safflower oil (588.2.0 +/- 43.0 to 857.8 +/- 68.7 micromol/l, P < 0.01) groups after 4 h. EGP was similar at baseline (12.4 +/- 1.8 vs. 11.2 +/- 1.0 micromol x kg FFM(-1) x min(-1)). During a somatostatin-insulin clamp, the glucose infusion rate was significantly lower (AUC glucose infusion rate 195.8 +/- 50.7 vs. 377.8 +/- 38.0 micromol/kg FFM, P < 0.01), and rates of EGP were significantly higher (10.7 +/- 1.4 vs. 6.5 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < 0.01) after palm oil compared with safflower oil, respectively. Baseline rates of gluconeogenesis and glycogenolysis were also similar. However, after lipid infusion, rates of glycogenolysis were suppressed by safflower oil but not by palm oil. Thus these studies demonstrate, for the first time in humans, a differential effect of saturated fatty acids and PUFA on hepatic glucose metabolism. PMID:15082421

  11. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

    SciTech Connect

    Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska; Levels, Johannes H.M.; Quax, Paul H.A.; Meijers, Joost C.M.; Pannekoek, Hans; Groen, Albert K.; Vries, Carlie J.M. de

    2008-02-22

    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, 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.

  12. Environmental factors affecting pregnancy: endocrine disrupters, nutrients and metabolic pathways.

    PubMed

    Bazer, Fuller W; Wu, Guoyao; Johnson, Gregory A; Wang, Xiaoqiu

    2014-12-01

    Uterine adenogenesis, a unique post-natal event in mammals, is vulnerable to endocrine disruption by estrogens and progestins resulting in infertility or reduced prolificacy. The absence of uterine glands results in insufficient transport of nutrients into the uterine lumen to support conceptus development. Arginine, a component of histotroph, is substrate for production of nitric oxide, polyamines and agmatine and, with secreted phosphoprotein 1, it affects cytoskeletal organization of trophectoderm. Arginine is critical for development of the conceptus, pregnancy recognition signaling, implantation and placentation. Conceptuses of ungulates and cetaceans convert glucose to fructose which is metabolized via multiple pathways to support growth and development. However, high fructose corn syrup in soft drinks and foods may increase risks for metabolic disorders and increase insulin resistance in adults. Understanding endocrine disrupters and dietary substances, and novel pathways for nutrient metabolism during pregnancy can improve survival and growth, and prevent chronic metabolic diseases in offspring. PMID:25224489

  13. An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle

    PubMed Central

    Della Torre, Sara; Mitro, Nico; Fontana, Roberta; Gomaraschi, Monica; Favari, Elda; Recordati, Camilla; Lolli, Federica; Quagliarini, Fabiana; Meda, Clara; Ohlsson, Claes; Crestani, Maurizio; Uhlenhaut, Nina Henriette; Calabresi, Laura; Maggi, Adriana

    2016-01-01

    Summary Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism. PMID:27050513

  14. Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

    SciTech Connect

    Kim, Young C. Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

    2007-08-15

    Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.

  15. Effects of formula composition on hepatic and intestinal drug metabolism during enteral nutrition.

    PubMed

    Knodell, R G

    1990-01-01

    Significant compositional differences in protein and lipid content are present in currently available enteral nutrition preparations. Since variations in dietary protein and/or lipid have previously been shown to produce alterations in liver and gut drug metabolism, effects of five commonly used enteral nutrition regimens on several drug metabolic parameters were assessed in rats. Study formulations included: 1) Vivonex: low protein -no lipid; 2) High Protein Vivonex: normal protein -no lipid; 3) Vital: normal protein -normal lipid; 4) Sustacal: high protein -high lipid; 5) Isocal: normal protein -high lipid. Hepatic and intestinal microsomes were prepared after a continuous 7-day intragastric infusion of one of the formulations, and measurements of cytochrome P-450 content and assays of drug metabolizing activity were performed. No differences in intestinal microsomal cytochrome P-450 content or meperidine demethylase activity were seen among the various alimentation groups. However, significantly decreased amounts of cytochrome P-450 and reduced meperidine demethylase and pentobarbital hydroxylase activity were present in hepatic microsomes of animals receiving the lipid-poor Vivonex and High Nitrogen Vivonex preparations compared to the other alimentation groups. These data suggest that the composition of enteral nutrition formulations may significantly impact on hepatic function and specifically that the presence of lipid in such preparations may be important for maintaining normal levels of hepatic drug metabolism. PMID:2109111

  16. Influence of long (16L:8D) and short (8L:16D) photoperiods on blood metabolites and hepatic metabolism in Olive flounder, Paralichthys olivaceus.

    PubMed

    Zou, Huafeng; Bai, Xianshou; Feng, Yuhong; Zhang, Ying; Wang, Youji; Lu, Weiqun

    2016-01-01

    In the present study the influence of long photoperiod (LP, 16L:8D) and short photoperiod (SP, 8L:16D) on hepatic energy metabolism in the olive flounder (Paralichthys olivaceus) was investigated. Flounders were maintained under LP or SP conditions for 2 weeks then plasmatic and hepatic parameters were assessed. At the plasmatic level, the concentration of cortisol was enhanced in flounder maintained under LP compared to SP. Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) enzyme activities in plasma also increased in LP flounder. There was no significant difference in plasma glucose levels between the two experimental groups. Plasma osmotic pressure, Na and Cl levels were significantly higher in LP compared to the SP group. In liver, a significant decrease of triglycerides together with an increase in glycogen was observed in the LP group. Hepatic hsl and pepck and muscle hsl mRNA expression in LP was significantly higher in the SP group. Overall the results indicate that the LP treatment caused a mild stress response and increased hepatic energy metabolism in the flounder, which in turn could affect osmoregulation. In conclusion, it would appear that LP treatment can adversely influence hepatic energy metabolism in adult olive flounder under fasting condition. PMID:27386368

  17. Lysine-Specific Demethylase 2 Suppresses Lipid Influx and Metabolism in Hepatic Cells

    PubMed Central

    Nagaoka, Katsuya; Sakamoto, Akihisa; Anan, Kotaro; Takase, Ryuta; Umehara, Takashi; Yokoyama, Shigeyuki; Sasaki, Yutaka

    2015-01-01

    Cells link environmental fluctuations, such as nutrition, to metabolic remodeling. Epigenetic factors are thought to be involved in such cellular processes, but the molecular basis remains unclear. Here we report that the lysine-specific demethylase 2 (LSD2) suppresses the flux and metabolism of lipids to maintain the energy balance in hepatic cells. Using transcriptome and chromatin immunoprecipitation-sequencing analyses, we revealed that LSD2 represses the genes involved in lipid influx and metabolism through demethylation of histone H3K4. Selective recruitment of LSD2 at lipid metabolism gene loci was mediated in part by a stress-responsive transcription factor, c-Jun. Intriguingly, LSD2 depletion increased the intracellular levels of many lipid metabolites, which was accompanied by an increased susceptibility to toxic cell damage in response to fatty acid exposure. Our data demonstrate that LSD2 maintains metabolic plasticity under fluctuating environment in hepatocytes by mediating the cross talk between the epigenome and metabolism. PMID:25624347

  18. MicroRNAs and Noncoding RNAs in Hepatic Lipid and Lipoprotein Metabolism: Potential Therapeutic Targets of Metabolic Disorders

    PubMed Central

    Sud, Neetu; Taher, Jennifer; Su, Qiaozhu

    2015-01-01

    Noncoding RNAs and microRNAs (miRNAs) represent an important class of regulatory molecules that modulate gene expression. The role of miRNAs in diverse cellular processes such as cancer, apoptosis, cell differentiation, cardiac remodeling, and inflammation has been intensively explored. Recent studies further demonstrated the important roles of miRNAs and noncoding RNAs in modulating a broad spectrum of genes involved in lipid synthesis and metabolic pathways. This overview focuses on the role of miRNAs in hepatic lipid and lipoprotein metabolism and their potential as therapeutic targets for metabolic syndrome. This included recent advances made in the understanding of their target pathways and the clinical development of miRNAs in lipid metabolic disorders. PMID:26286650

  19. Hepatic ERK activity plays a role in energy metabolism.

    PubMed

    Jiao, Ping; Feng, Bin; Li, Yujie; He, Qin; Xu, Haiyan

    2013-08-15

    Mitogen activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK) and P38, have been reported to play important roles in energy homeostasis. In this study, we show that the activity of extracellular signal-regulated kinase (ERK) is increased in the livers of diet induced and genetically obese mice. Activation of ERK in the livers of lean mice by over-expressing the constitutively active MAPK kinase 1 (MEK CA) results in decreased energy expenditure, lowered expression of genes involved in fatty acid oxidation, increases fasting hyperglycemia and causes systemic insulin resistance. Interestingly, hepatic glycogen content is markedly increased and expression of G6Pase gene is decreased in mice over-expressing MEK CA compared to control mice expressing green fluorescent protein (GFP), therefore hepatic glucose output is not likely the major contributor of hyperglycemia. One potential mechanism of decreased expression of G6Pase gene by MEK CA is likely due to ERK mediated phosphorylation and cytosolic retention of FOXO1. Adipocytes isolated from MEK CA mice display increased lipolysis. Circulating levels of free fatty acids (FFAs) in these mice are also increased, which possibly contribute to systemic insulin resistance and subsequent hyperglycemia. Consistent with these results, knocking down ERK expression in the liver of diet induced obese (DIO) mice improves systemic insulin and glucose tolerance. These results indicate that increased hepatic ERK activity in DIO mice may contribute to increased liver glycogen content and decreased energy expenditure in obesity. PMID:23732116

  20. Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma

    PubMed Central

    Wu, Jian-Min; Skill, Nicholas J; Maluccio, Mary A

    2010-01-01

    Objectives Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC). Methods Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions. Results Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P ≤ 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC. Conclusions Our data support the notion that HCV-related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms. PMID:20961371

  1. Metabolism of Oxycodone in Human Hepatocytes from Different Age Groups and Prediction of Hepatic Plasma Clearance

    PubMed Central

    Korjamo, Timo; Tolonen, Ari; Ranta, Veli-Pekka; Turpeinen, Miia; Kokki, Hannu

    2012-01-01

    Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1, and 10 μM) was incubated with hepatocytes for 4 h, and 1 μM oxycodone also with CYP3A inhibitor ketoconazole (1 μM). Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography–mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. The data suggests that there are no children-specific metabolites of oxycodone. Moreover, CYP3A activity seems to be the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches. PMID:22291644

  2. Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity.

    PubMed

    Kucejova, Blanka; Duarte, Joao; Satapati, Santhosh; Fu, Xiaorong; Ilkayeva, Olga; Newgard, Christopher B; Brugarolas, James; Burgess, Shawn C

    2016-07-12

    Dysregulated mitochondrial metabolism during hepatic insulin resistance may contribute to pathophysiologies ranging from elevated glucose production to hepatocellular oxidative stress and inflammation. Given that obesity impairs insulin action but paradoxically activates mTORC1, we tested whether insulin action and mammalian target of rapamycin complex 1 (mTORC1) contribute to altered in vivo hepatic mitochondrial metabolism. Loss of hepatic insulin action for 2 weeks caused increased gluconeogenesis, mitochondrial anaplerosis, tricarboxylic acid (TCA) cycle oxidation, and ketogenesis. However, activation of mTORC1, induced by the loss of hepatic Tsc1, suppressed these fluxes. Only glycogen synthesis was impaired by both loss of insulin receptor and mTORC1 activation. Mice with a double knockout of the insulin receptor and Tsc1 had larger livers, hyperglycemia, severely impaired glycogen storage, and suppressed ketogenesis, as compared to those with loss of the liver insulin receptor alone. Thus, activation of hepatic mTORC1 opposes the catabolic effects of impaired insulin action under some nutritional states. PMID:27346353

  3. In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. II. A reevaluation of hepatic metabolic pathways.

    PubMed

    Selinsky, B S; Perlman, M E; London, R E

    1988-05-01

    Methoxyflurane (2,2-dichloro-1,1-difluoro-ethyl methyl ether) is believed to be metabolized via two convergent metabolic pathways. The relative flux through these two metabolic pathways has been investigated using a combination of in vivo surface coil NMR techniques and in vitro analyses of urinary metabolites. Analysis of the measured concentrations of inorganic fluoride, oxalate, and methoxydifluoroacetate in the urine of methoxyflurane-treated rats for 4 days after anesthesia indicates that the anesthetic is metabolized primarily via dechlorination to yield methoxydifluoroacetate. The methoxydifluoroacetate is largely excreted without further metabolism, although a small percentage of this metabolite is broken down to yield fluoride and oxalate, as determined by urine analysis of rats dosed with synthetic methoxydifluoroacetate. At early times after methoxyflurane exposure, the relative concentrations of methoxyflurane metabolites indicate that a significant fraction of the metabolic flux occurs via a different pathway, presumably demethylation, to yield dichloroacetate as an intermediate. Direct analysis of dichloroacetate in the urine using water-suppressed proton NMR indicates that the level of this metabolite is below the detection threshold of the method. Measurements made on the urine of rats dosed directly with dichloroacetate indicate that this compound is quickly metabolized, and dichloroacetate levels in urine are again found to be below the detection threshold. These results demonstrate the quantitative importance of the dechlorination pathway in the metabolism of methoxyflurane in rats. PMID:3367904

  4. A link between hepatic glucose production and peripheral energy metabolism via hepatokines

    PubMed Central

    Abdul-Wahed, Aya; Gautier-Stein, Amandine; Casteras, Sylvie; Soty, Maud; Roussel, Damien; Romestaing, Caroline; Guillou, Hervé; Tourette, Jean-André; Pleche, Nicolas; Zitoun, Carine; Gri, Blandine; Sardella, Anne; Rajas, Fabienne; Mithieux, Gilles

    2014-01-01

    Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes. PMID:25061558

  5. Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism*

    PubMed Central

    Perry, Rachel J.; Borders, Candace B.; Cline, Gary W.; Zhang, Xian-Man; Alves, Tiago C.; Petersen, Kitt Falk; Rothman, Douglas L.; Kibbey, Richard G.; Shulman, Gerald I.

    2016-01-01

    In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography/tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-13C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously at doses previously used as a tracer, it increased VPyr-Cyc/VMito by 20–30-fold, increased hepatic TCA metabolite concentrations 2–3-fold, and increased endogenous glucose production rates by 20–100%. The physiologic stimuli, glucagon and epinephrine, both increased hepatic glucose production, but only glucagon suppressed VPyr-Cyc/VMito. These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable tracer to assess hepatic glycolytic, gluconeogenic, and mitochondrial metabolism in vivo. PMID:27002151

  6. Tribbles-1: a novel regulator of hepatic lipid metabolism in humans

    PubMed Central

    Bauer, Robert C.; Yenilmez, Batuhan O.; Rader, Daniel J.

    2015-01-01

    The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target. PMID:26517927

  7. Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism.

    PubMed

    Perry, Rachel J; Borders, Candace B; Cline, Gary W; Zhang, Xian-Man; Alves, Tiago C; Petersen, Kitt Falk; Rothman, Douglas L; Kibbey, Richard G; Shulman, Gerald I

    2016-06-01

    In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography/tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-(13)C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously at doses previously used as a tracer, it increased VPyr-Cyc/VMito by 20-30-fold, increased hepatic TCA metabolite concentrations 2-3-fold, and increased endogenous glucose production rates by 20-100%. The physiologic stimuli, glucagon and epinephrine, both increased hepatic glucose production, but only glucagon suppressed VPyr-Cyc/VMito These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable tracer to assess hepatic glycolytic, gluconeogenic, and mitochondrial metabolism in vivo. PMID:27002151

  8. Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes.

    PubMed

    Gancheva, Sofiya; Bierwagen, Alessandra; Kaul, Kirti; Herder, Christian; Nowotny, Peter; Kahl, Sabine; Giani, Guido; Klueppelholz, Birgit; Knebel, Birgit; Begovatz, Paul; Strassburger, Klaus; Al-Hasani, Hadi; Lundbom, Jesper; Szendroedi, Julia; Roden, Michael

    2016-07-01

    Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases. PMID:27207512

  9. Environmentally Relevant Dose of Bisphenol A Does Not Affect Lipid Metabolism and Has No Synergetic or Antagonistic Effects on Genistein’s Beneficial Roles on Lipid Metabolism

    PubMed Central

    Fan, Ying; Li, Hongyu; Zhao, Nana; Yang, Huiqin; Ye, Xiaolei; He, Dongliang; Yang, Hui; Jin, Xin; Tian, Chong; Ying, Chenjiang

    2016-01-01

    Both bisphenol A (BPA, an endocrine disrupting chemicals) and genistein (a phytoestrogen mainly derived from leguminosae) are able to bind to estrogen receptors, but they are considered to have different effects on metabolic syndrome, surprisingly. We here investigate the effects of an environmentally relevant dose of BPA alone and the combined effects with genistein on lipid metabolism in rats. Eight groups of adult male Wistar rats, fed with either standard chow diet or high-fat diet, were treated with BPA (50μg/kg/day), genistein (10mg/kg/day), and BPA plus genistein for 35 weeks, respectively. Metabolic parameters in serum and liver were determined; the hematoxylin/eosin and oil Red O staining were used to observe liver histologically; gene expressions related to hepatic lipid metabolism were analyzed by Real-time PCR; protein expressions of PPARγ, PPARα and LC3 in liver were analyzed by western blotting. No difference of body weight gain, total energy intake, liver weight/body weight or body fat percentage in both STD- and HFD-fed sub-groups was observed after treatment with BPA, genistein, or BPA plus genistein (P>0.05). Genistein alleviated lipid metabolism disorder and decreased the mRNA and protein expression of PPARγ (P<0.05), and increased the protein expression of LC3II (P<0.05) in liver of HFD-fed rats. However, BPA treatment had no effect on lipid metabolism in rats alone (P>0.05) or combined with genistein. Our findings suggest that long-term environmentally relevant dose of BPA did not affect lipid metabolism, and had no synergetic or antagonistic roles on genistein’s beneficial function on hepatic lipid metabolism. PMID:27171397

  10. Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARα-dependent and -independent pathways

    PubMed Central

    Zhang, Haiyan; Shen, Wen-Jun; Cortez, Yuan; Kraemer, Fredric B.

    2013-01-01

    Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. Feeding ob/ob mice a chow diet supplemented with either low (0.83 g/kg diet) or high-dose (2.5 g/kg diet) NDGA for 16 wk significantly improved plasma triglyceride (TG), inflammatory chemokine levels, hyperinsulinemia, insulin sensitivity, and glucose intolerance. NDGA treatment caused a marked reduction in liver weight and TG content, while enhancing rates of fatty acid oxidation. Microarray analysis of hepatic gene expression demonstrated that NDGA treatment altered genes for lipid metabolism, with genes involved in fatty acid catabolism most significantly increased. NDGA upregulated the mRNA and nuclear protein levels of peroxisome proliferator-activated receptor α (PPARα), and the activated (phosphorylated) form of AMP-activated kinase. NDGA increased PPARα promoter activity in AML12 hepatocytes and also prevented the fatty acid suppression of PPARα expression. In contrast, PPARα siRNA abrogated the stimulatory effect of NDGA on fatty acid catabolism. Likewise, no stimulatory effect of NDGA on hepatic fatty acid oxidation was observed in the livers of PPARα-deficient mice, but the ability of NDGA to reverse fatty liver conditions was unaffected. In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα-dependent pathways. However, PPARα-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis. PMID:23104557

  11. Mediated effect of endotoxin and lead upon hepatic metabolism

    SciTech Connect

    Kuttner, R.E.; Ebata, T.; Schumer, W.

    1984-10-01

    A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after a systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.

  12. Hepatic xenobiotic metabolism of cylindrospermopsin in vivo in the mouse.

    PubMed

    Norris, R L G; Seawright, A A; Shaw, G R; Senogles, P; Eaglesham, G K; Smith, M J; Chiswell, R K; Moore, M R

    2002-04-01

    Cylindrospermopsin (CYN) is a hepatotoxin isolated from the blue-green alga Cylindrospermopsis raciborskii. The role of both glutathione (GSH) and the cytochrome P450 enzyme system (P450) in the mechanism of toxicity of CYN has been previously investigated in in vitro systems. We have investigated the role of GSH and P450 in vivo in mice. Mice pre-treated with buthionine sulphoximine and diethyl maleate to deplete hepatic GSH prior to dosing with 0.2mg/kg CYN showed a seven-day survival rate of 5/13 while the control group rate was 9/14. Dosing mice with 0.2mg/kg CYN produced a small decrease in hepatic GSH with a characteristic rebound effect at 24h. The magnitude of this effect is however small and combined with the non-significant difference in survival rates after GSH depletion suggest depletion of GSH by CYN could not be a primary mechanism for CYN toxicity. Conversely, pre-treatment with piperonyl butoxide, a P450 inhibitor, protected mice against CYN toxicity giving a survival rate of 10/10 compared with 4/10 in the control group (p < 0.05 Chi squared) and was protective at doses up to 0.8 mg/kg, suggesting activation of CYN by P450 is of primary importance in the mechanism of action. PMID:11738241

  13. Sexual Dimorphic Metabolic Alterations in Hepatitis C Virus-infected Patients

    PubMed Central

    Hu, Jing-Hong; Chen, Mei-Yen; Yeh, Chau-Ting; Lin, Huang-Shen; Lin, Ming-Shyan; Huang, Tung-Jung; Chang, Ming-Ling

    2016-01-01

    Abstract The impact of sex on metabolic alterations in individuals with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection remains elusive. A community-based study was performed to assess sex, age, body mass index, the lipid profile, blood pressure, glucose, alanine aminotransferase, HBV surface antigen (HBsAg), and HCV antibody levels, smoking and alcohol drinking habits, and cardiometabolic diseases, including diabetes, hypertension, cardiovascular events, and renal diseases. The HCV-RNA level and genotype were further assessed in HCV antibody-positive subjects, and the hepatitis B e antigen and HBV-DNA levels were further examined in HBsAg-positive subjects. Among the 10,959 adults enrolled, 1949 (17.8%) and 1536 (14.0%) were HBV and HCV-infected, respectively. Univariate and multivariate analyses showed that the lipid profile and hypertension were independently associated with HCV infection (95% confidence intervals of odds ratios [OR 95% CI]: total cholesterol [TC] = 0.508–0.677; triglycerides = 0.496–0.728; hypertension = 0.669–0.937), but not with HBV infection. Consistently, HCV, but not HBV infection, was negatively associated with the TC and triglyceride levels (OR 95% CI for TC: 0.450–0.601; triglycerides: 0.443–0.671). Generalized linear models revealed that HCV infection, sex, and age interactively affected the lipid profile (OR 95% CI TC = 1.189–1.385; triglycerides = 1.172–5.289). Age-stratification analysis showed that the lipid levels were lower in both the HCV-positive females aged ≥49 years (TC, P < 0.001; triglycerides, P = 0.001) and males of all ages (TC, P < 0.001; triglycerides, P < 0.001) compared with their sex and age-matched HCV-negative counterparts. HCV infection was associated with a higher body mass index (≥49 years, β = 0.405, P = 0.002) and increased rates of cardiovascular events (<49 years, OR 95% CI 1.23–9.566), diabetes (≥49 years, OR 95% CI 1.114–1

  14. In Vitro Rat Hepatic and Intestinal Metabolism of the Organophosphate Pesticides Chlorpyrifos and Diazinon

    SciTech Connect

    Poet, Torka S. ); Wu, Hong ); Kousba, Ahmed A. ); Timchalk, Charles

    2003-04-01

    Chlorpyrifos (CPF) and diazinon (DZN) are thionophosphorus organophosphate, insecticides; their toxicity is mediated through CYP450 metabolism to CPF-oxon and DZN-oxon, respectively. Conversely, CYP450s also detoxify these OPs to trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), respectively. In addition, A-esterase metabolism of CPF- and DZN-oxon also form TCP and IMHP. This study evaluated the role intestinal and hepatic metabolism may play in the first-pass elimination of CPF and DZN. Similar CYP450- and A-esterase-mediated metabolic profiles were demonstrated in microsomes from liver or isolated intestinal enterocytes. In enterocyte microsomes, the CYP450 metabolic efficiency (Vmax/Km) for metabolism to the oxon metabolites was~5-fold greater for CPF than DZN. Compared on a per nmol P450 basis, the Vmax for CPF in enterocytes was~2-3 times higher than in liver microsomes for the production of CPF-oxon and TCP. The affinity (Km) for the metabolism of CPF to CPF-oxon was comparable in liver and enterocyte microsomes, however the enterocyte Km for TCP production was higher (lower affinity). The smaller volume of intestine, lower amount of CYP450, and higher Km for TCP in the enterocyte microsomes, resulted in a lower catalytic efficiency (2 and 62 times) than in liver for oxon and TCP. A-esterase-mediated metabolism of CPF- and DZN-oxon was also demonstrated in liver and enterocyte microsomes. Although A-esterase affinity for the substrates were comparable in hepatic and enterocyte microsomes, the Vmax were 48 - to 275-fold, in the liver. These results suggest that intestinal metabolism may impact first-pass metabolism of CPF and DZN, especially following low-dose oral exposures.

  15. Sexual Dimorphism of Adipose and Hepatic Aquaglyceroporins in Health and Metabolic Disorders

    PubMed Central

    Rodríguez, Amaia; Marinelli, Raul A.; Tesse, Angela; Frühbeck, Gema; Calamita, Giuseppe

    2015-01-01

    Gender differences in the relative risk of developing metabolic complications, such as insulin resistance or non-alcoholic fatty liver disease (NAFLD), have been reported. The deregulation of glycerol metabolism partly contributes to the onset of these metabolic diseases, since glycerol constitutes a key substrate for the synthesis of triacylglycerols (TAGs) as well as for hepatic gluconeogenesis. The present mini-review covers the sex-­related differences in glycerol metabolism and aquaglyceroporins (AQPs) and its impact in the control of adipose and hepatic fat accumulation as well as in whole-body glucose homeostasis. Plasma glycerol concentrations are increased in women compared to men probably due to the higher lipolytic rate and larger AQP7 amounts in visceral fat as well as the well-known sexual dimorphism in fat mass with women showing higher adiposity. AQP9 represents the primary route for glycerol uptake in hepatocytes, where glycerol is converted by the glycerol-kinase enzyme into glycerol-3-phosphate, a key substrate for de novo synthesis of glucose and TAG. In spite of showing similar hepatic AQP9 protein, women exhibit lower hepatocyte glycerol permeability than men, which might contribute to their lower prevalence of insulin resistance and NAFLD. PMID:26594198

  16. KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression

    PubMed Central

    Chou, Chu-Fang; Zhu, Xiaolin; Lin, Yi-Yu; Gamble, Karen L.; Garvey, W. Timothy; Chen, Ching-Yi

    2015-01-01

    Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH-type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp−/− livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp−/− livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp−/− hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3′ untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability. PMID:25514904

  17. Effects of dry period length on milk production, body condition, metabolites, and hepatic glucose metabolism in dairy cows.

    PubMed

    Weber, C; Losand, B; Tuchscherer, A; Rehbock, F; Blum, E; Yang, W; Bruckmaier, R M; Sanftleben, P; Hammon, H M

    2015-03-01

    Dry period (DP) length affects energy metabolism around calving in dairy cows as well as milk production in the subsequent lactation. The aim of the study was to investigate milk production, body condition, metabolic adaptation, and hepatic gene expression of gluconeogenic enzymes in Holstein cows (>10,000 kg milk/305 d) with 28- (n=18), 56- (n=18), and 90-d DP (n=22) length (treatment groups) in a commercial farm. Cows were fed total mixed rations ad libitum adjusted for far-off (not for 28-d DP) and close-up DP and lactation. Milk yield was recorded daily and body condition score (BCS), back fat thickness (BFT), and body weight (BW) were determined at dry off, 1 wk before expected and after calving, and on wk 2, 4, and 8 postpartum (pp). Blood samples were taken on d -56, -28, -7, 1, 7, 14, 28, and 56 relative to calving to measure plasma concentrations of metabolites and hormones. Liver biopsies (n=11 per treatment) were taken on d -10 and 10 relative to calving to determine glycogen and total liver fat concentration (LFC) and to quantify mRNA levels of pyruvate carboxylase (PC), cytosolic phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase. Time course of milk yield during first 8 wk in lactation differed among treatment. Milk protein content was higher in 28-d than in 90-d DP cows. Milk fat to protein ratio was highest and milk urea was lowest in 90-d DP cows. Differences in BW, BFT, and BCS were predominantly seen before calving with greatest BW, BFT, and BCS in 90-d DP cows. Plasma concentrations of NEFA and BHBA were elevated during the transition period in all cows, and the greatest increase pp was seen in 90-d DP cows. Plasma glucose concentration decreased around calving and was greater in 28-d than in 90-d DP cows. Dry period length also affected plasma concentrations of urea, cholesterol, aspartate transaminase, and glutamate dehydrogenase. Plasma insulin concentration decreased around calving in all cows, but insulin concentration pp was

  18. Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice

    PubMed Central

    Udoh, Uduak S.; Swain, Telisha M.; Filiano, Ashley N.; Gamble, Karen L.; Young, Martin E.

    2015-01-01

    Chronic ethanol consumption has been shown to significantly decrease hepatic glycogen content; however, the mechanisms responsible for this adverse metabolic effect are unknown. In this study, we examined the impact chronic ethanol consumption has on time-of-day-dependent oscillations (rhythms) in glycogen metabolism processes in the liver. For this, male C57BL/6J mice were fed either a control or ethanol-containing liquid diet for 5 wk, and livers were collected every 4 h for 24 h and analyzed for changes in various genes and proteins involved in hepatic glycogen metabolism. Glycogen displayed a robust diurnal rhythm in the livers of mice fed the control diet, with the peak occurring during the active (dark) period of the day. The diurnal glycogen rhythm was significantly altered in livers of ethanol-fed mice, with the glycogen peak shifted into the inactive (light) period and the overall content of glycogen decreased compared with controls. Chronic ethanol consumption further disrupted diurnal rhythms in gene expression (glycogen synthase 1 and 2, glycogenin, glucokinase, protein targeting to glycogen, and pyruvate kinase), total and phosphorylated glycogen synthase protein, and enzyme activities of glycogen synthase and glycogen phosphorylase, the rate-limiting enzymes of glycogen metabolism. In summary, these results show for the first time that chronic ethanol consumption disrupts diurnal rhythms in hepatic glycogen metabolism at the gene and protein level. Chronic ethanol-induced disruption in these daily rhythms likely contributes to glycogen depletion and disruption of hepatic energy homeostasis, a recognized risk factor in the etiology of alcoholic liver disease. PMID:25857999

  19. Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance

    PubMed Central

    2013-01-01

    The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in

  20. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization

    PubMed Central

    Hong, Shangyu; Moreno-Navarrete, Jose M; Wei, Xiaojing; Kikukawa, Yusuke; Tzameli, Iphigenia; Prasad, Deepthi; Lee, Yoonjin; Asara, John M; Fernandez-Real, Jose Manuel; Maratos-Flier, Eleftheria; Pissios, Pavlos

    2015-01-01

    Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N1-methylnicotinamide (MNAM). Nnmt is an emerging metabolic regulator in adipocytes but its role in the liver, a tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and in humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect, which is required for their metabolic benefits. In summary, we describe a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy. PMID:26168293

  1. Serum metabolic signature of minimal hepatic encephalopathy by (1)H-nuclear magnetic resonance.

    PubMed

    Jiménez, Beatriz; Montoliu, Carmina; MacIntyre, David A; Serra, Miguel A; Wassel, Abdallah; Jover, María; Romero-Gomez, Manuel; Rodrigo, Jose M; Pineda-Lucena, Antonio; Felipo, Vicente

    2010-10-01

    Minimal hepatic encephalopathy (MHE) reduces quality of life of cirrhotic patients, predicts overt hepatic encephalopathy, and is associated with poor prognosis. We hypothesized that MHE arises once metabolic alterations derived from the liver reach a particular threshold. Our aim was to assess whether metabolic profiling of serum samples by high-field (1)H-nuclear magnetic resonance spectroscopy ((1)H NMR) and subsequent multivariate analyses would be useful to characterize metabolic perturbations associated with MHE and to identify potential metabolic biomarkers. Metabolic serum profiles from controls (n = 69) and cirrhotic patients without MHE (n = 62) and with MHE (n = 39) were acquired using high field NMR. Supervised modeling of the data provided perfect discrimination between healthy controls and cirrhotic patients and allowed the generation of a predictive model displaying strong discrimination between patients with and without MHE (R(2)Y = 0.68, Q(2)Y = 0.63). MHE patients displayed increased serum concentrations of glucose, lactate, methionine, TMAO, and glycerol, as well as decreased levels of choline, branch amino acids, alanine, glycine, acetoacetate, NAC, and lipid moieties. Serum metabonomics by (1)H NMR offers a useful approach for characterizing underlying metabolic differences between patients with and without MHE. This procedure shows great potential as a diagnostic tool of MHE as it objectively reflects measurable biochemical differences between the patient groups and may facilitate monitoring of both disease progression and effects of therapeutic treatments. PMID:20690770

  2. Hepatic Methionine Homeostasis Is Conserved in C57BL/6N Mice on High-Fat Diet Despite Major Changes in Hepatic One-Carbon Metabolism

    PubMed Central

    Dahlhoff, Christoph; Desmarchelier, Charles; Sailer, Manuela; Fürst, Rainer W.; Haag, Alexander; Ulbrich, Susanne E.; Hummel, Björn; Obeid, Rima; Geisel, Jürgen; Bader, Bernhard L.; Daniel, Hannelore

    2013-01-01

    Obesity is an underlying risk factor in the development of cardiovascular disease, dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Increased hepatic lipid accumulation is a hallmark in the progression of NAFLD and impairments in liver phosphatidylcholine (PC) metabolism may be central to the pathogenesis. Hepatic PC biosynthesis, which is linked to the one-carbon (C1) metabolism by phosphatidylethanolamine N-methyltransferase, is known to be important for hepatic lipid export by VLDL particles. Here, we assessed the influence of a high-fat (HF) diet and NAFLD status in mice on hepatic methyl-group expenditure and C1-metabolism by analyzing changes in gene expression, protein levels, metabolite concentrations, and nuclear epigenetic processes. In livers from HF diet induced obese mice a significant downregulation of cystathionine β-synthase (CBS) and an increased betaine-homocysteine methyltransferase (BHMT) expression were observed. Experiments in vitro, using hepatoma cells stimulated with peroxisome proliferator activated receptor alpha (PPARα) agonist WY14,643, revealed a significantly reduced Cbs mRNA expression. Moreover, metabolite measurements identified decreased hepatic cystathionine and L-α-amino-n-butyrate concentrations as part of the transsulfuration pathway and reduced hepatic betaine concentrations, but no metabolite changes in the methionine cycle in HF diet fed mice compared to controls. Furthermore, we detected diminished hepatic gene expression of de novo DNA methyltransferase 3b but no effects on hepatic global genomic DNA methylation or hepatic DNA methylation in the Cbs promoter region upon HF diet. Our data suggest that HF diet induces a PPARα-mediated downregulation of key enzymes in the hepatic transsulfuration pathway and upregulates BHMT expression in mice to accommodate to enhanced dietary fat processing while preserving the essential amino acid methionine. PMID:23472083

  3. Regulation of hepatic carbohydrate metabolism by Selenium during diabetes.

    PubMed

    Chen, Hongping; Qiu, Qinqin; Zou, Caiyan; Dou, Lianjun; Liang, Jun

    2015-05-01

    In the present study, we have tried to unravel the role of Selenium supplementation in containing hyperglycemia by regulating enzymes activities involved in carbohydrate metabolism in liver of diabetic animals. Male wistar rats were divided into four groups: normal control, diabetic, Selenium treated control and Selenium treated diabetic group. Diabetes was induced in the animals by injecting alloxan intraperitoneally at a dose level of 150 mg/kg body weight. Selenium in the form of sodium selenite was supplemented to rats at a dose level of 1 PPM in drinking water, ad libitum for two time durations of 2 and 4 weeks. Animals were sacrificed and livers were excised for the analyses of enzymes involved in carbohydrate metabolism as well as the levels of glycogen. In-vitro (14)C-d glucose uptake and its turnover were also assessed in liver slices of all the treatment groups using radiorespirometry. Selenium supplementation to the diabetic rats normalized the enzyme activities of glucose-6-phosphatase, lactate dehydrogenase and glycogen phosphorylase as well as restored the glycogen levels to within the normal limits which were altered during diabetes. Interestingly, when Selenium was supplemented to diabetic rats, (14)C-d glucose uptake and its turnover showed a statistically significant increase in their values which however, were decreased in diabetic rats. In conclusion, Selenium mediates insulin-like role during diabetes by tending to normalize the altered activities of glucose metabolizing enzymes and also improves the glucose uptake and its metabolism by the liver. PMID:25779343

  4. Calcium ions affect the hepatitis B virus core assembly

    SciTech Connect

    Choi, Yongwook; Gyoo Park, Sung; Yoo, Jun-hi; Jung, Guhung . E-mail: drjung@snu.ac.kr

    2005-02-05

    Previous report showed that cytosolic Ca{sup 2+} induced by hepatitis B virus X protein (HBx) promotes HBV replication. In this study, in vitro experiments showed that (i) HBV core assembly in vitro was promoted by Ca{sup 2+} through the sucrose density gradient and the analytical ultracentrifuge analysis. Also (ii) transmission electron microscope analysis demonstrated these assembled HBV core particles were the capsids. Ex vivo experiments showed that the treatment of BAPTA-AM and cyclosporine A (CsA) reduced HBV capsids in the transfected HepG2 cells. In addition to that, the treatment of Thapsigargin (TG) increased HBV capsids in the transfected HepG2 cells. Furthermore, we investigated the increased HBV core assembly by HBx. The results show that the increased cytosolic calcium ions by HBx promote the HBV core assembly.

  5. Characterizing the Network of Drugs and Their Affected Metabolic Subpathways

    PubMed Central

    Li, Jing; Han, Junwei; Wang, Shuyuan; Yao, Qianlan; Wang, Yingying; Zhang, Yunpeng; Zhang, Chunlong; Xu, Yanjun; Jiang, Wei; Li, Xia

    2012-01-01

    A fundamental issue in biology and medicine is illustration of the overall drug impact which is always the consequence of changes in local regions of metabolic pathways (subpathways). To gain insights into the global relationship between drugs and their affected metabolic subpathways, we constructed a drug–metabolic subpathway network (DRSN). This network included 3925 significant drug–metabolic subpathway associations representing drug dual effects. Through analyses based on network biology, we found that if drugs were linked to the same subpathways in the DRSN, they tended to share the same indications and side effects. Furthermore, if drugs shared more subpathways, they tended to share more side effects. We then calculated the association score by integrating drug-affected subpathways and disease-related subpathways to quantify the extent of the associations between each drug class and disease class. The results showed some close drug–disease associations such as sex hormone drugs and cancer suggesting drug dual effects. Surprisingly, most drugs displayed close associations with their side effects rather than their indications. To further investigate the mechanism of drug dual effects, we classified all the subpathways in the DRSN into therapeutic and non-therapeutic subpathways representing drug therapeutic effects and side effects. Compared to drug side effects, the therapeutic effects tended to work through tissue-specific genes and these genes tend to be expressed in the adrenal gland, liver and kidney; while drug side effects always occurred in the liver, bone marrow and trachea. Taken together, the DRSN could provide great insights into understanding the global relationship between drugs and metabolic subpathways. PMID:23112813

  6. IN VITRO METABOLISM OF THE CHIRAL TRIAZOLE FUNGICIDE BROMUCONAZOLE 47 USING SUBSTRATE DEPLETION AND PRODUCT FORMATION KINETICS IN RAT HEPATIC MICROSOMES

    EPA Science Inventory

    Kinetic analysis of xenobiotic metabolism using in vitro hepatic microsomes are needed for predictive in vivo physiological modeling. Recently, much emphasis has been placed on the adverse effects of triazole fungicides in mammalian steroid metabolism. In vitro metabolism of the ...

  7. Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450

    SciTech Connect

    Marinello, A.J.; Bansal, S.K.; Paul, B.; Koser, P.L.; Love, J.; Struck, R.F.; Gurtoo, H.L.

    1984-10-01

    The hepatic cytochrome P-450-mediated metabolism and metabolic activation of (chloroethyl-3H)cyclophosphamide (( chloroethyl-3H)CP) and (4-14C)cyclophosphamide (( 4-14C)CP) were investigated in vitro in the reconstituted system containing cytochrome P-450 isolated from phenobarbital-treated rats. In addition, hepatic microsomal binding and the hepatic microsome-mediated metabolism of (14C)acrolein, a metabolite of (4-14C)CP, were also investigated. The metabolism of (chloroethyl-3H)CP and (4-14C)CP to polar metabolites was found to depend on the presence of NADPH and showed concentration dependence with respect to cytochrome P-450 and NADPH:cytochrome P-450 reductase. Km and Vmax values were essentially similar. The patterns of inhibition by microsomal mixed-function oxidase inhibitors, anti-cytochrome P-450 antibody, and heat denaturation of the cytochrome P-450 were essentially similar, with subtle differences between (4-14C)CP and (chloroethyl-3H)CP metabolism. The in vitro metabolic activation of CP in the reconstituted system demonstrated predominant binding of (chloroethyl-3H)CP to nucleic acids and almost exclusive binding of (4-14C)CP to proteins. Gel electrophoresis-fluorography of the proteins in the reconstituted system treated with (4-14C)CP demonstrated localization of the 14C label in the cytochrome P-450 region. To examine this association further, hepatic microsomes were modified with (14C)acrolein in the presence and the absence of NADPH. The results confirmed covalent association between (14C)acrolein and cytochrome P-450 in the microsomes and also demonstrated further metabolism of (14C)acrolein, apparently to an epoxide, which is capable of binding covalently to proteins. The results of these investigations not only confirm the significance of primary metabolism but also emphasize the potential role of the secondary metabolism of cyclophosphamide in some of its toxic manifestations.

  8. Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs.

    PubMed

    Niwa, Toshiro; Shiraga, Toshifumi; Ishii, Ikuko; Kagayama, Akira; Takagi, Akira

    2005-09-01

    The metabolic activities of six psychotropic drugs, diazepam, clotiazepam, tofisopam, etizolam, tandospirone, and imipramine, were determined for 14 isoforms of recombinant human hepatic cytochrome P450s (CYPs) and human liver microsomes by measuring the disappearance rate of parent compounds. In vitro kinetic studies revealed that Vmax/Km values in human liver microsomes were the highest for tofisopam, followed by tandospirone>clotiazepam>imipramine, diazepam, and etizolam. Among the recombinant CYPs, CYP3A4 exhibited the highest metabolic activities of all compounds except for clotiazepam and imipramine. The metabolism of clotiazepam was catalyzed by CYP2B6, CYP3A4, CYP2C18, and CYP2C19, and imipramine was metabolized by CYP2D6 most efficiently. In addition, the metabolic activities of diazepam, clotiazepam, and etizolam in human liver microsomes were inhibited by 2.5 microM ketoconazole, a CYP3A4 inhibitor, by 97.5%, 65.1%, and 83.5%, respectively, and the imipramine metabolism was not detected after the addition of 1 or 10 microM quinidine, a CYP2D6 inhibitor. These results suggest that the psychotropic drugs investigated are metabolized predominantly by CYP3A4, except that CYP2D6 catalyzes the metabolism of imipramine. In addition, this approach based on the disappearance rate appears to be useful for the identification of the responsible CYP isoform(s) of older drugs, for which metabolic profiles have not been reported. PMID:16141545

  9. JNK REGULATION OF HEPATIC MANIFESTATIONS OF THE METABOLIC SYNDROME

    PubMed Central

    Czaja, Mark J.

    2010-01-01

    Nonalcoholic fatty liver disease (NAFLD) is now recognized as both an important component of the metabolic syndrome and the most prevalent liver disease in the United States. Although the mechanisms for development of steatosis and chronic liver injury in NAFLD remain unclear, recent investigations have indicated that overactivation of c-Jun N-terminal kinase (JNK) is critical to this process. These findings, together with evidence for the involvement of JNK signaling in other manifestations of the metabolic syndrome such as obesity and insulin resistance, have suggested that JNK may be a novel therapeutic target in this disorder. This review details findings that JNK mediates lipid accumulation and cell injury in fatty liver disease and discusses the possible cellular mechanisms of JNK actions. PMID:20888782

  10. Hepatic drug metabolism and lipid peroxidation in thiamine deficient rats.

    PubMed

    Galdhar, N R; Pawar, S S

    1976-01-01

    In vitro metabolism of aminopyrene, ethylmorphine (Type I substrates), N-methylaniline and acetanilide (Type II substrates) in liver microsomal fraction from thiamine deficient male and female rats was studied. No significant change in microsomal protein content was noticed during the period of thiamine deficiency. However, a significant increase in the in vitro oxidation of aminopyrene, ethylmorphine, N-methylaniline and hydroxylation of acetanilide was observed. The NADPH linked and ascorbate induced lipid peroxidation was also increased during thiamine deficiency. The levels of NADPH cytochrome c-reductase, cytochrome b5 and heme were noticeably increased in thiamine deficient animals as compared to normal rats. Phenobarbital treatment induced the activities of all drug enzymes and inhibited the lipid peroxidation in either sex during the period of thiamine deficiency. It appears that thiamine intake is an important determination in drug metabolism and lipid peroxidation. PMID:816749

  11. Ontogeny of Hepatic Energy Metabolism Genes in Mice as Revealed by RNA-Sequencing

    PubMed Central

    Renaud, Helen J.; Cui, Yue Julia; Lu, Hong; Zhong, Xiao-bo; Klaassen, Curtis D.

    2014-01-01

    The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age). The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5–Day 5 (perinatal-enriched), Day 10–Day 20 (pre-weaning-enriched), and Day 25–Day 60 (adolescence/adulthood-enriched). Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty acids-like 3

  12. [Glutamate metabolism in cerebral cortex obtained from chronic hepatic failure rats].

    PubMed

    Ito, M; Matsumoto, H; Kikuchi, S; Yachi, A

    1986-09-01

    The present investigation was carried out in order to elucidate the amino acid metabolism in hepatic failure with particular emphasis placed on glutamate. For this purpose, chronic hepatic failure models were produced in adult male Wistar rats by successive carbontetrachloride injection (0.20 ml/100 g. B. W., twice/week) for 13 weeks. They were confirmed to develop chemical changes compartible with hepatic failure, showing markedly elevated serum levels of NH3, GOT and ALP. Animals were killed by decapitation during fasting and the brains were removed immediately. After the parietal cortical slices were incubated for 45 min at 37 degrees C together with L-(U-14C) glutamate in O2-saturated Gey's balanced salt solution, they were homogenized in 75% ethanol and deproteinized with water saturated chloroform. The radioactivities of liberated CO2, glutamate and its metabolites (glutamine, aspartate and GABA) obtained from the slices were measured. The amount of radioactivity recovered from CO2, glutamine and aspartate revealed a significant increase (p less than 0.001), while that of glutamate and GABA remained unchanged. The main source of the CO2 is believed to originate from TCA cycle rather than the decarboxylation of glutamate to form GABA, and glutamate forms glutamine when it fixes ammonia. Furthermore, glutamate is converted into aspartate via TCA cycle when the carbon was labeled. Therefore, the results indicate that in chronic hepatic failure brains glutamate metabolism is enhanced through TCA cycle as well as ammonia fixation mechanism. PMID:3790365

  13. Estrogen Signalling and the Metabolic Syndrome: Targeting the Hepatic Estrogen Receptor Alpha Action

    PubMed Central

    Matic, Marko; Bryzgalova, Galyna; Gao, Hui; Antonson, Per; Humire, Patricia; Omoto, Yoko; Portwood, Neil; Pramfalk, Camilla; Efendic, Suad; Berggren, Per-Olof; Gustafsson, Jan-Åke; Dahlman-Wright, Karin

    2013-01-01

    An increasing body of evidence now links estrogenic signalling with the metabolic syndrome (MS). Despite the beneficial estrogenic effects in reversing some of the MS symptoms, the underlying mechanisms remain largely undiscovered. We have previously shown that total estrogen receptor alpha (ERα) knockout (KO) mice exhibit hepatic insulin resistance. To determine whether liver-selective ablation of ERα recapitulates metabolic phenotypes of ERKO mice we generated a liver-selective ERαKO mouse model, LERKO. We demonstrate that LERKO mice have efficient reduction of ERα selectively within the liver. However, LERKO and wild type control mice do not differ in body weight, and have a comparable hormone profile as well as insulin and glucose response, even when challenged with a high fat diet. Furthermore, LERKO mice display very minor changes in their hepatic transcript profile. Collectively, our findings indicate that hepatic ERα action may not be the responsible factor for the previously identified hepatic insulin resistance in ERαKO mice. PMID:23451233

  14. Hepatitis C virus: How genetic variability affects pathobiology of disease.

    PubMed

    Chayama, Kazuaki; Hayes, C Nelson

    2011-01-01

    As an RNA virus, hepatitis C virus (HCV) shows a characteristically high level of nucleotide diversity. Accumulation of nucleotide substitutions in the virus has resulted in diversification into quasispecies, subtypes and distinct genotypes. Pathobiological studies linking nucleotide and amino acid sequences with clinical findings have identified relationships between certain genotypes and characteristic biological properties. Genotype 3 HCV infection was found to be associated with a high level of liver steatosis. Genotypes 1 and 4 were found to be more resistant to interferon (IFN) based therapies than genotypes 2 and 3. Studies of genotype 1 sequences obtained from patients treated with IFN have identified a relationship between favorable response to interferon therapy and amino acid substitutions in the NS5A region (interferon response determining region; ISDR). Further studies have identified a relationship between the effect of IFN therapy and other regions of the NS5A protein. More recently, a relationship has been found between poor response to peg-IFN plus ribavirin combination therapy and substitutions at amino acid 70 and 91 in the core protein. Furthermore, a correlation between human genetic variation in the IL28B (IFN-lamda 3) locus and core amino acid substitutions has been characterized. In this review we briefly summarize the discovery, classification and nomenclature of HCV genotypes and subtypes. We also discuss amino acid substitutions within specific regions that have been reported to be associated with outcome of IFN and peg-IFN plus ribavirin combination therapy. PMID:21199518

  15. Biogeochemical interactions affecting hepatic trace element levels in aquatic birds

    SciTech Connect

    Moeller, G.

    1996-07-01

    Knowledge of elemental interactions is important to the toxicological assessment of wildlife in the geochemical environment. This study determines the concentrations of Al, As, B, Ba, Be, Cd, Cr, Cu, Fe, Pb, Li, Mg, Mn, Hg, Mo, Ni, Se, Ag, V, and Zn in aquatic bird liver, fish liver, whole bivalves, insects, and waters in several aquatic ecosystems in northern California. There is evidence of strong in vivo and environmental interactions, including the observation of manganese as a possible cofactor or indicator in selenium bioaccumulation. The nearest neighbor selenium correlation in aquatic bird liver tissue that results from this work is Cd-Mn-Se-Hg-As. The correlation of liver selenium to manganese in vivo and the result that the majority of the variance in liver selenium concentration is contained in the manganese term of the regression model relating Se to Cd, Mn, and Hg is new knowledge in the study of aquatic birds. A linear relationship between liver selenium and environmental manganese (water and sediment) is found in the data, suggesting a water chemistry compartmentalization or activation of toxicants. Alternatively, the hepatic concentrations of selenium, manganese, and iron suggest induction of enzymes in response to oxidative stress.

  16. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance

    PubMed Central

    Dietrich, Christoph G; Götze, Oliver; Geier, Andreas

    2016-01-01

    Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests. PMID:26755861

  17. Dietary fat and hepatic lipogenesis: mitochondrial citrate carrier as a sensor of metabolic changes.

    PubMed

    Ferramosca, Alessandra; Zara, Vincenzo

    2014-05-01

    Citrate carrier (CIC) is an integral protein of the inner mitochondrial membrane that has a fundamental role in hepatic intermediary metabolism. Its primary function is to catalyze the transport of citrate from mitochondria, where this molecule is formed, to cytosol, where this molecule is used for fatty acid (FA) and cholesterol synthesis. Therefore, mitochondrial CIC acts upstream of cytosolic lipogenic reactions, and its regulation is particularly important in view of the modulation of hepatic lipogenesis. Although a great deal of data are currently available on the dietary modulation of cytosolic lipogenic enzymes, little is known about the nutritional regulation of CIC transport activity. In this review, we describe the differential effects of distinct FAs present in the diet on the activity of mitochondrial CIC. In particular, polyunsaturated FAs were powerful modulators of the activity of mitochondrial CIC by influencing its expression through transcriptional and posttranscriptional mechanisms. On the contrary, saturated and monounsaturated FAs did not influence mitochondrial CIC activity. Moreover, variations in CIC activity were connected to similar alterations in the metabolic pathways to which the transported citrate is channeled. Therefore, CIC may be considered as a sensor for changes occurring inside the hepatocyte and may represent an important target for the regulation of hepatic lipogenesis. The crucial role of this protein is reinforced by the recent discovery of its involvement in other cellular processes, such as glucose-stimulated insulin secretion, inflammation, tumorigenesis, genome stability, and sperm metabolism. PMID:24829468

  18. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age.

    PubMed

    Keith, Dove; Finlay, Liam; Butler, Judy; Gómez, Luis; Smith, Eric; Moreau, Régis; Hagen, Tory

    2014-07-18

    It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks. PMID:24944020

  19. Leucine metabolism in cirrhotic patients with hepatic encephalopathy

    SciTech Connect

    McGhee, A.S.

    1985-01-01

    The purpose of this study was to determine whether increased oxidation of or protein synthesis requiring leucine occurs in cirrhotic patients. Five control subjects and four subjects with cirrhosis were equilibrated on a baseline diet (0.6 g protein per kg ideal body weight (IBW)) with sufficient nonprotein calories to preclude negative nitrogen balance. An additional four patients were equilibrated on the same type of diet with a higher protein level (0.75 g per kg IBW). Control subjects and the patients were then studied during continuous infusion of L-(/sup 15/N, 1-/sup 13/C) leucine in the fasted state and, in the fed state, with a Propac diet which had the same distribution of energy nutrients as the baseline diets. Plasma levels of L-(/sup 15/N, 1-/sup 13/C), L-(1-/sup 13/C) and L-(/sup 15/N) leucine were measured during isotopic steady state by gas chromatography-mass spectrometry and fractional excretion of /sup 13/CO/sup 2/ in breath samples were analyzed by isotopic ratio mass spectrometry. During the fasted and fed states leucine metabolism was measured to quantitate rates of nitrogen flux (Q/sub N/), carbon flux (Q/sub c/) and oxidation to carbon dioxide and water (C). From these measured values, proteins breakdown (B), protein synthesis (S), deamination (X/sup 0/) and reamination (X/sub N/) were calculated. The results showed that protein synthesis and leucine metabolism were identical in controls and patients when both were fed a diet with 0.6 g protein/kg IBW and maintenance level of nonprotein calories. The data also showed that leucine metabolism can be quantitatively and reproducibly measured in subjects with cirrhosis.

  20. Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice.

    PubMed

    Souidi, M; Racine, R; Grandcolas, L; Grison, S; Stefani, J; Gourmelon, P; Lestaevel, P

    2012-04-01

    Depleted uranium (DU) is uranium with a lower content of the fissile isotope U-235 than natural uranium. It is a radioelement and a waste product from the enrichment process of natural uranium. Because of its very high density, it is used in the civil industry and for military purposes. DU exposure can affect many vital systems in the human body, because in addition to being weakly radioactive, uranium is a toxic metal. It should be emphasized that, to be exposed to radiation from DU, you have to eat, drink, or breathe it, or get it on your skin. This particular study is focusing on the health effects of DU for the cholesterol metabolism. Previous studies on the same issue have shown that the cholesterol metabolism was modulated at molecular level in the liver of laboratory rodents contaminated for nine months with DU. However, this modulation was not correlated with some effects at organs or body levels. It was therefore decided to use a "pathological model" such as hypercholesterolemic apolipoprotein E-deficient laboratory mice in order to try to clarify the situation. The purpose of the present study is to assess the effects of a chronic ingestion (during 3 months) of a low level DU-supplemented water (20 mg L(-1)) on the above mentioned mice in order to determine a possible contamination effect. Afterwards the cholesterol metabolism was studied in the liver especially focused on the gene expressions of cholesterol-catabolising enzymes (CYP7A1, CYP27A1 and CYP7B1), as well as those of associated nuclear receptors (LXRα, FXR, PPARα, and SREBP 2). In addition, mRNA levels of other enzymes of interest were measured (ACAT 2, as well as HMGCoA Reductase and HMGCoA Synthase). The gene expression study was completed with SRB1 and LDLr, apolipoproteins A1 and B and membrane transporters ABC A1, ABC G5. The major effect induced by a low level of DU contamination in apo-E deficient mice was a decrease in hepatic gene expression of the enzyme CYP7B1 (-23%) and nuclear

  1. Cellular cofactors affecting hepatitis C virus infection and replication

    PubMed Central

    Randall, Glenn; Panis, Maryline; Cooper, Jacob D.; Tellinghuisen, Timothy L.; Sukhodolets, Karen E.; Pfeffer, Sebastien; Landthaler, Markus; Landgraf, Pablo; Kan, Sherry; Lindenbach, Brett D.; Chien, Minchen; Weir, David B.; Russo, James J.; Ju, Jingyue; Brownstein, Michael J.; Sheridan, Robert; Sander, Chris; Zavolan, Mihaela; Tuschl, Thomas; Rice, Charles M.

    2007-01-01

    Recently identified hepatitis C virus (HCV) isolates that are infectious in cell culture provide a genetic system to evaluate the significance of virus–host interactions for HCV replication. We have completed a systematic RNAi screen wherein siRNAs were designed that target 62 host genes encoding proteins that physically interact with HCV RNA or proteins or belong to cellular pathways thought to modulate HCV infection. This includes 10 host proteins that we identify in this study to bind HCV NS5A. siRNAs that target 26 of these host genes alter infectious HCV production >3-fold. Included in this set of 26 were siRNAs that target Dicer, a principal component of the RNAi silencing pathway. Contrary to the hypothesis that RNAi is an antiviral pathway in mammals, as has been reported for subgenomic HCV replicons, siRNAs that target Dicer inhibited HCV replication. Furthermore, siRNAs that target several other components of the RNAi pathway also inhibit HCV replication. MicroRNA profiling of human liver, human hepatoma Huh-7.5 cells, and Huh-7.5 cells that harbor replicating HCV demonstrated that miR-122 is the predominant microRNA in each environment. miR-122 has been previously implicated in positively regulating the replication of HCV genotype 1 replicons. We find that 2′-O-methyl antisense oligonucleotide depletion of miR-122 also inhibits HCV genotype 2a replication and infectious virus production. Our data define 26 host genes that modulate HCV infection and indicate that the requirement for functional RNAi for HCV replication is dominant over any antiviral activity this pathway may exert against HCV. PMID:17616579

  2. Hepatic and renal metabolism before and after portasystemic shunts in patients with cirrhosis.

    PubMed Central

    Owen, O E; Mozzoli, M A; Reichle, F A; Kreulen, T H; Owen, R S; Boden, G; Polansky, M

    1985-01-01

    Hepatic cirrhosis with portal hypertension and gastroesophageal hemorrhage is a disease complex that continues to be treated by surgical portasystemic shunts. Whether or not a reduction or diversion of portal blood flow to the liver adversely affects the ability of the liver to maintain fuel homeostasis via gluconeogenesis, glycogenolysis, and ketogenesis is unknown. 11 patients with biopsy-proven severe hepatic cirrhosis were studied before and after distal splenorenal or mesocaval shunts. Hepatic, portal, and renal blood flow rates and glucose, lactate, pyruvate, glycerol, amino acids, ketone bodies, free fatty acids, and triglyceride arteriovenous concentration differences were determined to calculate net precursor-product exchange rates across the liver, gut, and kidney. The study showed that hepatic contribution of glucose and ketone bodies and the caloric equivalents of these fuels delivered to the blood was not adversely affected by either a distal splenorenal or mesocaval shunt. In addition to these general observations, isolated findings emerged. Mesocaval shunts reversed portal venous blood and functionally converted this venous avenue into hepatic venous blood. The ability of the kidney to make a substantial net contribution of ketone bodies to the blood was also observed. PMID:4044831

  3. Chronic central leptin infusion modulates the glycemia response to insulin administration in male rats through regulation of hepatic glucose metabolism.

    PubMed

    Burgos-Ramos, Emma; Canelles, Sandra; Rodríguez, Amaia; Gómez-Ambrosi, Javier; Frago, Laura M; Chowen, Julie A; Frühbeck, Gema; Argente, Jesús; Barrios, Vicente

    2015-11-01

    Leptin and insulin use overlapping signaling mechanisms to modify hepatic glucose metabolism, which is critical in maintaining normal glycemia. We examined the effect of an increase in central leptin and insulin on hepatic glucose metabolism and its influence on serum glucose levels. Chronic leptin infusion increased serum leptin and reduced hepatic SH-phosphotyrosine phosphatase 1, the association of suppressor of cytokine signaling 3 to the insulin receptor in liver and the rise in glycemia induced by central insulin. Leptin also decreased hepatic phosphoenolpyruvate carboxykinase levels and increased insulin's ability to phosphorylate insulin receptor substrate-1, Akt and glycogen synthase kinase on Ser9 and to stimulate glucose transporter 2 and glycogen levels. Peripheral leptin treatment reproduced some of these changes, but to a lesser extent. Our data indicate that leptin increases the hepatic response to a rise in insulin, suggesting that pharmacological manipulation of leptin targets may be of interest for controlling glycemia. PMID:26296906

  4. Effect of structural modification on the gastrointestinal stability and hepatic metabolism of α-aminoxy peptides.

    PubMed

    Ma, Bin; Yin, Chun; Yang, Dan; Lin, Ge

    2012-11-01

    α-Aminoxy peptide AxyP1 has been reported to form synthetic chloride channel in living cells, thus it may have therapeutic potential for the treatment of diseases associated with chloride channel dysfunction. However, this study revealed significant gastrointestinal (GI) instability and extensive hepatic metabolism of AxyP1. To improve its GI and metabolic stability, structural modifications were conducted by replacing the isobutyl side chains of AxyP1 with methyl group (AxyP2), hydroxymethyl group (AxyP3), 4-aminobutyl group (AxyP4) and 3-carboxyl propyl group (AxyP5). Compared with AxyP1 (41 and 47 % degradation), GI stability of the modified peptides was significantly improved by 8-fold (AxyP2), 9-fold (AxyP3) and 12-fold (AxyP5) with no degradation for AxyP4 in simulated gastric fluid within 1 h, and by 12-fold (AxyP2) and 9-fold (AxyP3) with no degradation for AxyP4 and AxyP5 in simulated intestinal fluid within 3 h, respectively. The hepatic metabolic stability of the four modified peptides within 30 min in rat liver S9 preparation was also improved significantly with no metabolism of AxyP5 and threefold (AxyP2 and AxyP4) and eightfold (AxyP3) less metabolism compared with AxyP1 (39 % metabolism). Unlike hydrolysis as the major metabolism of peptides of natural α-amino acids, oxidation mediated by the cytochrome P450 enzymes, especially CYP3A subfamily, to form the corresponding mono-hydroxyl metabolites was the predominant hepatic metabolism of the five α-aminoxy peptides tested. The present findings demonstrate that structural modification can significantly improve the GI and metabolic stability of α-aminoxy peptides and thus increase their potential for therapeutic use in the treatment of chloride channel related diseases. PMID:22526242

  5. Experimental nonalcoholic steatohepatitis compromises ureagenesis, an essential hepatic metabolic function.

    PubMed

    Thomsen, Karen Louise; Grønbæk, Henning; Glavind, Emilie; Hebbard, Lionel; Jessen, Niels; Clouston, Andrew; George, Jacob; Vilstrup, Hendrik

    2014-08-01

    Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity. PMID:24924745

  6. Fermentation and Hydrogen Metabolism Affect Uranium Reduction by Clostridia

    DOE PAGESBeta

    Gao, Weimin; Francis, Arokiasamy J.

    2013-01-01

    Previously, it has been shown that not only is uranium reduction under fermentation condition common among clostridia species, but also the strains differed in the extent of their capability and the pH of the culture significantly affected uranium(VI) reduction. In this study, using HPLC and GC techniques, metabolic properties of those clostridial strains active in uranium reduction under fermentation conditions have been characterized and their effects on capability variance of uranium reduction discussed. Then, the relationship between hydrogen metabolism and uranium reduction has been further explored and the important role played by hydrogenase in uranium(VI) and iron(III) reduction bymore » clostridia demonstrated. When hydrogen was provided as the headspace gas, uranium(VI) reduction occurred in the presence of whole cells of clostridia. This is in contrast to that of nitrogen as the headspace gas. Without clostridia cells, hydrogen alone could not result in uranium(VI) reduction. In alignment with this observation, it was also found that either copper(II) addition or iron depletion in the medium could compromise uranium reduction by clostridia. In the end, a comprehensive model was proposed to explain uranium reduction by clostridia and its relationship to the overall metabolism especially hydrogen (H 2 ) production.« less

  7. Fermentation and hydrogen metabolism affect uranium reduction by clostridia.

    PubMed

    Gao, Weimin; Francis, Arokiasamy J

    2013-01-01

    Previously, it has been shown that not only is uranium reduction under fermentation condition common among clostridia species, but also the strains differed in the extent of their capability and the pH of the culture significantly affected uranium(VI) reduction. In this study, using HPLC and GC techniques, metabolic properties of those clostridial strains active in uranium reduction under fermentation conditions have been characterized and their effects on capability variance of uranium reduction discussed. Then, the relationship between hydrogen metabolism and uranium reduction has been further explored and the important role played by hydrogenase in uranium(VI) and iron(III) reduction by clostridia demonstrated. When hydrogen was provided as the headspace gas, uranium(VI) reduction occurred in the presence of whole cells of clostridia. This is in contrast to that of nitrogen as the headspace gas. Without clostridia cells, hydrogen alone could not result in uranium(VI) reduction. In alignment with this observation, it was also found that either copper(II) addition or iron depletion in the medium could compromise uranium reduction by clostridia. In the end, a comprehensive model was proposed to explain uranium reduction by clostridia and its relationship to the overall metabolism especially hydrogen (H2) production. PMID:25937978

  8. Fermentation and Hydrogen Metabolism Affect Uranium Reduction by Clostridia

    PubMed Central

    Gao, Weimin; Francis, Arokiasamy J.

    2013-01-01

    Previously, it has been shown that not only is uranium reduction under fermentation condition common among clostridia species, but also the strains differed in the extent of their capability and the pH of the culture significantly affected uranium(VI) reduction. In this study, using HPLC and GC techniques, metabolic properties of those clostridial strains active in uranium reduction under fermentation conditions have been characterized and their effects on capability variance of uranium reduction discussed. Then, the relationship between hydrogen metabolism and uranium reduction has been further explored and the important role played by hydrogenase in uranium(VI) and iron(III) reduction by clostridia demonstrated. When hydrogen was provided as the headspace gas, uranium(VI) reduction occurred in the presence of whole cells of clostridia. This is in contrast to that of nitrogen as the headspace gas. Without clostridia cells, hydrogen alone could not result in uranium(VI) reduction. In alignment with this observation, it was also found that either copper(II) addition or iron depletion in the medium could compromise uranium reduction by clostridia. In the end, a comprehensive model was proposed to explain uranium reduction by clostridia and its relationship to the overall metabolism especially hydrogen (H2) production. PMID:25937978

  9. Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

    PubMed Central

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. PMID:22761565

  10. Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement

    PubMed Central

    Bajaj, J. S.; Cordoba, J.; Mullen, K. D.; Amodio, P.; Shawcross, D. L.; Butterworth, R. F.; Morgan, M. Y.

    2014-01-01

    Summary Background The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. Aims To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. Methods A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. Results It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. Conclusions The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed. PMID:21306407

  11. The nuclear receptor FXR regulates hepatic transport and metabolism of glutamine and glutamate.

    PubMed

    Renga, Barbara; Mencarelli, Andrea; Cipriani, Sabrina; D'Amore, Claudio; Zampella, Angela; Monti, Maria Chiara; Distrutti, Eleonora; Fiorucci, Stefano

    2011-11-01

    Hepatic transport and metabolism of glutamate and glutamine are regulated by intervention of several proteins. Glutamine is taken up by periportal hepatocytes and is the major source of ammonia for urea synthesis and glutamate for N-acetylglutamate (NAG) synthesis, which is catalyzed by the N-acetylglutamate synthase (NAGS). Glutamate is taken up by perivenous hepatocytes and is the main source for the synthesis of glutamine, catalyzed by glutamine synthase (GS). Accumulation of glutamate and ammonia is a common feature of chronic liver failure, but mechanism that leads to failure of the urea cycle in this setting is unknown. The Farnesoid X Receptor (FXR) is a bile acid sensor in hepatocytes. Here, we have investigated its role in the regulation of the metabolism of both glutamine and glutamate. In vitro studies in primary cultures of hepatocytes from wild type and FXR(-/-) mice and HepG2 cells, and in vivo studies, in FXR(-/-) mice as well as in a rodent model of hepatic liver failure induced by carbon tetrachloride (CCl(4)), demonstrate a role for FXR in regulating this metabolism. Further on, promoter analysis studies demonstrate that both human and mouse NAGS promoters contain a putative FXRE, an ER8 sequence. EMSA, ChIP and luciferase experiments carried out to investigate the functionality of this sequence demonstrate that FXR is essential to induce the expression of NAGS. In conclusion, FXR activation regulates glutamine and glutamate metabolism and FXR ligands might have utility in the treatment of hyperammonemia states. PMID:21757002

  12. Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism.

    PubMed

    Kwong, Eric; Li, Yunzhou; Hylemon, Phillip B; Zhou, Huiping

    2015-03-01

    The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism. PMID:26579441

  13. The metabolic activator FOXO1 binds hepatitis B virus DNA and activates its transcription

    SciTech Connect

    Shlomai, Amir; Shaul, Yosef

    2009-04-17

    Hepatitis B virus (HBV) is a small DNA virus that targets the liver and infects humans worldwide. Recently we have shown that the metabolic regulator PGC-1{alpha} coactivates HBV transcription thereby rendering the virus susceptible to fluctuations in the nutritional status of the liver. PGC-1{alpha} coactivation of HBV is mediated through the liver-enriched nuclear receptor HNF4{alpha} and through another yet unknown transcription factor(s). Here we show that the forkhead transcription factor FOXO1, a known target for PGC-1{alpha} coactivation and a central mediator of glucose metabolism in the liver, binds HBV core promoter and activates its transcription. This activation is further enhanced in the presence of PGC-1{alpha}, implying that FOXO1 is a target for PGC-1{alpha} coactivation of HBV transcription. Thus, our results identify another key metabolic regulator as an activator of HBV transcription, thereby supporting the principle that HBV gene expression is regulated in a similar way to key hepatic metabolic genes.

  14. Associated Factors for Metabolic Syndrome in the Older Adults with Chronic Virus Hepatitis in the Community.

    PubMed

    Kuo, Yuan-Hung; Tsai, Ming-Chao; Kee, Kwong-Ming; Chang, Kuo-Chin; Wang, Jing-Houng; Lin, Chun-Yin; Lin, Sheng-Che; Lu, Sheng-Nan

    2016-01-01

    This study was to evaluate the association between metabolic syndrome (MetS) and chronic virus hepatitis elders in the community. Those subjects with positive hepatitis B surface antigen (HBsAg) and/or anti-hepatitis C virus (anti-HCV) screened in the community before were invited to this study and 451 responded. All participants underwent anthropometric measurements, blood tests, ultrasound and fibroscan examinations. The cut-off of liver stiffness measurement-liver cirrhosis (LSM-LC) was 10 kPa for chronic hepatitis B (CHB) patients and 12 kPa for chronic hepatitis C (CHC) patients, respectively. Among 451 responders, 56 were excluded due to negative HBsAg or anti-HCV. Three hundreds and ninety-five subjects included 228 CHB patients, 156 CHC patients and 11 dual hepatitis patients, had a mean age of 62±12.6 years. Fifty-four (23.7%) CHB patients coexisted with MetS whereas 40 (25.6%) CHC patients also had MetS. Those patients with MetS had more LSM-LC cases than those without (20.4% vs 9.8%, p = 0.04 in CHB patients; 28.2% vs 13.5%, p = 0.037 in CHC patients, respectively). In multivariate logistic analysis, detectable viremia was reversely associated with MetS in CHB patients after adjustment for age, gender and body mass index (odds ratio (OR): 0.42; 95% confidence interval (CI): 0.18-0.99; p = 0.047). Regarding CHC patients, higher LSM level was the only factor contributed to MetS (OR: 1.1; 95% CI: 1.02-1.19; p = 0.012). In conclusion, elder CHB patients coexisted with MetS might experience an inactive virus replication but have an advanced liver fibrosis. In elder CHC patients, only higher LSM level was associated with MetS. PMID:27177024

  15. Interactions between dietary boron and thiamine affect lipid metabolism

    SciTech Connect

    Herbel, J.L.; Hunt, C.D. )

    1991-03-15

    An experiment was designed to test the hypothesis that dietary boron impacts upon the function of various coenzymes involved in energy metabolism. In a 2 {times} 7 factorially-arranged experiment, weanling, vitamin D{sub 3}-deprived rats were fed a ground corn-casein-corn oil based diet supplemented with 0 or 2 mg boron/kg and 50% of the requirement for thiamine (TM), riboflavin (RF), pantothenic acid (PA) or pyridoxine (PX); 0% for folic acid (FA) or nicotinic acid (NA). All vitamins were supplemented in adequate amounts in the control diet. At 8 weeks of age, the TM dietary treatment was the one most affected by supplemental dietary boron (SDB). In rats that were fed 50% TM, SDB increased plasma concentrations of triglyceride (TG) and activity of alanine transaminase (ALT), and the liver to body weight (L/B) ratio. However, in the SDB animals, adequate amounts of TM decreased the means of those variables to near that observed in non-SDB rats fed 50% TM. The findings suggest that an interaction between dietary boron and TM affects lipid metabolism.

  16. The characterization and metabolism of rat hepatic nascent HLD subfractions

    SciTech Connect

    Winkler, K.E.

    1988-01-01

    Nascent HDL was isolated from recirculating rat liver perfusates and separated by heparin-sepharose chromatography into a non-retained fraction (A) and a fraction (B) that eluted with 0.5 M NaCl. Fractions A and B contained 70% and 30% of the nascent HDL protein, respectively. Livers perfused by the single-pass technique produced fractions A and B in the same ratio as livers perfused by recirculation. The apolipoprotein compositions were similar to those in the recirculating perfusion; however, both fractions A and B had more triglyceride (greater than 50% of total lipid). In a preliminary study designed to investigate whether nascent HDL-apo E was secreted by Kupffer cells or hepatocytes, label was targeted to Kupffer cells by perfusing rat livers with {sup 3}H-acetylated LDL or {sup 3}H-amino acids incorporated into large multilamellar vesicles. For metabolic studies, nascent HDL and nascent VLDL were isolated from rat livers that had been perfused with {sup 3}H-glycerol to label the triglyceride.

  17. Effects of tin-protoporphyrin administration on hepatic xenobiotic metabolizing enzymes in the juvenile rat

    SciTech Connect

    Stout, D.L.; Becker, F.F.

    1988-01-01

    The heme analogue tin-protoporphyrin IX (SnP) is a potent inhibitor of microsomal heme oxygenase. Administration of SnP to neonatal rats can prevent hyperbilirubinemia by blocking the postnatal increase of heme oxygenase activity. Apparently innocuous at therapeutic doses, it is of potential clinical value for chemoprevention of neonatal jaundice. We found that when 50-g male Sprague-Dawley rats were treated daily with 50 mumol of SnP/kg sc for 6 days, hepatic microsomal cytochromes b5 and P-450 were significantly diminished. Cytochrome P-450 reductase, two P-450-dependent monooxygenases, aminopyrine demethylase and benzo(a)pyrene hydroxylase, and catalase, a peroxisomal hemoprotein, were also significantly diminished. These results suggested that SnP might significantly affect the metabolism of other xenobiotics. This possibility was confirmed by the finding that hexobarbital-induced sleep lasted 4 times longer in SnP-treated rats than in controls. Inhibition of protein synthesis by SnP was ruled out as the cause of hemoprotein loss when administration of (/sup 3/H)leucine to SnP-treated and control rats demonstrated that proteins of the microsomal, cytosolic, and plasma membrane fractions of the livers from both groups incorporated similar levels of leucine. When /sup 55/FeCl/sub 3/ and (2-/sup 14/C)glycine were administered to measure heme synthesis, heme extract from the livers of SnP-treated rats contained 4 times more label from iron and glycine than did heme from control livers. Despite the apparent increased rate of heme synthesis in SnP-treated rats, each of the three cell fractions demonstrated a significant loss of heme but contained sizable amounts of SnP. These findings suggest that SnP causes a decrease of functional hemoprotein and partial loss of enzymic activity by displacing intracellular heme.

  18. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice

    PubMed Central

    Sala-Vila, Aleix; Navarro-Lérida, Inmaculada; Sánchez-Alvarez, Miguel; Bosch, Marta; Calvo, Carlos; López, Juan Antonio; Calvo, Enrique; Ferguson, Charles; Giacomello, Marta; Serafini, Annalisa; Scorrano, Luca; Enriquez, José Antonio; Balsinde, Jesús; Parton, Robert G.; Vázquez, Jesús; Pol, Albert; Del Pozo, Miguel A.

    2016-01-01

    The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed. PMID:27272971

  19. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice.

    PubMed

    Sala-Vila, Aleix; Navarro-Lérida, Inmaculada; Sánchez-Alvarez, Miguel; Bosch, Marta; Calvo, Carlos; López, Juan Antonio; Calvo, Enrique; Ferguson, Charles; Giacomello, Marta; Serafini, Annalisa; Scorrano, Luca; Enriquez, José Antonio; Balsinde, Jesús; Parton, Robert G; Vázquez, Jesús; Pol, Albert; Del Pozo, Miguel A

    2016-01-01

    The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed. PMID:27272971

  20. Role of BAF60a/BAF60c in chromatin remodeling and hepatic lipid metabolism.

    PubMed

    Zhang, Ping; Li, Lulu; Bao, Zhengxi; Huang, Feiruo

    2016-01-01

    The switching defective/sucrose non-fermenting (SWI/SNF) complexes play an important role in hepatic lipid metabolism regulating both transcriptional activation and repression. BAF60a is a core subunit of the SWI/SNF chromatin-remodeling complexes that activates the transcription of fatty acid oxidation genes during fasting/glucagon. BAF60c, another subunit of SWI/SNF complexes, is recruited to form the lipoBAF complex that activates lipogenic genes, promoting lipogenesis and increasing the triglyceride level in response to feeding/insulin. Interestingly, hepatocytes located in the periportal and perivenous zones of the liver display a remarkable heterogeneity in the activity of various enzymes, metabolic functions and gene expression. Especially, fatty-acid oxidation was shown to be mostly periportal, whereas lipogenesis was mostly perivenous. Therefore, the present review highlights the role of of SWI/SNF regulating lipid metabolism under nutritional and hormonal control, which may be associated with hepatocyte heterogeneity. PMID:27127533

  1. How aluminum, an intracellular ROS generator promotes hepatic and neurological diseases: the metabolic tale.

    PubMed

    Han, Sungwon; Lemire, Joseph; Appanna, Varun P; Auger, Christopher; Castonguay, Zachary; Appanna, Vasu D

    2013-04-01

    Metal pollutants are a global health risk due to their ability to contribute to a variety of diseases. Aluminum (Al), a ubiquitous environmental contaminant is implicated in anemia, osteomalacia, hepatic disorder, and neurological disorder. In this review, we outline how this intracellular generator of reactive oxygen species (ROS) triggers a metabolic shift towards lipogenesis in astrocytes and hepatocytes. This Al-evoked phenomenon is coupled to diminished mitochondrial activity, anerobiosis, and the channeling of α-ketoacids towards anti-oxidant defense. The resulting metabolic reconfiguration leads to fat accumulation and a reduction in ATP synthesis, characteristics that are common to numerous medical disorders. Hence, the ability of Al toxicity to create an oxidative environment promotes dysfunctional metabolic processes in astrocytes and hepatocytes. These molecular events triggered by Al-induced ROS production are the potential mediators of brain and liver disorders. PMID:23463459

  2. Hepatic drug metabolizing profile of Flinders Sensitive Line rat model of depression.

    PubMed

    Kotsovolou, Olga; Ingelman-Sundberg, Magnus; Lang, Matti A; Marselos, Marios; Overstreet, David H; Papadopoulou-Daifoti, Zoi; Johanson, Inger; Fotopoulos, Andrew; Konstandi, Maria

    2010-08-16

    The Flinders Sensitive Line (FSL) rat model of depression exhibits some behavioral, neurochemical, and pharmacological features that have been reported in depressed patients and has been very effective in screening antidepressants. Major factor that determines the effectiveness and toxicity of a drug is the drug metabolizing capacity of the liver. Therefore, in order to discriminate possible differentiation in the hepatic drug metabolism between FSL rats and Sprague-Dawley (SD) controls, their hepatic metabolic profile was investigated in this study. The data showed decreased glutathione (GSH) content and glutathione S-transferase (GST) activity and lower expression of certain major CYP enzymes, including the CYP2B1, CYP2C11 and CYP2D1 in FSL rats compared to SD controls. In contrast, p-nitrophenol hydroxylase (PNP), 7-ethoxyresorufin-O-dealkylase (EROD) and 16alpha-testosterone hydroxylase activities were higher in FSL rats. Interestingly, the wide spread environmental pollutant benzo(alpha)pyrene (B(alpha)P) induced CYP1A1, CYP1A2, CYP2B1/2 and ALDH3c at a lesser extend in FSL than in SD rats, whereas the antidepressant mirtazapine (MIRT) up-regulated CYP1A1/2, CYP2C11, CYP2D1, CYP2E1 and CYP3A1/2, mainly, in FSL rats. The drug also further increased ALDH3c whereas suppressed GSH content in B(alpha)P-exposed FSL rats. In conclusion, several key enzymes of the hepatic biotransformation machinery are differentially expressed in FSL than in SD rats, a condition that may influence the outcome of drug therapy. The MIRT-induced up-regulation of several drug-metabolizing enzymes indicates the critical role of antidepressant treatment that should be always taken into account in the designing of treatment and interpretation of insufficient pharmacotherapy or drug toxicity. PMID:20595028

  3. Effects of atrazine on hepatic metabolism and endocrine homeostasis in rainbow trout (Oncorhynchus mykiss)

    SciTech Connect

    Salaberria, Iurgi Hansen, Bjorn Henrik; Asensio, Vega; Olsvik, Pal A.; Andersen, Rolf A.; Jenssen, Bjorn Munro

    2009-01-01

    The herbicide atrazine (ATZ) is one of the most widely used pesticides in the world and is now under scrutiny for its alleged capacity to disrupt the endocrine system. Exhibiting negligible interaction with the estrogen receptor (ER), ATZ's mode of action remains to be elucidated. ATZ may act as an inducer of the enzyme aromatase, which converts androgens to estrogens, although other mechanisms should also be taken into consideration such as impairment of hepatic metabolism. Therefore we administered juvenile rainbow trout (Oncorhynchus mykiss) a dose of either 2 or 200 {mu}g ATZ/kg, or of carrier control phosphate buffered saline (PBS) and we measured plasma concentrations of testosterone (T), 17beta-estradiol (E2) and vitellogenin (Vtg) 6 days after exposure. Simultaneously we analyzed hepatic gene expression of cytochrome P450 (CYP) 1A and pi-class glutathione S-transferase (GST-P), and catalase (CAT) activity. Although sex steroid levels showed no significant alterations, we found a dose-dependent increase in Vtg and a concomitant decrease in CYP1A. There was no effect of ATZ on GST-P mRNA levels but GST-P was positively correlated with CYP1A. Also, CYP1A was negatively correlated with liver CAT and E2, and varied with T concentrations in a hormetic manner. The results showed that ATZ can alter hepatic metabolism, induce estrogenic effects and oxidative stress in vivo, and that these effects are linked.

  4. Glucose absorption, hormonal release and hepatic metabolism after guar gum ingestion

    NASA Technical Reports Server (NTRS)

    Simoes Nunes, C.; Malmlof, K.

    1992-01-01

    Six non-anaesthetized Large White pigs (mean body weight 59 +/- 1.7 kg) were fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein and with electromagnetic flow probes around the portal vein and the hepatic artery. The animals were provided a basal none-fibre diet (diet A) alone or together with 6% guar gum (diet B) or 15% purified cellulose (diet C). The diets were given for 1 week and according to a replicated 3 x 3 latin-square design. On the last day of each adaptation period test meals of 800 g were given prior to blood sampling. The sampling was continued for 8 h. Guar gum strongly reduced the glucose absorption as well as the insulin, gastric inhibitory polypeptide (GIP) and insulin-like growth factor-1 (IGF-1) production. However, the reduction in peripheral blood insulin levels caused by guar gum was not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly produced by the gut. The liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut produced IGF-1. Guar gum ingestion also appeared to decrease pancreatic glucagon secretion. Cellulose at the level consumed had very little effect on the parameters considered. It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the latter internal metabolic effects.

  5. Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene*

    PubMed Central

    Tao, Rongya; Wei, Dan; Gao, Hanlin; Liu, Yunlong; DePinho, Ronald A.; Dong, X. Charlie

    2011-01-01

    FoxO transcription factors have been implicated in lipid metabolism; however, the underlying mechanisms are not well understood. Here, in an effort to elucidate such mechanisms, we examined the phenotypic consequences of liver-specific deletion of three members of the FoxO family: FoxO1, FoxO3, and FoxO4. These liver-specific triply null mice, designated LTKO, exhibited elevated triglycerides in the liver on regular chow diet. More remarkably, LTKO mice developed severe hepatic steatosis following placement on a high fat diet. Further analyses revealed that hepatic NAD+ levels and Sirt1 activity were decreased in the liver of the LTKO mice relative to controls. At the mechanistic level, expression profile analyses showed that LTKO livers had significantly down-regulated expression of the nicotinamide phosphoribosyltransferase (Nampt) gene encoding the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis. Luciferase reporter assays and chromatin immunoprecipitation analyses demonstrated that Nampt is a transcriptional target gene of FoxOs. Significantly, overexpression of Nampt gene reduced, whereas knockdown increased, hepatic triglyceride levels in vitro and in vivo. Thus, FoxOs control the Nampt gene expression and the NAD+ signaling in the regulation of hepatic triglyceride homeostasis. PMID:21388966

  6. Association between hepatitis B and metabolic syndrome: Current state of the art

    PubMed Central

    Jarcuska, Peter; Drazilova, Sylvia; Fedacko, Jan; Pella, Daniel; Janicko, Martin

    2016-01-01

    Chronic hepatitis B (CHB) is a global health issue that increases the risk of liver cirrhosis and hepatocellular carcinoma in infected patients. Metabolic syndrome (MetS) is a disease endemic mostly to the developed countries. It is associated with high cardiovascular mortality and morbidity, diabetes mellitus as well as cancer. In this manuscript, we systematically review the published data on the relationship between MetS and CHB infection. Multiple studies have described highly variable correlations between CHB on one hand and MetS, non-alcoholic fatty liver disease and dyslipidemia on the other. No association between CHB and diabetes mellitus or atherosclerosis has been described as of now. The presence of MetS in patients infected with hepatitis B virus increases the risk of fibrosis, cirrhosis and hepatocellular carcinoma. Appropriate lifestyle, but also pharmacological interventions are needed to prevent the development of these complications. PMID:26755867

  7. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age

    SciTech Connect

    Keith, Dove; Finlay, Liam; Butler, Judy; Gómez, Luis; Smith, Eric; Moreau, Régis; Hagen, Tory

    2014-07-18

    Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.

  8. 1-Deoxynojirimycin Alleviates Liver Injury and Improves Hepatic Glucose Metabolism in db/db Mice.

    PubMed

    Liu, Qingpu; Li, Xuan; Li, Cunyu; Zheng, Yunfeng; Wang, Fang; Li, Hongyang; Peng, Guoping

    2016-01-01

    The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg·kg(-1)·day(-1)), DNJ-40 (DNJ 40 mg·kg(-1)·day(-1)) and DNJ-80 (DNJ 80 mg·kg(-1)·day(-1)). All doses were treated intravenously by tail vein for four weeks. DNJ was observed to significantly reduce the levels of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and liver TG, as well as activities of serum alanine aminotransferase (ALT), and aspartate transaminase (AST); DNJ also alleviated macrovesicular steatosis and decreased tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) levels in liver tissue. Furthermore, DNJ treatment significantly increased hepatic glycogen content, the activities of hexokinase (HK), pyruvate kinase (PK) in liver tissue, and decreased the activities of glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, DNJ increased the phosphorylation of phosphatidylinositol 3 kinase (PI3K) on p85, protein kinase B (PKB) on Ser473, glycogen synthase kinase 3β (GSK-3β) on Ser9, and inhibited phosphorylation of glycogen synthase (GS) on Ser645 in liver tissue of db/db mice. These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin-stimulated PKB/GSK-3β signal pathway and by modulating glucose metabolic enzymes in db/db mice. Moreover, DNJ also can improve lipid homeostasis and attenuate hepatic steatosis in db/db mice. PMID:26927057

  9. Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR

    PubMed Central

    de Vries, E. M.; Lammers, L. A.; Achterbergh, R.; Klümpen, H-J; Mathot, R. A. A.; Boelen, A.; Romijn, J. A.

    2016-01-01

    Introduction Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. Methods To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). Results Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. Conclusion We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR. PMID

  10. Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression

    PubMed Central

    Jia, Hong-mei; Li, Qi; Zhou, Chao; Yu, Meng; Yang, Yong; Zhang, Hong-wu; Ding, Gang; Shang, Hai; Zou, Zhong-mei

    2016-01-01

    Depression is a complex disease characterized by a series of pathological changes. Research on depression is mainly focused on the changes in brain, but not on liver. Therefore, we initially explored the metabolic profiles of hepatic extracts from rats treated with chronic unpredictive mild stress (CUMS) by UPLC-Q-TOF/MS. Using multivariate statistical analysis, a total of 26 altered metabolites distinguishing CUMS-induced depression from normal control were identified. Using two-stage receiver operating characteristic (ROC) analysis, 18 metabolites were recognized as potential biomarkers related to CUMS-induced depression via 12 metabolic pathways. Subsequently, we detected the mRNA expressions levels of apoptosis-associated genes such as Bax and Bcl-2 and four key enzymes including Pla2g15, Pnpla6, Baat and Gad1 involved in phospholipid and primary bile acid biosynthesis in liver tissues of CUMS rats by real-time qRT-PCR assay. The expression levels of Bax, Bcl-2, Pla2g15, Pnpla6 and Gad1 mRNA were 1.43,1.68, 1.74, 1.67 and 1.42-fold higher, and those of Baat, Bax/Bcl-2 ratio mRNA were 0.83, 0.85-fold lower in CUMS rats compared with normal control. Results of liver-targeted metabonomics and mRNA expression demonstrated that CUMS-induced depression leads to variations in hepatic metabolic profile and gene expression, and ultimately results in liver injury. PMID:27006086

  11. Comparative effect of nitroarenes and their parent arenes on hepatic drug and carcinogen metabolism in rats

    SciTech Connect

    Asokan, P.; Das, M.; Bickers, D.; Mukhtar, H.

    1986-03-01

    The effect of a single topical application of several nitroarenes (1-nitropyrene, nitropyrenes mixture, nitrobenzo(ghi)perylenes mixture, 3-nitrofluoranthene (3-NF), nitrofluoranthenes mixture (NFM), and nitroperylenes mixture (NPM) and their corresponding parent arenes was studied for their effect on hepatic drug and carcinogen metabolism in neonatal rats. All compounds caused highly significant induction of aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin O-deethylase (ERD), 7-ethoxycoumarin O-deethylase activities, and benzo(a)pyrene (BP) metabolism. The induction by each nitroarene was significant when compared to controls or to their corresponding parent non-nitrated arenes. 1-Nitropyrene was least effective in this regard. The inducing effect of NFM and NP was closely similar to 3-methylcholanthrene (3-MC). Benzphentamine N-demethylase, NADPH-cytochrome c reductase, NADH-ferricyanide reductase activities and the levels of cytochrome P-450 and cytochrome b/sub 5/ remained uncharged following treatment with arenes or nitroarenes. However, a shift of approximately 1 nm to the blue region in the absorption of P-450 was observed in nitroarenes-treated animals. A single topical or parenteral administration of 3-NF or NFM to adult rats also resulted in significant induction of ERD and AHH activities and BP metabolism. The parent arene, fluoranthene was ineffective in this regard. The authors studies suggest that nitroarenes are inducers of hepatic monooxygenases and they resemble the 3-MC type of inducers in rats.

  12. Black leaf streak disease affects starch metabolism in banana fruit.

    PubMed

    Saraiva, Lorenzo de Amorim; Castelan, Florence Polegato; Shitakubo, Renata; Hassimotto, Neuza Mariko Aymoto; Purgatto, Eduardo; Chillet, Marc; Cordenunsi, Beatriz Rosana

    2013-06-12

    Black leaf streak disease (BLSD), also known as black sigatoka, represents the main foliar disease in Brazilian banana plantations. In addition to photosynthetic leaf area losses and yield losses, this disease causes an alteration in the pre- and postharvest behavior of the fruit. The aim of this work was to investigate the starch metabolism of fruits during fruit ripening from plants infected with BLSD by evaluating carbohydrate content (i.e., starch, soluble sugars, oligosaccharides, amylose), phenolic compound content, phytohormones, enzymatic activities (i.e., starch phosphorylases, α- and β-amylase), and starch granules. The results indicated that the starch metabolism in banana fruit ripening is affected by BLSD infection. Fruit from infested plots contained unusual amounts of soluble sugars in the green stage and smaller starch granules and showed a different pattern of superficial degradation. Enzymatic activities linked to starch degradation were also altered by the disease. Moreover, the levels of indole-acetic acid and phenolic compounds indicated an advanced fruit physiological age for fruits from infested plots. PMID:23692371

  13. OCT1 mediates hepatic uptake of sumatriptan and loss-of-function OCT1 polymorphisms affect sumatriptan pharmacokinetics.

    PubMed

    Matthaei, J; Kuron, D; Faltraco, F; Knoch, T; Dos Santos Pereira, J N; Abu Abed, M; Prukop, T; Brockmöller, J; Tzvetkov, M V

    2016-06-01

    The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP(+) . Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 (P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment. PMID:26659468

  14. Studies on the hormonal regulation of hepatic metabolism

    SciTech Connect

    Conricode, K.M.

    1990-01-01

    The effects of hormones on glycolysis, glycogenolysis, and the pentose phosphate pathway in freshly isolated rat hepatocytes were studied. Epidermal growth factor (EGF) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulated glycolysis, as measured by lactate production. Both of these agents also increased [sup 3]H[sub 2]O release from [3-[sup 3]H]glucose, a measure of flux through phosphofructo-1-kinase, the key regulatory enzyme of glycolysis. The stimulations of glycolysis were not secondary to stimulation of glycogenolysis, since neither EGF nor TPA affected glucose production by hepatocytes. EGF, but not TPA, produced a small increase in the level of fructose 2,6-bisphosphate, an activator of phosphofructo-1-kinase. Both EGF and TPA produced a small decrease in the level of citrate, an inhibitor of phosphofructo-1-kinase. In addition, both of these agents stimulated flux through the pentose phosphate pathway, as measured by [sup 14]CO[sub 2] production from [1-[sup 14]C]glucose. The similar effects of EGF and TPA suggest that protein kinase C may be a mediator of EGF action in hepatocytes. EGF and vasopressin, a Ca[sup 2+]-mobilizing hormone in liver, stimulated glycolysis in Ca[sup 2+]-depleted cells, in which hormones are unable to mobilize Ca[sup 2+] from internal pools. This suggests that protein kinase C is also involved in the stimulation of glycolysis by vasopressin. The hypothesis that regulation of phospholipase A[sub 2] by specific inhibitory proteins is involved in hormone action was also examined. Several proteins were found to inhibit or stimulate phospholipase A[sub 2] in vitro in a fashion that was entirely dependent upon assay conditions. The nonspecificity of proteins an the variation of effects with assay condition casts doubt on the importance of this mechanism of regulation in cellular signal transduction.

  15. [Hepatic steatosis, visceral fat and metabolic alterations in apparently healthy overweight/obese individuals].

    PubMed

    Ryder, Elena; Mijac, Volga; Fernández, Erika; Palazzi, Nora; Morales, María Carolina; Connell, Lissette; Parra, Agner; Romero, Marlon; Fernández, Nelson

    2014-03-01

    Clinical observation indicates that many obese individuals do not display important metabolic alterations. Consequently, the objective of this study was to establish whether simple obesity, non concurrent with other important risk factors, was associated with metabolic alterations; or if the phenomenon known as "obesity paradox" was present. A clinical history, measurements of anthropometric and metabolic parameters and estimation of hepatic steatosis and visceral fat, were determined in 30, apparently healthy, individuals from Maracaibo, Venezuela, between 20 and 59 years of age and a body mass index (BMI) above 25 kg/m2, and compared to a lean control group of 11 individuals with BMI less than 25 kg/m2. The study demonstrated that only one third of overweight/obese individuals (OW/OB), with high body mass index (BMI) and waist circumference (WC), presented elevated values of insulin, HOMA-IR and triglycerides. Nevertheless, the presence of hepatic steatosis was elevated in the OW/OB group (91%) vs. 9% in the control group. The visceral fat in the lean control group was associated with both, WC and glycemia; however, it was not related to the BMI or insulin, HOMA-IR and HDLc. The visceral fat in the OW/OB group, although elevated in relation to the lean group, revealed a loss of these associations. In the OW/OB it was the BMI that was associated with insulin and HOMA-IR. The results emphasize the importance of investigating for the presence of hepatic steatosis, rather than visceral fat, in individuals with OW/OB, to identify subjects with high cardiometabolic risk. PMID:24758097

  16. Effects of petroleum on adrenocortical activity and on hepatic naphthalene-metabolizing activity in mallard ducks

    USGS Publications Warehouse

    Gorsline, J.; Holmes, W.N.

    1981-01-01

    Unstressed mallard ducks (Anas platyrhychos), given uncontaminated food and maintained on a short photoperiod, show two daily maxima in plasma corticosterone concentration ([B]); one occurring early in the light phase and a second just before the onset of darkness. After one week of exposure to food containing 3% (v/w) South Louisiana crude oil, plasma [B] were significantly lowered throughout the day. Similar abrupt declines in plasma [B] also occurred during the first 10 days of exposure to food containing 1% and 0.5% crude oil. Although the plasma [B] in birds consuming food contaminated with 0.5% crude oil increased between 10 and 50 days of exposure, the concentration after 50 days was still lower than normal. During the same interval, normal plasma [B] were restored in birds consuming food containing 1% and 3% crude oil. Significant increases occurred in the naphthalene-metabolizing properties of hepatic microsomes prepared from birds acutely exposed to all levels of petroleum-contaminated food and elevated levels were sustained throughout the first 50 days of exposure. Birds given food containing 3% crude oil for more than 50 days, however, showed steady declines in hepatic naphthalene-metabolizing activity. After 500 days, the activity was similar to that found in contemporaneous controls. During the same interval, the plasma [B] increased until the levels were higher than normal after 500 days of exposure; at this time, an inverse relationship, similar to that seen during the first week of exposure to contaminated food, was once more established between plasma [B] and the concomitant hepatic naphthalene-metabolizing activity.

  17. Lipoprotein Metabolism during Acute Inhibition of Hepatic Triglyceride Lipase in the Cynomolgus Monkey

    PubMed Central

    Goldberg, Ira J.; Le, Ngoc-Anh; Paterniti, James R.; Ginsberg, Henry N.; Lindgren, Frank T.; Brown, W. Virgil

    1982-01-01

    The role of the enzyme hepatic triglyceride lipase was investigated in a primate model, the cynomolgus monkey. Antisera produced against human postheparin hepatic lipase fully inhibited cynomolgus monkey posttheparin plasma hepatic triglyceride lipase activity. Lipoprotein lipase activity was not inhibited by this antisera. Hepatic triglyceride lipase activity in liver biopsies was decreased by 65-90% after intravenous infusion of this antisera into the cynomolgus monkey. After a 3-h infusion of the antisera, analytic ultracentrifugation revealed an increase in mass of very low density lipoproteins (Sf 20-400). Very low density lipoprotein triglyceride isolated by isopycnic ultracentrifugation increased by 60-300%. Analytic ultracentrifugation revealed an increase in mass of lipoproteins with flotation greater than Sf 9 (n = 4). The total mass of intermediate density lipoproteins (Sf 12-20) approximately doubled during the 3 h of in vivo enzyme inhibition. While more rapidly floating low density lipoproteins (Sf 9-12) increased, the total mass of low density lipoproteins decreased after infusion of the antibodies. The changes in high density lipoproteins did not differ from those in control experiments. In order to determine whether the increases of plasma concentrations of very low density lipoproteins were due to an increase in the rate of synthesis or a decrease in the rate of clearance of these particles, the metabolism of radiolabeled homologous very low density lipoproteins was studied during intravenous infusion of immunoglobulin G prepared from the antisera against hepatic triglyceride lipase (n = 3) or preimmune goat sera (n = 3). Studies performed in the same animals during saline infusion were used as controls for each immunoglobulin infusion. There was a twofold increase in the apparent half-life of the very low density lipoprotein apolipoprotein-B tracer in animals receiving the antibody, consistent with a decreased catabolism of very low density

  18. Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

    PubMed Central

    Dixon, John; Lane, Katie; MacPhee, Iain; Philips, Barbara

    2014-01-01

    Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth. PMID:24531139

  19. Hepatic glucagon metabolism. Correlation of hormone processing by isolated canine hepatocytes with glucagon metabolism in man and in the dog.

    PubMed Central

    Hagopian, W A; Tager, H S

    1987-01-01

    We have found that canine and rat hepatocytes convert (125I)iodoTyr10-glucagon to a peptide metabolite lacking the NH2-terminal three residues of the hormone. The peptide is released into the cell incubation medium and its formation is unaffected by a variety of lysosomotropic or other agents. Use of specific radioimmunoassays and gel filtration demonstrated in both normal subjects and in chronic renal failure patients a plasma peptide having the properties of the hormone fragment identified by cell studies. Studies of the dog revealed a positive gradient of the fragment across the liver and no differential gradient of the fragment and glucagon across the kidney. We conclude that the glucagon fragment arises from the cell-mediated processing of the hormone on a superficial aspect of the hepatocyte, the glucagon fragment identified during experiments in vitro represents the cognate of a peptide formed during the hepatic metabolism of glucagon in vivo, and measurement of the fragment by COOH-terminal radioimmunoassays could lead to an understimulation of hepatic glucagon extraction. PMID:2879853

  20. Interspecies differences in the hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin: role in toxicity

    SciTech Connect

    Wroblewski, V.J.

    1987-01-01

    These studies examined the hepatic metabolism of TCDD in suspensions of isolated hepatocytes from the guinea pig and hamster. /sup 14/C- TCDD was metabolized at a similar rate in hepatocytes from the three species. TCDD pretreatment 72 hours prior to hepatocyte isolation increased cytochrome P-448-mediated monooxygenase activities and increased the rate of TCDD metabolism in rat and hamster hepatocytes 5-6-fold over the control rate. However, pretreatment of guinea pigs with TCDD had not effect on the rate of /sup 14/C-TCDD metabolism in isolated hepatocytes from this species. The findings suggest that the inability of TCDD to induce its own rate of hepatic metabolism in the guinea pig may contribute to the persistence of TCDD and unique sensitivity of this species to the acute toxicity of TCDD.

  1. The seeds from Plantago ovata lower plasma lipids by altering hepatic and bile acid metabolism in guinea pigs.

    PubMed

    Romero, Ana Lourdes; West, Kristy L; Zern, Tosca; Fernandez, Maria Luz

    2002-06-01

    Psyllium, the husks from Plantago ovata (PO), is recognized as a potent agent in lowering plasma cholesterol. In this study, we tested the potential hypolipidemic effects of the seeds from PO and the mechanisms associated with the lowering of plasma lipids. Male Hartley guinea pigs (n = 30; 10 per group) were fed either a control diet or diets containing 7.5 or 10 g/100 g PO for 4 wk. Diets were identical in composition except for the fiber source. The control diet contained 10 g/100 g cellulose and 2.5 g/100 g guar gum, whereas the PO diets were adjusted to a total of 12.5 g/100 g fiber with cellulose. Although a dose response was not observed, plasma triglycerides and LDL cholesterol were 34 and 23% lower in the PO groups compared with the control (P < 0.01). Lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activities were significantly affected by the PO diets. The control group had 100 and 36% higher LCAT and CETP (P < 0.01) activities, respectively, compared with the PO groups. Hepatic total and free cholesterol concentrations were not affected by PO, but cholesteryl ester concentrations were 50% (P < 0.01) lower in the PO groups compared with the control. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis was up-regulated in the PO groups by 37%. Similarly, the activity of cholesterol 7alpha-hydroxylase, the regulatory enzyme of cholesterol catabolism to bile acids was 33% higher in the PO groups (P < 0.02). Fecal bile acids were 3 times higher in the PO groups than in the control group. These results suggest that PO exerts its hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism. PMID:12042433

  2. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    PubMed

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome. PMID:24816278

  3. From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations

    PubMed Central

    Green, Charlotte J.; Pramfalk, Camilla; Morten, Karl J.

    2014-01-01

    The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD. PMID:25352434

  4. Deregulation of energy metabolism promotes antifibrotic effects in human hepatic stellate cells and prevents liver fibrosis in a mouse model.

    PubMed

    Karthikeyan, Swathi; Potter, James J; Geschwind, Jean-Francois; Sur, Surojit; Hamilton, James P; Vogelstein, Bert; Kinzler, Kenneth W; Mezey, Esteban; Ganapathy-Kanniappan, Shanmugasundaram

    2016-01-15

    Liver fibrosis and cirrhosis result from uncontrolled secretion and accumulation of extracellular matrix (ECM) proteins by hepatic stellate cells (HSCs) that are activated by liver injury and inflammation. Despite the progress in understanding the biology liver fibrogenesis and the identification of potential targets for treating fibrosis, development of an effective therapy remains elusive. Since an uninterrupted supply of intracellular energy is critical for the activated-HSCs to maintain constant synthesis and secretion of ECM, we hypothesized that interfering with energy metabolism could affect ECM secretion. Here we report that a sublethal dose of the energy blocker, 3-bromopyruvate (3-BrPA) facilitates phenotypic alteration of activated LX-2 (a human hepatic stellate cell line), into a less-active form. This treatment-dependent reversal of activated-LX2 cells was evidenced by a reduction in α-smooth muscle actin (α-SMA) and collagen secretion, and an increase in activity of matrix metalloproteases. Mechanistically, 3-BrPA-dependent antifibrotic effects involved down-regulation of the mitochondrial metabolic enzyme, ATP5E, and up-regulation of glycolysis, as evident by elevated levels of lactate dehydrogenase, lactate production and its transporter, MCT4. Finally, the antifibrotic effects of 3-BrPA were validated in vivo in a mouse model of carbon tetrachloride-induced liver fibrosis. Results from histopathology & histochemical staining for collagen and α-SMA substantiated that 3-BrPA promotes antifibrotic effects in vivo. Taken together, our data indicate that sublethal, metronomic treatment with 3-BrPA blocks the progression of liver fibrosis suggesting its potential as a novel therapeutic for treating liver fibrosis. PMID:26525850

  5. Impact of gender and menopausal status on metabolic parameters in chronic hepatitis C infection.

    PubMed

    Gonzales, C A; Bacchetti, P; Khalili, M

    2016-03-01

    Hepatitis C infection (HCV) and menopause are associated with insulin resistance (IR), and IR accelerates HCV-induced liver disease. The relationship between menopause and IR has not been studied in this population. This study aimed to assess the impact of menopause on IR and metabolic syndrome in HCV. One hundred and three (69 men, 16 premenopausal, 18 postmenopausal women) noncirrhotic, nondiabetic HCV-infected adults underwent IR measurement via steady-state plasma glucose during a 240-min insulin suppression test. Metabolic syndrome was defined by at least three of five standard laboratory/clinical criteria. The patient characteristics were as follows: mean age 48 years, waist circumference 94.4 ± 12.4 cm and 37.9% Caucasian. SSPG was higher in postmenopausal than premenopausal women or men (mean difference 18, 95% CI -41 to 76 and 35, 95% CI -3 to 72 mg/dL; respectively). After adjusting for waist circumference, female gender, nonwhite race and triglycerides were positively associated and high-density lipoprotein negatively associated with steady-state plasma glucose. Compared to men, both pre- (Coef 48, 95% CI 12-84) and postmenopausal women (Coef 49, 95% CI 17-82) had higher steady-state plasma glucose. Compared to premenopausal women, men (OR 2.0, 95% CI 0.38-10.2) and postmenopausal women (OR 2.9, 95% CI 0.46-18.8) had higher odds of metabolic syndrome, but this was statistically nonsignificant. Both liver inflammation (OR 7.9) and nonwhite race (OR 6.9) were associated with metabolic syndrome. We conclude that women are at inc-reased risk for IR in HCV. There may also be an increased risk of metabolic syndrome postmenopause. Along with lifestyle modification and weight loss, women with metabolic abnormalities represent an especially at-risk group warranting HCV treatment to prevent adverse metabolic outcomes. PMID:26554398

  6. Identification of plasma and hepatic parameters related to metabolic robustness in dairy cows.

    PubMed

    Graber, M; Kohler, S; Müller, A; Burgermeister, K; Kaufmann, T; Bruckmaier, R M; van Dorland, H A

    2012-02-01

    Blood plasma and hepatic parameters were identified that describe the differences between metabolically robust or vulnerable dairy cows grouped according to their past health status. Data from a field study on dairy cows were used from which metabolically challenged dairy cows were selected that had a milk fat percentage of >4.5 mg/g and a fat to protein ratio of >1.5 in their previous early lactation. The selected cows were either classified as metabolically robust or vulnerable based on the occurrence of various metabolic and (re)production disorders in their previous lactations. Blood and liver tissue samples were collected in week 3 ante partum (a.p.) (-3 wk), in week 4 (+4 wk) and in week 13 (+13 wk) post-partum (p.p.). Plasma concentrations of metabolites and hormones and mRNA expression of genes involved in metabolic pathways in the liver were used as variables for a two-group discriminant analysis (DA). Average discriminant scores (centroids) were different (p < 0.05) in -3 wk, +4 wk and in +13 wk. In -3 wk, significant variables that best explained the differences between metabolically robust and vulnerable cows were parity, plasma triglycerides, glucose and mRNA abundance of carnitine palmitoyltransferase 2 (CPT2). In addition, based on the classification matrix, 69% of the dairy cows were correctly classified. In +4 wk, identified significant parameters were parity, plasma glucose and urea, and 67% of the cows were correctly classified. In +13 wk, significant variables that explained the differences between the groups were parity, mRNA abundance of acyl-CoA synthetase long-chain 1 and CPT1, and 66% of the cows were correctly classified. In conclusion, the identified variables may distinguish from metabolically challenged cows, those cows that had a poorer health performance in their previous lactations. PMID:21244526

  7. Effects of methapyrilene on rat hepatic xenobiotic metabolizing enzymes and liver morphology.

    PubMed

    Graichen, M E; Neptun, D A; Dent, J G; Popp, J A; Leonard, T B

    1985-02-01

    Short-term treatment of rats with hepatocarcinogens elicits a consistent pattern of phenotypic changes in hepatic drug metabolizing enzymes, the most striking of which is a marked increase in microsomal epoxide hydrolase (EH) activity. The antihistaminic drug methapyrilene induces a high incidence of hepatocellular carcinoma in F-344 rats. The studies reported here were designed to assess the effects of methapyrilene on hepatic EH activity, cytochrome P-450-dependent mixed-function oxidase activities, liver morphology, and liver-derived serum enzymes. Male F-344 rats were treated with three daily oral doses of methapyrilene-HCl, up to 300 mg/kg/day, and were sacrificed 48 hr after the last dose. Hepatic microsomal EH and cytosolic DT-diaphorase activities were increased in a dose-related fashion, to 420 and 230% of control, respectively. Cytochrome P-450 content and benzphetamine-N-demethylase and ethoxycoumarin-O-deethylase activities were concomitantly decreased to 35-50% of control. Serum gamma-glutamyl transpeptidase and alanine aminotransferase activities were elevated 22- to 27-fold, and serum bile acids to 36-fold by treatment with methapyrilene. Periportal lesions, characterized by inflammation, nuclear and nucleolar enlargement, bile duct hyperplasia, and hepatocellular necrosis, were observed following methapyrilene administration. The severity of the periportal lesion correlated with elevations in the serum chemistry parameters. The increases noted in microsomal EH activity supports the suggestion that this enzyme may be a useful biochemical marker for exposure to hepatocarcinogens. PMID:2859228

  8. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells

    PubMed Central

    Pallett, Laura J.; Gill, Upkar S.; Quaglia, Alberto; Sinclair, Linda V.; Jover-Cobos, Maria; Schurich, Anna; Singh, Kasha P.; Thomas, Niclas; Das, Abhishek; Chen, Antony; Fusai, Giuseppe; Bertoletti, Antonio; Cantrell, Doreen A.; Kennedy, Patrick T.; Davies, Nathan A.; Haniffa, Muzlifah; Maini, Mala K.

    2015-01-01

    Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: it can replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSC) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSC (gMDSC) expanded transiently in acute resolving HBV, decreasing before peak hepatic injury. In persistent infection, arginase-expressing gMDSC (and circulating arginase) increased most in phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSC expressed liver-homing chemokine receptors and accumulated in the liver, their expansion being supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSC potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system-L amino acid transporters to increase uptake of essential nutrients and attempt metabolic reprogramming. These data demonstrate the capacity of expanded arginase-expressing gMDSC to regulate liver immunopathology in HBV infection. PMID:25962123

  9. Multiple dietary supplements do not affect metabolic and cardiovascular health.

    PubMed

    Soare, Andreea; Weiss, Edward P; Holloszy, John O; Fontana, Luigi

    2013-09-01

    Dietary supplements are widely used for health purposes. However, little is known about the metabolic and cardiovascular effects of combinations of popular over-the-counter supplements, each of which has been shown to have anti-oxidant, anti-inflammatory and pro-longevity properties in cell culture or animal studies. This study was a 6-month randomized, single-blind controlled trial, in which 56 non-obese (BMI 21.0-29.9 kg/m2) men and women, aged 38 to 55 yr, were assigned to a dietary supplement (SUP) group or control (CON) group, with a 6-month follow-up. The SUP group took 10 dietary supplements each day (100 mg of resveratrol, a complex of 800 mg each of green, black, and white tea extract, 250 mg of pomegranate extract, 650 mg of quercetin, 500 mg of acetyl-l-carnitine, 600 mg of lipoic acid, 900 mg of curcumin, 1 g of sesamin, 1.7 g of cinnamon bark extract, and 1.0 g fish oil). Both the SUP and CON groups took a daily multivitamin/mineral supplement. The main outcome measures were arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors. Twenty-four weeks of daily supplementation with 10 dietary supplements did not affect arterial stiffness or endothelial function in nonobese individuals. These compounds also did not alter body fat measured by DEXA, blood pressure, plasma lipids, glucose, insulin, IGF-1, and markers of inflammation and oxidative stress. In summary, supplementation with a combination of popular dietary supplements has no cardiovascular or metabolic effects in non-obese relatively healthy individuals. PMID:24036417

  10. Multiple dietary supplements do not affect metabolic and cardiovascular health

    PubMed Central

    Holloszy, John O.; Fontana, Luigi

    2014-01-01

    Dietary supplements are widely used for health purposes. However, little is known about the metabolic and cardiovascular effects of combinations of popular over-the-counter supplements, each of which has been shown to have anti-oxidant, anti-inflammatory and pro-longevity properties in cell culture or animal studies. This study was a 6-month randomized, single-blind controlled trial, in which 56 non-obese (BMI 21.0-29.9 kg/m2) men and women, aged 38 to 55 yr, were assigned to a dietary supplement (SUP) group or control (CON) group, with a 6-month follow-up. The SUP group took 10 dietary supplements each day (100 mg of resveratrol, a complex of 800 mg each of green, black, and white tea extract, 250 mg of pomegranate extract, 650 mg of quercetin, 500 mg of acetyl-l-carnitine, 600 mg of lipoic acid, 900 mg of curcumin, 1 g of sesamin, 1.7 g of cinnamon bark extract, and 1.0 g fish oil). Both the SUP and CON groups took a daily multivitamin/mineral supplement. The main outcome measures were arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors. Twenty-four weeks of daily supplementation with 10 dietary supplements did not affect arterial stiffness or endothelial function in nonobese individuals. These compounds also did not alter body fat measured by DEXA, blood pressure, plasma lipids, glucose, insulin, IGF-1, and markers of inflammation and oxidative stress. In summary, supplementation with a combination of popular dietary supplements has no cardiovascular or metabolic effects in non-obese relatively healthy individuals. PMID:24659610

  11. Effects of naturally occurring coumarins on hepatic drug-metabolizing enzymes inmice

    SciTech Connect

    Kleiner, Heather E. Xia, Xiaojun; Sonoda, Junichiro; Zhang, Jun; Pontius, Elizabeth; Abey, Jane; Evans, Ronald M.; Moore, David D.; DiGiovanni, John

    2008-10-15

    Cytochromes P450 (P450s) and glutathione S-transferases (GSTs) constitute two important enzyme families involved in carcinogen metabolism. Generally, P450s play activation or detoxifying roles while GSTs act primarily as detoxifying enzymes. We previously demonstrated that oral administration of the linear furanocoumarins, isopimpinellin and imperatorin, modulated P450 and GST activities in various tissues of mice. The purpose of the present study was to compare a broader range of naturally occurring coumarins (simple coumarins, and furanocoumarins of the linear and angular type) for their abilities to modulate hepatic drug-metabolizing enzymes when administered orally to mice. We now report that all of the different coumarins tested (coumarin, limettin, auraptene, angelicin, bergamottin, imperatorin and isopimpinellin) induced hepatic GST activities, whereas the linear furanocoumarins possessed the greatest abilities to induce hepatic P450 activities, in particular P450 2B and 3A. In both cases, this corresponded to an increase in protein expression of the enzymes. Induction of P4502B10, 3A11, and 2C9 by xenobiotics often is a result of activation of the pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR). Using a pregnane X receptor reporter system, our results demonstrated that isopimpinellin activated both PXR and its human ortholog SXR by recruiting coactivator SRC-1 in transfected cells. In CAR transfection assays, isopimpinellin counteracted the inhibitory effect of androstanol on full-length mCAR, a Gal4-mCAR ligand-binding domain fusion, and restored coactivator binding. Orally administered isopimpinellin induced hepatic mRNA expression of Cyp2b10, Cyp3a11, and GSTa in CAR(+/+) wild-type mice. In contrast, the induction of Cyp2b10 mRNA by isopimpinellin was attenuated in the CAR(-/-) mice, suggesting that isopimpinellin induces Cyp2b10 via the CAR receptor. Overall, the current data indicate that naturally occurring coumarins have

  12. Hepatitis

    MedlinePlus

    ... be serious. Some can lead to scarring, called cirrhosis, or to liver cancer. Sometimes hepatitis goes away by itself. If it does not, it can be treated with drugs. Sometimes hepatitis lasts a lifetime. Vaccines can help prevent some viral forms.

  13. Associated Factors for Metabolic Syndrome in the Older Adults with Chronic Virus Hepatitis in the Community

    PubMed Central

    Kuo, Yuan-Hung; Tsai, Ming-Chao; Kee, Kwong-Ming; Chang, Kuo-Chin; Wang, Jing-Houng; Lin, Chun-Yin; Lin, Sheng-Che; Lu, Sheng-Nan

    2016-01-01

    This study was to evaluate the association between metabolic syndrome (MetS) and chronic virus hepatitis elders in the community. Those subjects with positive hepatitis B surface antigen (HBsAg) and/or anti-hepatitis C virus (anti-HCV) screened in the community before were invited to this study and 451 responded. All participants underwent anthropometric measurements, blood tests, ultrasound and fibroscan examinations. The cut-off of liver stiffness measurement-liver cirrhosis (LSM-LC) was 10 kPa for chronic hepatitis B (CHB) patients and 12 kPa for chronic hepatitis C (CHC) patients, respectively. Among 451 responders, 56 were excluded due to negative HBsAg or anti-HCV. Three hundreds and ninety-five subjects included 228 CHB patients, 156 CHC patients and 11 dual hepatitis patients, had a mean age of 62±12.6 years. Fifty-four (23.7%) CHB patients coexisted with MetS whereas 40 (25.6%) CHC patients also had MetS. Those patients with MetS had more LSM-LC cases than those without (20.4% vs 9.8%, p = 0.04 in CHB patients; 28.2% vs 13.5%, p = 0.037 in CHC patients, respectively). In multivariate logistic analysis, detectable viremia was reversely associated with MetS in CHB patients after adjustment for age, gender and body mass index (odds ratio (OR): 0.42; 95% confidence interval (CI): 0.18–0.99; p = 0.047). Regarding CHC patients, higher LSM level was the only factor contributed to MetS (OR: 1.1; 95% CI: 1.02–1.19; p = 0.012). In conclusion, elder CHB patients coexisted with MetS might experience an inactive virus replication but have an advanced liver fibrosis. In elder CHC patients, only higher LSM level was associated with MetS. PMID:27177024

  14. Oral Exposure of Mice to Carbendazim Induces Hepatic Lipid Metabolism Disorder and Gut Microbiota Dysbiosis.

    PubMed

    Jin, Yuanxiang; Zeng, Zhaoyang; Wu, Yan; Zhang, Songbin; Fu, Zhengwei

    2015-09-01

    Carbendazim (CBZ) has been considered as an endocrine disruptor that caused mammalian toxicity in different endpoints. Here, we revealed that oral administrations with CBZ at 100 and 500 mg/kg body weight for 28 days induced hepatic lipid metabolism disorder which was characterized by significant increases of hepatic lipid accumulation and triglyceride (TG) levels in mice. The serum cholesterol (TC), high-density lipoprotein, and low-density lipoprotein levels also increased after CBZ exposure. Correspondingly, the relative mRNA levels of some key genes related to lipogenesis and TG synthesis increased significantly both in the liver and fat. Moreover, the increase in serum IL-1β and IL-6 levels by the treatment of CBZ indicated the occurring of inflammation. Furthermore, the levels of bioaccumulation of CBZ in the liver and gut were very low as compared in the feces, indicating that most of CBZ stayed in gastrointestinal tract and interacted with gut microbiota until excreted. At phylum level, the amounts of the Bacteroidetes decreased significantly in the feces after 5 days CBZ exposure. High throughput sequencing of the 16S rRNA gene V3-V4 region revealed a significant reduction in richness and diversity of gut microbiota in the cecum of CBZ-treated mice. UniFrac principal coordinates analysis observed a marked shift of the gut microbiota structure in CBZ-treated mice away from that of the controls. More deeply, operational taxonomic units' analysis identified that a total of 361 gut microbes were significant changed. In CBZ-treated groups, the relative abundance of Firmicutes, Proteobacteria, and Actinobacteria increased and that of Bacteroidetes decreased. Our findings suggested that CBZ could lead hepatic lipid metabolism disorder and gut microbiota dysbiosis in mice. PMID:26071454

  15. Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

    PubMed Central

    Delgado, Miguel; Garrido, Francisco; Pérez-Miguelsanz, Juliana; Pacheco, María; Partearroyo, Teresa; Pérez-Sala, Dolores

    2014-01-01

    Abstract Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of

  16. Subchronic Exposure of Mice to Cadmium Perturbs Their Hepatic Energy Metabolism and Gut Microbiome.

    PubMed

    Zhang, Songbin; Jin, Yuanxiang; Zeng, Zhaoyang; Liu, Zhenzhen; Fu, Zhengwei

    2015-10-19

    Cadmium (Cd) is an environmental pollutant known to cause liver damage; however, the mechanisms of its hepatotoxicity remain poorly understood. In this study, the effects of subchronic exposure in mice to low doses of Cd on energy metabolism and the gut microbiome were evaluated. The exposure of mice to 10 mg/L Cd supplied in drinking water for 10 weeks increased hepatic triacylglycerol (TG), serum free fatty acid (FFA), and TG levels. The mRNA levels of several key genes involved in both de novo FFA synthesis and transport pathways and in TG synthesis in the liver also increased significantly in the Cd-treated mice, indicating that alterations of these genes may be a possible mechanism to explain subchronic Cd exposure induced hepatic toxicity at a molecular level. As for the gut microbiome, at the phylum level, the amounts of Firmicutes and γ-proteobacteria decreased significantly in the feces after 4 weeks of Cd exposure, and the quantity of Firmicutes decreased significantly in the cecum contents after 10 weeks of Cd exposure. In addition, 16S rRNA gene sequencing further revealed that Cd exposure significantly perturbed the gut microflora structure and richness at family and genus levels. The alteration of gut microbiome composition might result in an increase in serum lipopolysaccharide (LPS) and induce hepatic inflammation, which may indirectly cause perturbations of energy homeostasis after Cd exposure. Taken together, the present study indicated that subchronic Cd exposure caused the dysregulation of energy metabolism and changed the gut microbiome composition in mice. PMID:26352046

  17. Hepatitis B Vaccine

    MedlinePlus

    ... as a combination product containing Hepatitis A Vaccine, Hepatitis B Vaccine) ... What is hepatitis B?Hepatitis B is a serious infection that affects the liver. It is caused by the hepatitis B virus. ...

  18. Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats.

    PubMed

    Zhang, Min; Xie, Zongkai; Gao, Weina; Pu, Lingling; Wei, Jingyu; Guo, Changjiang

    2016-03-01

    Quercetin, a common member of the flavonoid family, is widely present in plant kingdom. Despite that quercetin is implicated in regulating cholesterol metabolism, the molecular mechanism is poorly understood. We hypothesized that quercetin regulates cholesterol homeostasis through regulating the key enzymes involved in hepatic cholesterol metabolism. To test this hypothesis, we compared the profile of key enzymes and transcription factors involved in the hepatic cholesterol metabolism in rats with or without quercetin supplementation. Twenty male Wistar rats were randomly divided into control and quercetin-supplemented groups. Serum total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total bile acids in feces and bile were measured. Hepatic enzymatic activities were determined by activity assay kit and high-performance liquid chromatography-based analyses. The messenger RNA (mRNA) and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. The results showed that the activity of hepatic cholesterol 7α-hydroxylase, a critical enzyme in the conversion of cholesterol to bile acids, was significantly elevated by quercetin. The expression of cholesterol 7α-hydroxylase, as well as liver X receptor α, an important transcription factor, was also increased at both mRNA and protein levels by quercetin. However, quercetin exposure had no impact on the activity of hepatic HMG-CoA reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. We also found that quercetin treatment significantly increased ATP binding cassette transporter G1 mRNA and protein expression in the liver, suggesting that quercetin may increase hepatic cholesterol efflux. Collectively, the results presented here indicate that quercetin regulates hepatic cholesterol metabolism mainly through the pathways that promote cholesterol-to-bile acid conversion and

  19. Human variation and CYP enzyme contribution in benfuracarb metabolism in human in vitro hepatic models.

    PubMed

    Abass, Khaled; Reponen, Petri; Mattila, Sampo; Rautio, Arja; Pelkonen, Olavi

    2014-01-13

    Human responses to the toxicological effects of chemicals are often complicated by a substantial interindividual variability in toxicokinetics, of which metabolism is often the most important factor. Therefore, we investigated human variation and the contributions of human-CYP isoforms to in vitro metabolism of benfuracarb. The primary metabolic pathways were the initial sulfur oxidation to benfuracarb-sulfoxide and the nitrogen-sulfur bond cleavage to carbofuran (activation). The Km, Vmax, and CL(int) values of carbofuran production in ten individual hepatic samples varied 7.3-, 3.4-, and 5.4-fold, respectively. CYP2C9 and CYP2C19 catalyzed benfuracarb sulphur oxidation. Carbofuran formation, representing from 79% to 98% of the total metabolism, was catalyzed predominantly by CYP3A4. The calculated relative contribution of CYP3A4 to carbofuran formation was 93%, while it was 4.4% for CYP2C9. The major contribution of CYP3A4 in benfuracarb metabolism was further substantiated by showing a strong correlation with CYP3A4-selective markers midazolam-1'-hydroxylation and omeprazole-sulfoxidation (r=0.885 and 0.772, respectively). Carbofuran formation was highly inhibited by the CYP3A inhibitor ketoconazole. Moreover, CYP3A4 marker activities were relatively inhibited by benfuracarb. These results confirm that human CYP3A4 is the major enzyme involved in the in vitro activation of benfuracarb and that CYP3A4-catalyzed metabolism is the primary source of interindividual differences. PMID:24016712

  20. Is hepatic lipid metabolism of beef cattle influenced by breed and dietary silage level?

    PubMed Central

    2014-01-01

    Background In ruminants, unsaturated dietary fatty acids are biohydrogenated in the rumen and are further metabolised in various tissues, including liver, which has an important role in lipid and lipoprotein metabolism. Therefore, manipulation of muscle fatty acid composition should take into account liver metabolism. In the present study, the influence of breed and diet on liver lipid composition and gene expression was investigated in order to clarify the role of this organ in the lipid metabolism of ruminants. Forty purebred young bulls from two phylogenetically distant autochthonous cattle breeds, Alentejana and Barrosã, were assigned to two different diets (low vs. high silage) and slaughtered at 18 months of age. Liver fatty acid composition, mRNA levels of enzymes and transcription factors involved in lipid metabolism, as well as the plasma lipid profile, were assessed. Results In spite of similar plasma non-esterified fatty acids levels, liver triacylglycerols content was higher in Barrosã than in Alentejana bulls. Moreover, the fatty acid composition of liver was clearly distinct from the remaining tissues involved in fatty acid metabolism of ruminants, as shown by Principal Components Analysis. The hepatic tissue is particularly rich in α-linolenic acid and their products of desaturation and elongation. Results indicate that DGAT1, ELOVL2, FADS1 and FADS2 genes influence the fatty acid composition of the liver the most. Moreover, genes such as DGAT1 and ELOVL2 appear to be more sensitive to genetic background than to dietary manipulation, whereas genes encoding for desaturases, such as FADS1, appear to be modulated by dietary silage level. Conclusions Our results indicate that liver plays an important role in the biosynthesis of n-3 LC-PUFA. It is also suggested that dietary silage level influences the hepatic fatty acid metabolism in a breed-dependent manner, through changes in the expression of genes encoding for enzymes associated with the

  1. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    SciTech Connect

    Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. |; Giometti, C.S.; Mishler, K.; Slavin, B.G.

    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 these 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.

  2. A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice.

    PubMed

    Grimsley, Aidan; Foster, Alison; Gallagher, Richard; Hutchison, Michael; Lundqvist, Anders; Pickup, Kathryn; Wilson, Ian D; Samuelsson, Kristin

    2014-12-15

    The hepatic cytochrome P450 reductase null (HRN) mouse, which has no functional hepatic Cyp P450s, may represent a useful model for examining extra-hepatic P450-related oxidative metabolism. Here the pharmacokinetics and metabolic fate of midazolam, a drug known to undergo such extra-hepatic metabolism, have been investigated in the HRN mouse and compared with a phenotypically normal strain (C57BL/6J). In addition, the effects of co-administration of the pan-P450 inhibitor 1'-aminobenzotriazole (ABT) on the metabolic profile have been compared in both strains. Significant pharmacokinetic differences for midazolam were observed between the two strains of mice with the HRN mice showing lower circulating concentrations of 1'-hydroxymidazolam but higher concentrations of 1'-hydroxymidazolam-O-glucuronide. A significant increase in midazolam exposure was seen upon ABT exposure for both strains of mice, but no differences in the area under the concentration time curves (AUC) for the monitored metabolites were observed. Although oxidative metabolism of midazolam was not abolished, significant decreases in 1'-hydroxymidazolam formation ratios were observed for both strains of mice exposed to ABT. Metabolite profiling of blood and bile showed a number of qualitative and quantitative differences between HRN and normal mice. These differences in midazolam metabolism between the two strains of mice clearly demonstrate the role that liver P450 enzymes play in the murine metabolism of midazolam. The fate of the compound in the HRN mice shows the importance of extrahepatic metabolism and also showed that these mice appear to be more capable of forming circulating phase II glucuronides than the normal strain. PMID:25450676

  3. Associations between hepatic metabolism of propionate and palmitate in liver slices from transition dairy cows.

    PubMed

    McCarthy, M M; Piepenbrink, M S; Overton, T R

    2015-10-01

    Multiparous Holstein cows (n=95) were used to evaluate changes in hepatic propionate and palmitate metabolism and liver composition over time during the transition period, along with the relationships of these variables with cumulative increases in nonesterified fatty acids and β-hydroxybutyrate during the periparturient period. Data from 3 previous experiments were used to address the study objectives, accounting for a total of 95 multiparous Holstein cows. Liver slices from biopsies on d -21, 1, and 21 relative to parturition were used to determine conversion of [1-(14)C]palmitate to CO2 and esterified products (EP) and the conversion of [1-(14)C]propionate to CO2 and glucose. Hepatic glycogen content was highest on d -21 and was 26.9 and 36.5% of prepartum values on d 1 and 21, respectively. Liver triglyceride content was lowest at d -21 and was 271 and 446% of prepartum values on d 1 and 21, respectively. We detected no difference in the capacity for the liver to oxidize [1-(14)C]palmitate to CO2 between d -21 and d 1; however, on d 21, oxidation was 84% of prepartum values. The capacity of the liver to convert [1-(14)C]palmitate to EP was 148 and 139% of prepartum values on d 1 and 21, respectively. The capacity of liver to convert [1-(14)C]propionate to CO2 was 127 and 83% of prepartum values on d 1 and 21, and the capacity of liver to convert [1-(14)C]propionate to glucose was 126 and 85% of prepartum values on d 1 and 21, respectively. Correlation relationships suggest that overall, cows with elevated prepartum liver triglyceride content had elevated triglycerides throughout the transition period along with increased [1-(14)C]palmitate oxidation and conversion to EP and a decreased propensity to convert [1-(14)C]propionate to glucose. Cows with increased [1-(14)C]propionate oxidation had increased conversion of [1-(14)C]propionate to glucose throughout the transition period. Overall, conditions that lead to impairments in fatty acid metabolism during the

  4. Three Peptides from Soy Glycinin Modulate Glucose Metabolism in Human Hepatic HepG2 Cells.

    PubMed

    Lammi, Carmen; Zanoni, Chiara; Arnoldi, Anna

    2015-01-01

    Ile-Ala-Val-Pro-Gly-Glu-Val-Ala (IAVPGEVA), Ile-Ala-Val-Pro-Thr-Gly-Val-Ala (IAVPTGVA) and Leu-Pro-Tyr-Pro (LPYP), three peptides deriving from soy glycinin hydrolysis, are known to regulate cholesterol metabolism in human hepatic HepG2 cells. We have recently demonstrated that the mechanism of action involves the activation of adenosine monophosphate-activated protein kinase (AMPK). This fact suggested a potential activity of the same peptides on glucose metabolism that prompted us to also investigate this aspect in the same cells. After treatment with IAVPGEVA, IAVPTGVA and LPYP, HepG2 cells were analyzed using a combination of molecular techniques, including western blot analysis, glucose uptake experiments and fluorescence microscopy evaluation. The results showed that these peptides are indeed able to enhance the capacity of HepG2 cells to uptake glucose, via glucose transporter 1 GLUT1 and glucose transporter 4 GLUT4 activation, through the stimulation of protein kinase B Akt and adenosine monophosphate-activated protein kinase AMPK pathways, both involved in glucose metabolism. PMID:26580610

  5. Three Peptides from Soy Glycinin Modulate Glucose Metabolism in Human Hepatic HepG2 Cells

    PubMed Central

    Lammi, Carmen; Zanoni, Chiara; Arnoldi, Anna

    2015-01-01

    Ile-Ala-Val-Pro-Gly-Glu-Val-Ala (IAVPGEVA), Ile-Ala-Val-Pro-Thr-Gly-Val-Ala (IAVPTGVA) and Leu-Pro-Tyr-Pro (LPYP), three peptides deriving from soy glycinin hydrolysis, are known to regulate cholesterol metabolism in human hepatic HepG2 cells. We have recently demonstrated that the mechanism of action involves the activation of adenosine monophosphate-activated protein kinase (AMPK). This fact suggested a potential activity of the same peptides on glucose metabolism that prompted us to also investigate this aspect in the same cells. After treatment with IAVPGEVA, IAVPTGVA and LPYP, HepG2 cells were analyzed using a combination of molecular techniques, including western blot analysis, glucose uptake experiments and fluorescence microscopy evaluation. The results showed that these peptides are indeed able to enhance the capacity of HepG2 cells to uptake glucose, via glucose transporter 1 GLUT1 and glucose transporter 4 GLUT4 activation, through the stimulation of protein kinase B Akt and adenosine monophosphate-activated protein kinase AMPK pathways, both involved in glucose metabolism. PMID:26580610

  6. Modulation of host lipid metabolism by hepatitis C virus: Role of new therapies

    PubMed Central

    Del Campo, José A; Romero-Gómez, Manuel

    2015-01-01

    It is well established that hepatitis C virus (HCV) infection and replication relies on host lipid metabolism. HCV proteins interact and associate with lipid droplets to facilitate virion assembly and production. Besides, circulating infective particles are associated with very low-density lipoprotein. On the other hand, higher serum lipid levels have been associated with sustained viral response to pegylated interferon and ribavirin therapy in chronic HCV infection, suggesting a relevant role in viral clearance for host proteins. Host and viral genetic factors play an essential role in chronic infection. Lipid metabolism is hijacked by viral infection and could determine the success of viral replication. Recently development of direct acting antiviral agents has shown a very high efficacy (> 90%) in sustained viral response rates even for cirrhotic patients and most of the viral genotypes. HCV RNA clearance induced by Sofosbuvir has been associated with an increased concentration and size of the low-density lipoprotein particles. In this review, host genetic factors, viral factors and the interaction between them will be depicted to clarify the major issues involved in viral infection and lipid metabolism. PMID:26478669

  7. A Role for Timp3 in Microbiota-Driven Hepatic Steatosis and Metabolic Dysfunction.

    PubMed

    Mavilio, Maria; Marchetti, Valentina; Fabrizi, Marta; Stöhr, Robert; Marino, Arianna; Casagrande, Viviana; Fiorentino, Loredana; Cardellini, Marina; Kappel, Ben; Monteleone, Ivan; Garret, Celine; Mauriello, Alessandro; Monteleone, Giovanni; Farcomeni, Alessio; Burcelin, Remy; Menghini, Rossella; Federici, Massimo

    2016-07-19

    The effect of gut microbiota on obesity and insulin resistance is now recognized, but the underlying host-dependent mechanisms remain poorly undefined. We find that tissue inhibitor of metalloproteinase 3 knockout (Timp3(-/-)) mice fed a high-fat diet exhibit gut microbiota dysbiosis, an increase in branched chain and aromatic (BCAA) metabolites, liver steatosis, and an increase in circulating soluble IL-6 receptors (sIL6Rs). sIL6Rs can then activate inflammatory cells, such as CD11c(+) cells, which drive metabolic inflammation. Depleting the microbiota through antibiotic treatment significantly improves glucose tolerance, hepatic steatosis, and systemic inflammation, and neutralizing sIL6R signaling reduces inflammation, but only mildly impacts glucose tolerance. Collectively, our results suggest that gut microbiota is the primary driver of the observed metabolic dysfunction, which is mediated, in part, through IL-6 signaling. Our findings also identify an important role for Timp3 in mediating the effect of the microbiota in metabolic diseases. PMID:27373162

  8. The metabolic sensors FXRα, PGC-1α, and SIRT1 cooperatively regulate hepatitis B virus transcription.

    PubMed

    Curtil, Claire; Enache, Liviu S; Radreau, Pauline; Dron, Anne-Gaëlle; Scholtès, Caroline; Deloire, Alexandre; Roche, Didier; Lotteau, Vincent; André, Patrice; Ramière, Christophe

    2014-03-01

    Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor α (FXRα) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXRα modulators, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo. Whereas PGC-1α induction was shown to increase HBV replication, the effect of SIRT1 on HBV transcription remains unknown. Here, we showed that, in hepatocarcinoma-derived Huh-7 cells, combined activation of FXRα by GW4064 and SIRT1 by activator 3 increased HBV core promoter-controlled luciferase expression by 25-fold, compared with a 10-fold increase with GW4064 alone. Using cell lines differentially expressing FXRα in overexpression and silencing experiments, we demonstrated that SIRT1 activated the core promoter in an FXRα- and PGC-1α-dependent manner. Maximal activation (>150-fold) was observed in FXRα- and PGC-1α-overexpressing Huh-7 cells treated with FXRα and SIRT1 activators. Similarly, in cells transfected with full-length HBV genomes, maximal induction (3.5-fold) of core promoter-controlled synthesis of 3.5-kb RNA was observed in the same conditions of transfection and treatments. Thus, we identified a subnetwork of metabolic factors regulating HBV replication, strengthening the hypothesis that transcription of HBV and metabolic genes is similarly controlled. PMID:24297698

  9. Urinary metabolites to assess in vivo ontogeny of hepatic drug metabolism in early neonatal life.

    PubMed

    Allegaert, K; Verbesselt, R; Rayyan, M; Debeer, A; de Hoon, J

    2007-05-01

    In addition to size-dependent allometric metabolic activity, most isoenzymes display age-dependent isoenzyme-specific ontogeny. We therefore need probe drugs to describe isoenzyme-specific ontogeny to develop more sophisticated, physiologically based models. We illustrate the feasibility and the relevance of in vivo assessment of hepatic metabolism, based on observations on urinary elimination of paracetamol and tramadol metabolites in neonates. On the basis of the observations on tramadol disposition, we were able to document that O-demethylation phenotypic activity developed sooner when compared with N-demethylation. During repeated administration of intravenous paracetamol, it was documented that, in addition to postmenstrual and postnatal age (PNA), repeated administration also contributed to the urinary excretion of glucuronidated paracetamol. In both probe drugs evaluated, age only in part explained the interindividual variability observed. Urine metabolites to assess in vivo metabolism of drugs routinely administered in neonates likely increase both the feasibility and clinical relevance of studies on in vivo isoenzyme-specific ontogeny in neonates. PMID:17609736

  10. Quantification of hepatic and visceral fat by CT and MR imaging: relevance to the obesity epidemic, metabolic syndrome and NAFLD.

    PubMed

    Graffy, Peter M; Pickhardt, Perry J

    2016-06-01

    Trends in obesity have continued to increase in the developed world over the past few decades, along with related conditions such as metabolic syndrome, which is strongly associated with this epidemic. Novel and innovative methods to assess relevant obesity-related biomarkers are needed to determine the clinical significance, allow for surveillance and intervene if appropriate. Aggregations of specific types of fat, specifically hepatic and visceral adiposity, are now known to be correlated with these conditions, and there are a variety of imaging techniques to identify and quantify their distributions and provide diagnostic information. These methods are particularly salient for metabolic syndrome, which is related to both hepatic and visceral adiposity but currently not defined by it. Simpler non-specific fat measurements, such as body weight, abdominal circumference and body mass index are more frequently used but lack the ability to characterize fat location. In addition, non-alcoholic fatty liver disease (NAFLD) is a related condition that carries relevance not only for obesity-related diseases but also for the progression of the liver-specific disease, including non-alcoholic steatohepatitis and cirrhosis, albeit at a much lower frequency. Recent CT and MRI techniques have emerged to potentially optimize diagnosing metabolic syndrome and NAFLD through non-invasive quantification of visceral fat and hepatic steatosis with high accuracy. These imaging modalities should aid us in further understanding the relationship of hepatic and visceral fat to the obesity-related conditions such as metabolic syndrome, NAFLD and cardiovascular disease. PMID:26876880

  11. In vitro metabolic clearance of pyrethroid pesticides by rat and human hepatic microsomes and cytochrome P450 isoforms

    EPA Science Inventory

    Species differences in the intrinsic clearance (CLint) and the enzymes involved in the metabolism of pyrethroid pesticides were examined in rat and human hepatic microsomes. The pyrethroids bifenthrin, S-bioallethrin, bioresmethrin, β-cyfluthrin, cypermethrin, cis-per...

  12. FTO contributes to hepatic metabolism regulation through regulation of leptin action and STAT3 signalling in liver

    PubMed Central

    2014-01-01

    Background The fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription 3 (LepR-STAT3) signalling pathway and FTO was recently suggested in the hypothalamus. Because of the presence of FTO in liver and the role of LepR-STAT3 in the control of hepatic metabolism, we investigated both in vitro and in vivo the potential interrelationship between FTO and LepR-STAT3 signalling pathway in liver and the impact of FTO overexpression on leptin action and glucose homeostasis in liver of mice. Results We found that FTO protein expression is regulated by both leptin and IL-6, concomitantly to an induction of STAT3 tyrosine phosphorylation, in leptin receptor (LepRb) expressing HuH7 cells. In addition, FTO overexpression in vitro altered both leptin-induced Y705 and S727 STAT3 phosphorylation, leading to dysregulation of glucose-6-phosphatase (G6P) expression and mitochondrial density, respectively. In vivo, liver specific FTO overexpression in mice induced a reducetion of Y705 phosphorylation of STAT3 in nuclear fraction, associated with reduced SOCS3 and LepR mRNA levels and with an increased G6P expression. Interestingly, FTO overexpression also induced S727 STAT3 phosphorylation in liver mitochondria, resulting in an increase of mitochondria function and density. Altogether, these data indicate that FTO promotes mitochondrial recruitment of STAT3 to the detriment of its nuclear localization, affecting in turn oxidative metabolism and the expression of leptin-targeted genes. Interestingly, these effects were associated in mice with alterations of leptin action and hyperleptinemia, as well as hyperglycemia, hyperinsulinemia and glucose intolerance. Conclusions Altogether, these data point a novel regulatory loop between FTO and leptin-STAT3 signalling pathways in liver cells, and highlight a new role of FTO in the regulation

  13. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.

    PubMed

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-11-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  14. Influence of neonatal hypothyroidism on hepatic gene expression and lipid metabolism in adulthood.

    PubMed

    Santana-Farré, Ruymán; Mirecki-Garrido, Mercedes; Bocos, Carlos; Henríquez-Hernández, Luis A; Kahlon, Nusrat; Herrera, Emilio; Norstedt, Gunnar; Parini, Paolo; Flores-Morales, Amilcar; Fernández-Pérez, Leandro

    2012-01-01

    Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood. PMID:22666351

  15. Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

    PubMed Central

    Bocos, Carlos; Henríquez-Hernández, Luis A.; Kahlon, Nusrat; Herrera, Emilio; Norstedt, Gunnar; Parini, Paolo; Flores-Morales, Amilcar; Fernández-Pérez, Leandro

    2012-01-01

    Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood. PMID:22666351

  16. Hepatic fat content is a determinant of metabolic phenotypes and increased carotid intima-media thickness in obese adults

    PubMed Central

    Zhang, Huijie; Ma, Zhimin; Pan, Lingling; Xu, Yanfang; Shao, Jin; Huang, Zhufeng; Chen, Zheng; Sun, Qian; Liu, Changqin; Lin, Mingzhu; Yang, Shuyu; Li, Xuejun

    2016-01-01

    Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40–65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95%CI = 0.65–0.75) and increased CIMT (AUC = 0.60, 95%CI = 0.54–0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI):1.29(1.01–1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis. PMID:26902311

  17. Hepatic fat content is a determinant of metabolic phenotypes and increased carotid intima-media thickness in obese adults.

    PubMed

    Zhang, Huijie; Ma, Zhimin; Pan, Lingling; Xu, Yanfang; Shao, Jin; Huang, Zhufeng; Chen, Zheng; Sun, Qian; Liu, Changqin; Lin, Mingzhu; Yang, Shuyu; Li, Xuejun

    2016-01-01

    Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40-65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95%CI = 0.65-0.75) and increased CIMT (AUC = 0.60, 95%CI = 0.54-0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI):1.29(1.01-1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis. PMID:26902311

  18. AMPK-dependent modulation of hepatic lipid metabolism by nesfatin-1.

    PubMed

    Yin, Yue; Li, Ziru; Gao, Ling; Li, Yin; Zhao, Jing; Zhang, Weizhen

    2015-12-01

    The aim of this study was to characterize the mechanism by which peripheral nesfatin-1 regulates hepatic lipid metabolism. Continuous peripheral infusion of nesfatin-1 reduced adiposity and plasma levels of triglyceride and cholesterol. In mice fed high fat diet, peripheral nesfatin-1 significantly decreased hepatic steatosis measured by triglyceride content and oil red staining area and diameter. These alterations were associated with a significant reduction in lipogenesis-related transcriptional factors PPARγ and SREBP1, as well as rate-limited enzyme genes such as acaca, fasn, gpam, dgat1 and dgat2. In primary hepatocytes, nesfatin-1 inhibited both basal and oleic acid stimulated triglyceride accumulation, which was accompanied by a decrement in lipogenesis-related genes and an increase in β-oxidation-related genes. In cultured hepatocytes, nesfatin-1 increased levels of AMPK phosphorylation. Inhibition of AMPK by compound C blocked the reduction of triglyceride content elicited by nesfatin-1. Our studies demonstrate that nesfatin-1 attenuates lipid accumulation in hepatocytes by an AMPK-dependent mechanism. PMID:26363221

  19. Soy protein isolate modified metabolic phenotype and hepatic Wnt signaling in obese Zucker rats.

    PubMed

    Cain, J; Banz, W J; Butteiger, D; Davis, J E

    2011-10-01

    We have previously shown that soy protein isolate (SPI) with intact phytoestrogen content prevented obesity-related dysfunction. Recent data have suggested that soy ingredients may act as regulators of adipogenic programming in adipose tissue (AT) and liver. Thus, the current study was undertaken to determine whether the beneficial effects of SPI are linked to changes in adipogenic regulators, such as the Wnt signaling cascade. For this, lean (LZR) and obese Zucker (OZR) rats were provided isocaloric and isonitrogenous diets containing SPI, sodium caseinate, or dairy whey protein for 17 weeks. At termination, SPI increased body weight and total adiposity in rodents, which corresponded with an increase in both adipocyte size and number. Furthermore, markers of inflammation, hypercholesterolemia, and hepatic steatosis were all reduced in OZR rats provided SPI. Transcript abundance of several canonical and noncanonical Wnt signaling intermediates in liver, but not AT, was distinctly modified by SPI. Collectively, these data confirm the protective SPI attenuated obesity-related metabolic dysfunction conceivably through regulation of adipogenic programming, as evident by changes in AT morphology and hepatic Wnt signaling. Collectively, this study confirmed the potential utilization of soy protein and its bioactive ingredients for prevention and treatment of obesity-related comorbidities. PMID:22009372

  20. Hepatic metabolism of cyclodiene insecticides by constitutive forms of cytochrome P-450 from lower vertebrates.

    PubMed

    Ronis, M J; Walker, C H; Peakall, D

    1987-01-01

    1. Multiple forms of cytochrome P-450 were separated from the hepatic microsomes of untreated male rats, pigeons (Columbia livia), razorbills (Alca torda), puffins (Fratercula arctica), and rainbow trout (Salmo gairdnerii), using anion exchange chromatography and DEAE-cellulose. 2. In some cases cytochrome P-450 forms were further purified on hydroxylapatite and carboxymethyl-sephadex columns. 3. Considerable differences in the distribution of forms between these five species were evident from elution profiles on DEAE cellulose, and on analysis of the cytochrome P-450 containing pools by SDS-PAGE. 4. The metabolism of two organochlorine compounds, aldrin and the dieldrin analogue HCE, were studied in (a) intact microsomes and (b) reconstituted systems containing cytochrome P-450, from each of the five species. 5. In spite of their close structural similarity, significant differences were found between the two substrates in the distribution of catalytic activity between the cytochrome P-450 isozymes of each species. PMID:2888582

  1. Hepatic Lipase: a Comprehensive View of its Role on Plasma Lipid and Lipoprotein Metabolism.

    PubMed

    Kobayashi, Junji; Miyashita, Kazuya; Nakajima, Katsuyuki; Mabuchi, Hiroshi

    2015-01-01

    Hepatic lipase (HL) is a key enzyme catalyzing the hydrolysis of triglycerides (TG) and phospholipids (PLs) in several lipoproteins. It is generally recognized that HL is involved in the remodeling of remnant, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and the production of small, dense low-density lipoproteins (sd-LDLs).On the other hand, it is unclear whether HL accelerates or retards atherosclerosis. From the clinical point of view, HL deficiency may provide useful information on answering this question, but the rarity of this disease makes it impossible to conduct epidemiological study.In this review, we describe a comprehensive and updated view of the clinical significance of HL on lipid and lipoprotein metabolism. PMID:26194979

  2. Influence of minor plant constituents on porcine hepatic lipid metabolism. Impact on serum lipids.

    PubMed

    Qureshi, A A; Crenshaw, T D; Abuirmeileh, N; Peterson, D M; Elson, C E

    1987-04-01

    The effects of plant constituents on lipid metabolism were examined in swine that had been fed for 4 weeks a standard diet containing, in addition, (per kg diet) 3.15 g of the methanol serial solvent fraction garlic bulbs or 3.5 g of the petroleum ether solubles high-protein barley flour or 5 mg of the plant growth regulator, AMO 1618. All treatments suppressed 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase activities. Modest increases in serum triglycerides were associated with significantly increased hepatic lipogenic activities in response to all treatments except that of the barley extract. The methanol solubles of a second lot of garlic were fractionated by HPLC and tested in an avian hepatocyte system. One component, an isoprenoid metabolite, MW 358, suppressed HMG-CoA reductase. PMID:3606707

  3. Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice.

    PubMed

    Cometa, Maria Francesca; Buratti, Franca Maria; Fortuna, Stefano; Lorenzini, Paola; Volpe, Maria Teresa; Parisi, Laura; Testai, Emanuela; Meneguz, Annarita

    2007-05-01

    Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects. PMID:17382447

  4. Leptin expression affects metabolic rate in zebrafish embryos (D. rerio)

    PubMed Central

    Dalman, Mark R.; Liu, Qin; King, Mason D.; Bagatto, Brian; Londraville, Richard L.

    2013-01-01

    We used antisense morpholino oligonucleotide technology to knockdown leptin-(A) gene expression in developing zebrafish embryos and measured its effects on metabolic rate and cardiovascular function. Using two indicators of metabolic rate, oxygen consumption was significantly lower in leptin morphants early in development [<48 hours post-fertilization (hpf)], while acid production was significantly lower in morphants later in development (>48 hpf). Oxygen utilization rates in <48 hpf embryos and acid production in 72 hpf embryos could be rescued to that of wildtype embryos by recombinant leptin coinjected with antisense morpholino. Leptin is established to influence metabolic rate in mammals, and these data suggest leptin signaling also influences metabolic rate in fishes. PMID:23847542

  5. How does metabolism affect cell death in cancer?

    PubMed

    Villa, Elodie; Ricci, Jean-Ehrland

    2016-07-01

    In cancer research, identifying a specificity of tumor cells compared with 'normal' proliferating cells for targeted therapy is often considered the Holy Grail for researchers and clinicians. Although diverse in origin, most cancer cells share characteristics including the ability to escape cell death mechanisms and the utilization of different methods of energy production. In the current paradigm, aerobic glycolysis is considered the central metabolic characteristic of cancer cells (Warburg effect). However, recent data indicate that cancer cells also show significant changes in other metabolic pathways. Indeed, it was recently suggested that Kreb's cycle, pentose phosphate pathway intermediates, and essential and nonessential amino acids have key roles. Renewed interest in the fact that cancer cells have to reprogram their metabolism in order to proliferate or resist treatment must take into consideration the ability of tumor cells to adapt their metabolism to the local microenvironment (low oxygen, low nutrients). This variety of metabolic sources might be either a strength, resulting in infinite possibilities for adaptation and increased ability to resist chemotherapy-induced death, or a weakness that could be targeted to kill cancer cells. Here, we discuss recent insights showing how energetic metabolism may regulate cell death and how this might be relevant for cancer treatment. PMID:26498911

  6. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism

    PubMed Central

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  7. Systematic analysis of the regulatory functions of microRNAs in chicken hepatic lipid metabolism.

    PubMed

    Li, Hong; Ma, Zheng; Jia, Lijuan; Li, Yanmin; Xu, Chunlin; Wang, Taian; Han, Ruili; Jiang, Ruirui; Li, Zhuanjian; Sun, Guirong; Kang, Xiangtao; Liu, Xiaojun

    2016-01-01

    Laying performance is an important economic trait in hens, and this physiological process is largely influenced by the liver function. The livers of hens at 20- and 30-week-old stages were investigated using the next generation sequencing to identify the differences of microRNA expression profiles. Compared with the 20-week-old hens, 67 down- and 13 up-regulated microRNAs were verified to be significant differentially expressed (false discovery rate, FDR ≤ 0.05) (SDE) in the 30-week-old. We also identified 13 down- and 6 up-regulated novel differentially expressed (DE) microRNAs. miR-22-3p and miR-146b-5p, which exhibit critical roles in mammalian lipid metabolism, showed the most abundant expression and the highest fold-change, respectively. A total of 648 potential target genes of the SDE microRNAs were identified through an integrated analysis of microRNAs and the DE genes obtained in previous RNA-sequencing, including FADS1, FADS2, ELOVL6 and ACSL5, which are critical lipid metabolism-related regulators. Bioinformatic analyses revealed that target genes were mainly enriched in lipid-related metabolism processes. This work provides the first study of the expression patterns of hepatic microRNAs between 20- and 30-week old hens. The findings may serve as a fundamental resource for understanding the detailed functions of microRNAs in the molecular regulatory systems of lipid metabolism. PMID:27535581

  8. Roles of hepatic glucokinase in intertissue metabolic communication: Examination of novel liver-specific glucokinase knockout mice.

    PubMed

    Hayashi, Hirofumi; Sato, Yoshifumi; Li, Zhenghua; Yamamura, Ken-ichi; Yoshizawa, Tatsuya; Yamagata, Kazuya

    2015-05-01

    Glucokinase is expressed principally in pancreatic β-cells and hepatocytes, and catalyzes the phosphorylation of glucose to glucose-6-phosphate, a rate-limiting step of glycolysis. To better understand the roles of hepatic glucokinase, we generated Gck knockout mice by ablating liver-specific exon 1b. The knockout mice exhibited impaired glucose tolerance, decreased hepatic glycogen content, and reduced Pklr and Fas gene expression in the liver, indicating that hepatic glucokinase plays important roles in glucose metabolism. It has also been reported that hepatic glucokinase regulates the expression of thermogenesis-related genes in brown adipose tissue (BAT) and insulin secretion in response to glucose. However, the liver-specific Gck knockout mice displayed neither altered expression of thermogenesis-related genes in BAT nor impaired insulin secretion by β-cells under a normal chow diet. These results suggest that chronic suppression of hepatic glucokinase has a small influence on intertissue (liver-to-BAT as well as liver-to-β-cell) metabolic communication. PMID:25817793

  9. Effects of a glucokinase activator on hepatic intermediary metabolism: study with 13C-isotopomer-based metabolomics

    PubMed Central

    Nissim, Itzhak; Horyn, Oksana; Nissim, Ilana; Daikhin, Yevgeny; Wehrli, Suzanne L.; Yudkoff, Marc; Matschinsky, Franz M.

    2013-01-01

    GKAs (glucokinase activators) are promising agents for the therapy of Type 2 diabetes, but little is known about their effects on hepatic intermediary metabolism. We monitored the fate of 13C-labelled glucose in both a liver perfusion system and isolated hepatocytes. MS and NMR spectroscopy were deployed to measure isotopic enrichment. The results demonstrate that the stimulation of glycolysis by GKA led to numerous changes in hepatic metabolism: (i) augmented flux through the TCA (tricarboxylic acid) cycle, as evidenced by greater incorporation of 13C into the cycle (anaplerosis) and increased generation of 13C isotopomers of citrate, glutamate and aspartate (cataplerosis); (ii) lowering of hepatic [Pi] and elevated [ATP], denoting greater phosphorylation potential and energy state; (iii) stimulation of glycogen synthesis from glucose, but inhibition of glycogen synthesis from 3-carbon precursors; (iv) increased synthesis of N-acetylglutamate and consequently augmented ureagenesis; (v) increased synthesis of glutamine, alanine, serine and glycine; and (vi) increased production and outflow of lactate. The present study provides a deeper insight into the hepatic actions of GKAs and uncovers the potential benefits and risks of GKA for treatment of diabetes. GKA improved hepatic bioenergetics, ureagenesis and glycogenesis, but decreased gluconeogenesis with a potential risk of lactic acidosis and fatty liver. PMID:22448977

  10. Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion

    PubMed Central

    Chen, Zhouji; Gropler, Matthew C.; Norris, Jin; Lawrence, John C.; Harris, Thurl E.; Finck, Brian N.

    2009-01-01

    Objective Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches. Methods and Results Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1—deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling. Conclusions Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance. PMID:18669885

  11. Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

    PubMed Central

    Schmidt, Robin H.; Jokinen, Jenny D.; Massey, Veronica L.; Falkner, K. Cameron; Shi, Xue; Yin, Xinmin; Zhang, Xiang; Beier, Juliane I.

    2013-01-01

    Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system’s mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug. PMID:23926289

  12. Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats.

    PubMed

    Zhou, Xin; Rougée, Luc R A; Bedwell, David W; Cramer, Jeff W; Mohutsky, Michael A; Calvert, Nathan A; Moulton, Richard D; Cassidy, Kenneth C; Yumibe, Nathan P; Adams, Lisa A; Ruterbories, Kenneth J

    2016-08-01

    The Zucker diabetic fatty (ZDF) rat, an inbred strain of obese Zucker fatty rat, develops early onset of insulin resistance and displays hyperglycemia and hyperlipidemia. The phenotypic changes resemble human type 2 diabetes associated with obesity and therefore the strain is used as a pharmacological model for type 2 diabetes. The aim of the current study was to compare the pharmacokinetics and hepatic metabolism in male ZDF and Sprague-Dawley (SD) rats of five antidiabetic drugs that are known to be cleared via various mechanisms. Among the drugs examined, metformin, cleared through renal excretion, and rosiglitazone, metabolized by hepatic cytochrome P450 2C, did not exhibit differences in the plasma clearance in ZDF and SD rats. In contrast, glibenclamide, metabolized by hepatic CYP3A, canagliflozin, metabolized mainly by UDP-glucuronosyltransferases (UGT), and troglitazone, metabolized by sulfotransferase and UGT, exhibited significantly lower plasma clearance in ZDF than in SD rats after a single intravenous administration. To elucidate the mechanisms for the difference in the drug clearance, studies were performed to characterize the activity of hepatic drug-metabolizing enzymes using liver S9 fractions from the two strains. The results revealed that the activity for CYP3A and UGT was decreased in ZDF rats using the probe substrates, and decreased unbound intrinsic clearance in vitro for glibenclamide, canagliflozin, and troglitazone was consistent with lower plasma clearance in vivo. The difference in pharmacokinetics of these two strains may complicate pharmacokinetic/pharmacodynamic correlations, given that ZDF is used as a pharmacological model, and SD rat as the pharmacokinetics and toxicology strain. PMID:27217490

  13. Ionizing Radiation Impairs T Cell Activation by Affecting Metabolic Reprogramming

    PubMed Central

    Li, Heng-Hong; Wang, Yi-wen; Chen, Renxiang; Zhou, Bin; Ashwell, Jonathan D.; Fornace, Albert J.

    2015-01-01

    Ionizing radiation has a variety of acute and long-lasting adverse effects on the immune system. Whereas measureable effects of radiation on immune cell cytotoxicity and population change have been well studied in human and animal models, little is known about the functional alterations of the surviving immune cells after ionizing radiation. The objective of this study was to delineate the effects of radiation on T cell function by studying the alterations of T cell receptor activation and metabolic changes in activated T cells isolated from previously irradiated animals. Using a global metabolomics profiling approach, for the first time we demonstrate that ionizing radiation impairs metabolic reprogramming of T cell activation, which leads to substantial decreases in the efficiency of key metabolic processes required for activation, such as glucose uptake, glycolysis, and energy metabolism. In-depth understanding of how radiation impacts T cell function highlighting modulation of metabolism during activation is not only a novel approach to investigate the pivotal processes in the shift of T cell homeostasis after radiation, it also may lead to new targets for therapeutic manipulation in the combination of radiotherapy and immune therapy. Given that appreciable effects were observed with as low as 10 cGy, our results also have implications for low dose environmental exposures. PMID:26078715

  14. [PREDICTING FACTORS OF THE LIFE SPAN IN PATIENTS, SUFFERING METASTATIC COLORECTAL CANCER AND SYNCHRONOUS HEPATIC AFFECTION AFTER SURGICAL TREATMENT].

    PubMed

    Kolesnik, O O; Burlaka, A A; Lukashenko, A V; Pryimak, V V; Zhukov, Yu O; Makhmudov, D E; Volk, M O; Shchepotin, I B

    2015-05-01

    The results of treatment of 125 patients, suffering metastatic hepatic affection in colorectal cancer (pT1--4N0--2M1--in colonic cancer and pT1--3N0--2M1--in cancer recti), to whom in 2008-2015 yrs a one-staged (Group 1) or two-staged (Group II) surgical treatment was done. In affection of 4 regional lymph nodes and more (pN2) late results were less favorable, than in pN1 or pN0, not depending from surgical approach choosed. In 48 (38.4%) patients with one syndromal hepatic metastatic focus, the indices of general three-year and five-year cumulative survival were the best, than in other groups--82 and 63% (p = 0.001) accordingly; in monolobar affection--68 and 49%, and in bilobar--23 and 0%, not depending from method of surgical treatment (p < 0.001) choosed. Predictive factors were established, which impact negatively the indices of general survival in patients, suffering metastatic hepatic affection in colorectal cancer: hepatic metastatic foci number 4 and more, bilobar hepatic metastatic affection. PMID:26419027

  15. Prevention of Hepatic Fibrosis in a Murine Model of Metabolic Syndrome with Nonalcoholic Steatohepatitis

    PubMed Central

    DeLeve, Laurie D.; Wang, Xiangdong; Kanel, Gary C.; Atkinson, Roscoe D.; McCuskey, Robert S.

    2008-01-01

    The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CB1 with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-4F. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyperleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-4F prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit. PMID:18772330

  16. Berberine Improves Glucose Metabolism in Diabetic Rats by Inhibition of Hepatic Gluconeogenesis

    PubMed Central

    Xia, Xuan; Yan, Jinhua; Shen, Yunfeng; Tang, Kuanxiao; Yin, Jun; Zhang, Yanhua; Yang, Dongjie; Liang, Hua; Ye, Jianping; Weng, Jianping

    2011-01-01

    Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway. PMID:21304897

  17. Pharmacokinetic interaction between metoprolol and SP-8203 in rats: competitive inhibition for the metabolism of metoprolol by SP-8203 via hepatic CYP2D subfamily.

    PubMed

    Han, Seung Yon; Yoon, Insoo; Chin, Young-Won; Cho, Il Whan; Lee, Myung Gull; Choi, Young Hee

    2012-10-01

    1. The occurrence of cerebral ischemia is prevalent in patients with hypertension and the combination drug therapy is needed. Thus, the pharmacokinetic interaction between metoprolol (anti-hypertension drug) and SP-8203 (a new drug candidate for cerebral ischemia) with respect to the metabolism via CYP isozymes was evaluated. 2. Metoprolol and SP-8203 were administered intravenously or orally to rats. Concentrations (I) of each drug in the liver and intestine in in vivo studies, the disappearance and apparent K(i) of each drug in in vitro microsomes and [I]/K(i) ratios for each drug were determined. In addition, the disappearance of each drug via CYPs in rat and human microsomes were measured. 3. The AUC and CL(NR) of intravenously administered metoprolol with SP-8203 were significantly greater and slower, respectively, than without SP-8203. However, pharmacokinetic parameters of oral metoprolol and intravenous/oral SP-8203 were not altered. 4. The hepatic metabolism of metoprolol via CYP2D was inhibited by SP-8203 in a competitive manner. However, the intestinal metabolism of metoprolol was not influenced by SP-8203. SP-8203 was not metabolized via CYP isozymes in rats and then co-administration of metoprolol did not affect the metabolism of SP-8203. PMID:22568632

  18. Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis

    PubMed Central

    Wang, Hai; Zhao, Miaoyun; Sud, Neetu; Christian, Patricia; Shen, Jing; Song, Yongyan; Pashaj, Anjeza; Zhang, Kezhong; Carr, Timothy; Su, Qiaozhu

    2016-01-01

    Insulin induced gene-2 (Insig-2) is an ER-resident protein that inhibits the activation of sterol regulatory element-binding proteins (SREBPs). However, cellular factors that regulate Insig-2 expression have not yet been identified. Here we reported that cyclic AMP-responsive element-binding protein H (CREBH) positively regulates mRNA and protein expression of a liver specific isoform of Insig-2, Insig-2a, which in turn hinders SREBP-1c activation and inhibits hepatic de novo lipogenesis. CREBH binds to the evolutionally conserved CRE-BP binding elements located in the enhancer region of Insig-2a and upregulates its mRNA and protein expression. Metabolic hormone glucagon and nutritional fasting activated CREBH, which upregulated expression of Insig-2a in hepatocytes and inhibited SREBP-1c activation. In contrast, genetic depletion of CREBH decreased Insig-2a expression, leading to the activation of SREBP-1c and its downstream lipogenic target enzymes. Compromising CREBH-Insig-2 signaling by siRNA interference against Insig-2 also disrupted the inhibitory effect of this signaling pathway on hepatic de novo triglyceride synthesis. These actions resulted in the accumulation of lipid droplets in hepatocytes and systemic hyperlipidemia. Our study identified CREBH as the first cellular protein that regulates Insig-2a expression. Glucagon activated the CREBH-Insig-2a signaling pathway to inhibit hepatic de novo lipogenesis and prevent the onset of hepatic steatosis and hypertriglyceridemia. PMID:27582413

  19. Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis.

    PubMed

    Wang, Hai; Zhao, Miaoyun; Sud, Neetu; Christian, Patricia; Shen, Jing; Song, Yongyan; Pashaj, Anjeza; Zhang, Kezhong; Carr, Timothy; Su, Qiaozhu

    2016-01-01

    Insulin induced gene-2 (Insig-2) is an ER-resident protein that inhibits the activation of sterol regulatory element-binding proteins (SREBPs). However, cellular factors that regulate Insig-2 expression have not yet been identified. Here we reported that cyclic AMP-responsive element-binding protein H (CREBH) positively regulates mRNA and protein expression of a liver specific isoform of Insig-2, Insig-2a, which in turn hinders SREBP-1c activation and inhibits hepatic de novo lipogenesis. CREBH binds to the evolutionally conserved CRE-BP binding elements located in the enhancer region of Insig-2a and upregulates its mRNA and protein expression. Metabolic hormone glucagon and nutritional fasting activated CREBH, which upregulated expression of Insig-2a in hepatocytes and inhibited SREBP-1c activation. In contrast, genetic depletion of CREBH decreased Insig-2a expression, leading to the activation of SREBP-1c and its downstream lipogenic target enzymes. Compromising CREBH-Insig-2 signaling by siRNA interference against Insig-2 also disrupted the inhibitory effect of this signaling pathway on hepatic de novo triglyceride synthesis. These actions resulted in the accumulation of lipid droplets in hepatocytes and systemic hyperlipidemia. Our study identified CREBH as the first cellular protein that regulates Insig-2a expression. Glucagon activated the CREBH-Insig-2a signaling pathway to inhibit hepatic de novo lipogenesis and prevent the onset of hepatic steatosis and hypertriglyceridemia. PMID:27582413

  20. Natural toxins that affect plant amino acid metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A diverse range of natural compounds interfere with the synthesis and other aspects of amino acid metabolism. Some are amino acid analogues, but most are not. This review covers a number of specific natural phytotoxic compounds by molecular target site. Inhibition of glutamine synthetase is of part...

  1. Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

    PubMed Central

    Wang, Ting; Babusis, Darius; Lepist, Eve-Irene; Sauer, Dorothea; Park, Yeojin; Vela, Jennifer E.; Shih, Robert; Birkus, Gabriel; Stefanidis, Dimitrios; Kim, Choung U.; Cho, Aesop

    2014-01-01

    The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5′-phosphate that release the nucleoside monophosphate in hepatocytes and a 3′-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3′-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans. PMID:24419340

  2. The influence of social status on hepatic glucose metabolism in rainbow trout Oncorhynchus mykiss.

    PubMed

    Gilmour, Kathleen M; Kirkpatrick, Sheryn; Massarsky, Andrey; Pearce, Brenda; Saliba, Sarah; Stephany, Céleste-Élise; Moon, Thomas W

    2012-01-01

    The effects of chronic social stress on hepatic glycogen metabolism were examined in rainbow trout Oncorhynchus mykiss by comparing hepatocyte glucose production, liver glycogen phosphorylase (GP) activity, and liver β-adrenergic receptors in dominant, subordinate, control, fasted, and cortisol-treated fish. Hepatocyte glucose production in subordinate fish was approximately half that of dominant fish, reflecting hepatocyte glycogen stores in subordinate trout that were just 16% of those in dominant fish. Fasting and/or chronic elevation of cortisol likely contributed to these differences based on similarities among subordinate, fasted, and cortisol-treated fish. However, calculation of the "glycogen gap"--the difference between glycogen stores used and glucose produced--suggested an enhanced gluconeogenic potential in subordinate fish that was not present in fasted or cortisol-treated trout. Subordinate, fasted, and cortisol-treated trout also exhibited similar GP activities (both total activity and that of the active or a form), and these activities were in all cases significantly lower than those in control trout, perhaps reflecting an attempt to protect liver glycogen stores or a modified capacity to activate GP. Dominant trout exhibited the lowest GP activities (20%-24% of the values in control trout). Low GP activities, presumably in conjunction with incoming energy from feeding, allowed dominant fish to achieve the highest liver glycogen concentrations (double the value in control trout). Liver membrane β-adrenoceptor numbers (assessed as the number of (3)H-CGP binding sites) were significantly lower in subordinate than in dominant trout, although this difference did not translate into attenuated adrenergic responsiveness in hepatocyte glucose production in vitro. Transcriptional regulation, likely as a result of fasting, was indicated by significantly lower β(2)-adrenoceptor relative mRNA levels in subordinate and fasted trout. Collectively, the data

  3. Hepatic and Whole-Body Insulin Metabolism during Proestrus and Estrus in Mongrel Dogs.

    PubMed

    Yu, Erin Nz; Winnick, Jason J; Edgerton, Dale S; Scott, Melanie F; Smith, Marta S; Farmer, Ben; Williams, Phillip E; Cherrington, Alan D; Moore, Mary Courtney

    2016-01-01

    Insulin resistance occurs during various stages of the estrus cycle in dogs. To quantify the effects of proestrus-estrus (PE) and determine whether PE affects liver insulin sensitivity, 11 female mongrel dogs were implanted with sampling and intraportal infusion catheters. Five of the dogs (PE group) entered proestrus after surgery; those remaining in anestrus were controls. The dogs were fasted overnight, [3-(3)H]glucose and somatostatin were infused through peripheral veins, and glucagon was infused intraportally. Insulin was infused intraportally, with the rate adjusted to maintain arterial plasma glucose at basal levels (PE, 294±25 μU/kg/min; control, 223±21 μU/kg/min). Subsequently the insulin infusion rate was increased by 0.2 mU/kg/min for 120 min (P1) and then to 1.5 mU/kg/min for the last 120 min (P2); glucose was infused peripherally as needed to maintain euglycemia. Insulin concentrations did not differ between groups at any time; they increased 3 μU/mL over baseline during P1 and to 3 times baseline during P2. The glucose infusion rate in PE dogs during P2 was 63% of that in control dogs. Net hepatic glucose output and the endogenous glucose production rate declined 40% to 50% from baseline in both groups during P1; during P2, both groups exhibited a low rate of net hepatic glucose uptake with full suppression of endogenous glucose production. The glucose disappearance rate during P1 and P2 was 35% greater in control than PE dogs. Therefore, PE in canines is associated with loss of nonhepatic (primarily muscle) but not hepatic insulin sensitivity. PMID:27298249

  4. Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering.

    PubMed

    Donato, M Teresa; Jover, Ramiro; Gómez-Lechón, M José

    2013-11-01

    One key issue in the pharmaceutical development of new compounds is knowledge on metabolism, the enzymes involved and the potential hepatotoxicity of a drug. Primary cultured hepatocytes are a valuable in vitro model for drug metabolism studies. However, human hepatocytes show phenotypic instability and have restricted accessibility and high batch-to-batch functional variability, which seriously complicates their use in routine testing. Therefore, several liver-derived cell models have been developed for drug metabolism and hepatotoxicity screening to circumvent these drawbacks. Hepatoma cell lines offer important advantages, availability, an unlimited life span and a stable phenotype, thus rendering them suitable models for such studies. However, currently available human hepatoma cell lines are not a good alternative to cultured hepatocytes as they show very limited expression for most drug-metabolising enzymes. Other approaches have been developed to generate immortalised hepatic cells with metabolic competence (use of plasmids encoding immortalising genes to transform human hepatocytes, cell lines obtained from transgenic animals, hepatocytomes or hydrid cells). Recombinant models heterologously expressing cytochrome P450 enzymes in hepatoma cells have also been generated, and are widely used in drug metabolism and toxicity evaluations. In recent years, new approaches to up-regulate the expression of drug-biotransformation enzymes in human cell lines (i.e., transfection with the expression vectors encoding key hepatic transcription factors) have also been investigated. This paper reviews the features of liver-derived cell lines, their suitability for drug metabolism and hepatotoxicity studies, and the state-of-the-art strategies pursued to generate metabolically competent hepatic cell lines. PMID:24160292

  5. Leucine metabolism in TNF-alpha- and endotoxin-treated rats: contribution of hepatic tissue.

    PubMed

    Holecek, M; Sprongl, L; Skopec, F; Andrýs, C; Pecka, M

    1997-12-01

    The effects of tumor necrosis factor-alpha (TNF-alpha; cachectin) and lipopolysaccharide of Salmonella enteritidis (LPS; endotoxin) on leucine metabolism in rats were evaluated in the whole body using intravenous infusion of L-[1-14C]leucine and in isolated perfused liver (IPL) using the single-pass perfusion technique with alpha-keto[1-14C]isocaproate as a tracer for measurement of ketoisocaproic acid (KIC) oxidation, and the recirculation technique for measurement of hepatic amino acid exchanges. The data obtained in TNF-alpha and LPS groups were compared with those obtained in controls. Both TNF-alpha and LPS treatment induced an increase of whole body leucine turnover, oxidation, and clearance. As the result of a higher increase of leucine oxidation than of incorporation into the pool of body proteins, the fractional oxidation of leucine was increased. The fractional rate of protein synthesis increased significantly in the spleen (both in TNF-alpha and LPS rats), in blood plasma, liver, colon, kidneys, gastrocnemius muscle (in LPS rats), and in lungs (TNF-alpha-treated rats), whereas it decreased in the jejunum (LPS rats). In IPL of TNF-alpha- and LPS-treated rats a decrease of KIC oxidation and higher uptake of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) were observed when compared with control animals. We hypothesize that the negative consequences of increased whole body proteolysis and of increased oxidation of BCAA induced by TNF-alpha and/or LPS are reduced by decreased activity of hepatic branched-chain ketoacid dehydrogenase that can help resupply BCAA to the body. PMID:9435518

  6. Gender- and dose-related effects of cyclosporin A on hepatic and bone metabolism.

    PubMed

    Jäger, Walter; Xu, Huiqing; Wlcek, Katrin; Schüler, Christiane; Rubel, Franz; Erben, Reinhold G

    2012-01-01

    Previous data have shown gender-related differences in the skeletal effects of the immunosuppressive drug cyclosporin A (CsA) in rats. To test the hypothesis that the gender-related skeletal effects of CsA are caused by gender-specific metabolism of this drug, we treated aged male and female sham-operated, gonadectomized (GX) as well as sex hormone-supplemented GX rats with 5 mg/kg CsA three times per week for 2 months, and analyzed the bone phenotype as well as the concentrations of CsA and its major metabolites AM1, AM1c, AM9, and AM4N in blood, urine, and liver tissue. CsA treatment induced high turnover osteopenia in males, but not females. Male rats showed several-fold higher CsA and CsA metabolite blood levels compared with females. Renal clearance data revealed that CsA undergoes selective tubular reabsorption in male, but not female rats. However, a mathematical modeling approach demonstrated that the higher CsA blood levels in males were almost exclusively caused by a 6-fold lower hepatic clearance rate compared with females. In addition, we subcutaneously treated female rats with up to 6-fold higher doses of CsA. Similar to males, high dose CsA induced high turnover osteopenia in female rats. Our data show that the gender-related differences in the skeletal effects of CsA are caused by a higher hepatic clearance rate for CsA in female compared to male rats, and not by a differential skeletal response to CsA. Moreover, our study indicates that CsA blood levels of ≤200 ng/ml measured by HPLC do not induce high turnover osteopenia in aged rats. PMID:22019458

  7. Deanol affects choline metabolism in peripheral tissues of mice.

    PubMed

    Haubrich, D R; Gerber, N H; Pflueger, A B

    1981-08-01

    Administration of 2-dimethylaminoethanol (deanol) to mice induced an increase in both the concentration and the rate of turnover of free choline in blood. Treatment with deanol also caused an increase in the concentration of choline in kidneys, and markedly inhibited the rates of oxidation and phosphorylation of intravenously administered [3H-methyl]choline. In the liver, deanol inhibited the rate of phosphorylation of [3H-methyl]choline, but did not inhibit its rate of oxidation or cause an increase in the level of free choline. These findings suggest that deanol increases the choline concentration in blood by inhibition of its metabolism in tissues. Deanol may ultimately produce its central cholinergic effects by inhibition of choline metabolism in peripheral tissues, causing free choline choline to accumulate in blood, enter the brain, and stimulate cholinergic receptors. PMID:7264671

  8. Scoparone affects lipid metabolism in primary hepatocytes using lipidomics.

    PubMed

    Zhang, Aihua; Qiu, Shi; Sun, Hui; Zhang, Tianlei; Guan, Yu; Han, Ying; Yan, Guangli; Wang, Xijun

    2016-01-01

    Lipidomics, which focuses on the global study of molecular lipids in biological systems, could provide valuable insights about disease mechanisms. In this study, we present a nontargeted lipidomics strategy to determine cellular lipid alterations after scoparone exposure in primary hepatocytes. Lipid metabolic profiles were analyzed by high-performance liquid chromatography coupled with time-of-flight mass spectrometry, and a novel imaging TransOmics tool has been developed for the analysis of high-resolution MS data, including the data pretreatment, visualization, automated identification, deconvolution and quantification of lipid species. Chemometric and statistical analyses of the obtained lipid fingerprints revealed the global lipidomic alterations and tested the therapeutic effects of scoparone. Identification of ten proposed lipids contributed to the better understanding of the effects of scoparone on lipid metabolism in hepatocytes. The most striking finding was that scoparone caused comprehensive lipid changes, as represented by significant changes of the identificated lipids. The levels of identified PG(19:1(9Z)/14:0), PE(17:1(9Z)/0:0), PE(19:1(9Z)/0:0) were found to be upregulated in ethanol-induced group, whereas the levels in scoparone group were downregulated. Lipid metabolism in primary hepatocytes was changed significantly by scoparone treatment. We believe that this novel approach could substantially broaden the applications of high mass resolution mass spectrometry for cellular lipidomics. PMID:27306123

  9. Scoparone affects lipid metabolism in primary hepatocytes using lipidomics

    PubMed Central

    Zhang, Aihua; Qiu, Shi; Sun, Hui; Zhang, Tianlei; Guan, Yu; Han, Ying; Yan, Guangli; Wang, Xijun

    2016-01-01

    Lipidomics, which focuses on the global study of molecular lipids in biological systems, could provide valuable insights about disease mechanisms. In this study, we present a nontargeted lipidomics strategy to determine cellular lipid alterations after scoparone exposure in primary hepatocytes. Lipid metabolic profiles were analyzed by high-performance liquid chromatography coupled with time-of-flight mass spectrometry, and a novel imaging TransOmics tool has been developed for the analysis of high-resolution MS data, including the data pretreatment, visualization, automated identification, deconvolution and quantification of lipid species. Chemometric and statistical analyses of the obtained lipid fingerprints revealed the global lipidomic alterations and tested the therapeutic effects of scoparone. Identification of ten proposed lipids contributed to the better understanding of the effects of scoparone on lipid metabolism in hepatocytes. The most striking finding was that scoparone caused comprehensive lipid changes, as represented by significant changes of the identificated lipids. The levels of identified PG(19:1(9Z)/14:0), PE(17:1(9Z)/0:0), PE(19:1(9Z)/0:0) were found to be upregulated in ethanol-induced group, whereas the levels in scoparone group were downregulated. Lipid metabolism in primary hepatocytes was changed significantly by scoparone treatment. We believe that this novel approach could substantially broaden the applications of high mass resolution mass spectrometry for cellular lipidomics. PMID:27306123

  10. Environmental factors affecting indole metabolism under anaerobic conditions

    SciTech Connect

    Madsen, E.L.; Francis, A.J.; Bollag, J.M.

    1988-01-01

    The influence of physiological and environmental factors on the accumulation of oxindole during anaerobic indole metabolism was investigated by high-performance liquid chromatography. Under methanogenic conditions, indole was temporarily converted to oxindole in stoichiometric amounts in media inoculated with three freshwater sediments and an organic soil. In media inoculated with methanogenic sewage sludge, the modest amounts of oxindole detected at 35/sup 0/C reached higher concentrations and persisted longer when the incubation temperature was decreased from 35 to 15/sup 0/C. Also, decreasing the concentration of sewage sludge used as an inoculum from 50 to 1% caused an increase in the accumulation of oxindole from 10 to 75% of the indole added. Under denitrifying conditions, regardless of the concentration or source of the inoculum, oxindole appeared in trace amounts but did not accumulate during indole metabolism. In addition, denitrifying consortia which previously metabolized indole degraded oxindole with no lag period. Our data suggest that oxindole accumulation under methanogenic, but not under denitrifying conditions is caused by differences between relative rates of oxindole production and destruction.

  11. Vescalagin from Pink Wax Apple [Syzygium samarangense (Blume) Merrill and Perry] Alleviates Hepatic Insulin Resistance and Ameliorates Glycemic Metabolism Abnormality in Rats Fed a High-Fructose Diet.

    PubMed

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

    2016-02-10

    This study investigates the ameliorative effect of vescalagin (VES) isolated from Pink wax apple fruit on hepatic insulin resistance and abnormal carbohydrate metabolism in high-fructose diet (HFD)-induced hyperglycemic rats. The results show that in HFD rats, VES significantly reduced the values of the area under the curve for glucose in an oral glucose tolerance test and the homeostasis model assessment of insulin resistance index. VES significantly enhanced the activity of hepatic antioxidant enzymes while reducing thiobarbituric acid-reactive substances in HFD rats. Western blot assay revealed that VES reduced hepatic protein expression involved in inflammation pathways while up-regulating expression of hepatic insulin signaling-related proteins. Moreover, VES up-regulated the expression of hepatic glycogen synthase and hepatic glycolysis-related proteins while down-regulating hepatic gluconeogenesis-related proteins in HFD rats. This study suggests some therapeutic potential of VES in preventing the progression of diabetes mellitus. PMID:26800576

  12. Metabolic transformations of dietary polyphenols: comparison between in vitro colonic and hepatic models and in vivo urinary metabolites.

    PubMed

    Vetrani, Claudia; Rivellese, Angela A; Annuzzi, Giovanni; Adiels, Martin; Borén, Jan; Mattila, Ismo; Orešič, Matej; Aura, Anna-Marja

    2016-07-01

    Studies on metabolism of polyphenols have revealed extensive transformations in the carbon backbone by colonic microbiota; however, the influence of microbial and hepatic transformations on human urinary metabolites has not been explored. Therefore, the aims of this study were (1) to compare the in vitro microbial phenolic metabolite profile of foods and beverages with that excreted in urine of subjects consuming the same foodstuff and (2) to explore the role of liver on postcolonic metabolism of polyphenols by using in vitro hepatic models. A 24-h urinary phenolic metabolite profile was evaluated in 72 subjects participating in an 8-week clinical trial during which they were randomly assigned to diets differing for polyphenol content. Polyphenol-rich foods and beverages used in the clinical trial were subjected to human fecal microbiota in the in vitro colon model. Metabolites from green tea, one of the main components of the polyphenol-rich diet, were incubated with primary hepatocytes to highlight hepatic conversion of polyphenols. The analyses were performed using targeted gas chromatography with mass spectrometer (GCxGC-TOFMS:colon model; GC-MS: urine and hepatocytes). A significant correlation was found between urinary and colonic metabolites with C1-C3 side chain (P=.040). However, considerably higher amounts of hippuric acid, 3-hydroxybenzoic acid and ferulic acid were detected in urine than in the colon model. The hepatic conversion showed additional amounts of these metabolites complementing the gap between in vitro colon model and the in vivo urinary excretion. Therefore, combining in vitro colon and hepatic models may better elucidate the metabolism of polyphenols from dietary exposure to urinary metabolites. PMID:27155917

  13. Effect and mechanism of waterborne prolonged Zn exposure influencing hepatic lipid metabolism in javelin goby Synechogobius hasta.

    PubMed

    Huang, Chao; Luo, Zhi; Hogstrand, Christer; Chen, Feng; Shi, Xi; Chen, Qi-Liang; Song, Yu-Feng; Pan, Ya-Xiong

    2016-07-01

    The present study was conducted to determine the effect and mechanism of waterborne Zn exposure influencing hepatic lipid deposition and metabolism in javelin goby Synechogobius hasta. S. hasta were exposed to four waterborne Zn concentrations (Zn 0.005 [control], 0.18, 0.36 and 0.55 mg l(-1) , respectively) for 60 days. Sampling occurred at days 20, 40 and 60, respectively. Zn exposure increased Zn content, declined hepatic lipid content and reduced viscerosomatic and hepatosomatic indices and lipogenic enzyme activities, including 6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS). At days 20 and 60, Zn exposure decreased hepatic mRNA levels of 6PGD, G6PD, ME, FAS, acetyl-CoA carboxylase (ACC)α, ACCβ, hormone-sensitive lipase (HSL)a, HSLb, sterol-regulator element-binding protein (SREBP)-1, peroxisome proliferators-activated receptor (PPAR)α and PPARγ. However, the mRNA levels of CPT 1 and adipose triglyceride lipase increased following Zn exposure. On day 40, Zn exposure reduced hepatic mRNA expression of 6PGD, G6PD, ME, FAS, ACCα, ACCβ, HSLa, HSLb, SREBP-1 and PPARγ but increased mRNA expression of CPT 1, adipose triglyceride lipase and PPARα. General speaking, Zn exposure reduced hepatic lipid content by inhibiting lipogenesis and stimulating lipolysis. For the first time, the present study provided evidence that chronic Zn exposure differentially influenced mRNA expression and activities of genes and enzymes involved in lipogenic and lipolytic metabolism in a duration-dependent manner, and provided new insight into the relationship between metal elements and lipid metabolism. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26602879

  14. 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 mice.

    PubMed

    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

    2014-04-01

    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

  15. 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

  16. Factors affecting effectiveness of vaccination against hepatitis B virus in hemodialysis patients

    PubMed Central

    Eleftheriadis, Theodoros; Pissas, Georgios; Antoniadi, Georgia; Liakopoulos, Vassilios; Stefanidis, Ioannis

    2014-01-01

    Hepatitis B virus (HBV) is a major global health problem. Despite the success of the general measures against blood transmitted infections in hemodialysis (HD) units, the prevalence of HBV infection among the HD patients is still high. Thus vaccination against HBV is indicating in this population. However, compared with the general population the seroprotection achieved in HD patients remains relatively low, at about 70%. In this review patient, HD procedure and vaccine-associated factors that affect the efficacy of HBV vaccination are analyzed. Also alternative routes of HBV vaccine administration as well as new and more immunogenic vaccine formulations are discussed. However, besides scientific progress, vigilance of HD physicians and staff regarding the general measures against the transmission of blood borne infections and the vaccination against HBV is also required for reducing the prevalence of this viral infection. PMID:25232238

  17. Factors affecting effectiveness of vaccination against hepatitis B virus in hemodialysis patients.

    PubMed

    Eleftheriadis, Theodoros; Pissas, Georgios; Antoniadi, Georgia; Liakopoulos, Vassilios; Stefanidis, Ioannis

    2014-09-14

    Hepatitis B virus (HBV) is a major global health problem. Despite the success of the general measures against blood transmitted infections in hemodialysis (HD) units, the prevalence of HBV infection among the HD patients is still high. Thus vaccination against HBV is indicating in this population. However, compared with the general population the seroprotection achieved in HD patients remains relatively low, at about 70%. In this review patient, HD procedure and vaccine-associated factors that affect the efficacy of HBV vaccination are analyzed. Also alternative routes of HBV vaccine administration as well as new and more immunogenic vaccine formulations are discussed. However, besides scientific progress, vigilance of HD physicians and staff regarding the general measures against the transmission of blood borne infections and the vaccination against HBV is also required for reducing the prevalence of this viral infection. PMID:25232238

  18. Hepatitis B virus and microRNAs: Complex interactions affecting hepatitis B virus replication and hepatitis B virus-associated diseases

    PubMed Central

    Lamontagne, Jason; Steel, Laura F; Bouchard, Michael J

    2015-01-01

    Chronic infection with the hepatitis B virus (HBV) is the leading risk factor for the development of hepatocellular carcinoma (HCC). With nearly 750000 deaths yearly, hepatocellular carcinoma is the second highest cause of cancer-related death in the world. Unfortunately, the molecular mechanisms that contribute to the development of HBV-associated HCC remain incompletely understood. Recently, microRNAs (miRNAs), a family of small non-coding RNAs that play a role primarily in post-transcriptional gene regulation, have been recognized as important regulators of cellular homeostasis, and altered regulation of miRNA expression has been suggested to play a significant role in virus-associated diseases and the development of many cancers. With this in mind, many groups have begun to investigate the relationship between miRNAs and HBV replication and HBV-associated disease. Multiple findings suggest that some miRNAs, such as miR-122, and miR-125 and miR-199 family members, are playing a role in HBV replication and HBV-associated disease, including the development of HBV-associated HCC. In this review, we discuss the current state of our understanding of the relationship between HBV and miRNAs, including how HBV affects cellular miRNAs, how these miRNAs impact HBV replication, and the relationship between HBV-mediated miRNA regulation and HCC development. We also address the impact of challenges in studying HBV, such as the lack of an effective model system for infectivity and a reliance on transformed cell lines, on our understanding of the relationship between HBV and miRNAs, and propose potential applications of miRNA-related techniques that could enhance our understanding of the role miRNAs play in HBV replication and HBV-associated disease, ultimately leading to new therapeutic options and improved patient outcomes. PMID:26139985

  19. Tissue lipid metabolism and hepatic metabolomic profiling in response to supplementation of fermented cottonseedmeal in the diets of broiler chickens*

    PubMed Central

    Nie, Cun-xi; Zhang, Wen-ju; Wang, Yong-qiang; Liu, Yan-feng; Ge, Wen-xia; Liu, Jian-cheng

    2015-01-01

    This study investigated the effects of fermented cottonseed meal (FCSM) on lipid metabolites, lipid metabolism-related gene expression in liver tissues and abdominal adipose tissues, and hepatic metabolomic profiling in broiler chickens. One hundred and eighty 21-d-old broiler chickens were randomly divided into three diet groups with six replicates of 10 birds in each group. The three diets consisted of a control diet supplemented with unfermented cottonseed meal, an experimental diet of cottonseed meal fermented by Candida tropicalis, and a second experimental diet of cottonseed meal fermented by C. tropicalis plus Saccharomyces cerevisae. The results showed that FCSM intake significantly decreased the levels of abdominal fat and hepatic triglycerides (P<0.05 for both). Dietary FCSM supplementation down-regulated the mRNA expression of fatty acid synthase and acetyl CoA carboxylase in liver tissues and the lipoprotein lipase expression in abdominal fat tissues (P<0.05 for both). FCSM intake resulted in significant metabolic changes of multiple pathways in the liver involving the tricarboxylic acid cycle, synthesis of fatty acids, and the metabolism of glycerolipid and amino acids. These findings indicated that FCSM regulated lipid metabolism by increasing or decreasing the expression of the lipid-related gene and by altering multiple endogenous metabolites. Lipid metabolism regulation is a complex process, this discovery provided new essential information about the effects of FCSM diets in broiler chickens and demonstrated the great potential of nutrimetabolomics in researching complex nutrients added to animal diets. PMID:26055906

  20. Hepatic SRC-1 Activity Orchestrates Transcriptional Circuitries of Amino Acid Pathways with Potential Relevance for Human Metabolic Pathogenesis

    PubMed Central

    Tannour-Louet, Mounia; York, Brian; Tang, Ke; Stashi, Erin; Bouguerra, Hichem; Zhou, Suoling; Yu, Hui; Wong, Lee-Jun C.; Stevens, Robert D.; Xu, Jianming; Newgard, Christopher B.; O'Malley, Bert W.

    2014-01-01

    Disturbances in amino acid metabolism are increasingly recognized as being associated with, and serving as prognostic markers for chronic human diseases, such as cancer or type 2 diabetes. In the current study, a quantitative metabolomics profiling strategy revealed global impairment in amino acid metabolism in mice deleted for the transcriptional coactivator steroid receptor coactivator (SRC)-1. Aberrations were hepatic in origin, because selective reexpression of SRC-1 in the liver of SRC-1 null mice largely restored amino acids concentrations to normal levels. Cistromic analysis of SRC-1 binding sites in hepatic tissues confirmed a prominent influence of this coregulator on transcriptional programs regulating amino acid metabolism. More specifically, SRC-1 markedly impacted tyrosine levels and was found to regulate the transcriptional activity of the tyrosine aminotransferase (TAT) gene, which encodes the rate-limiting enzyme of tyrosine catabolism. Consequently, SRC-1 null mice displayed low TAT expression and presented with hypertyrosinemia and corneal alterations, 2 clinical features observed in the human syndrome of TAT deficiency. A heterozygous missense variant of SRC-1 (p.P1272S) that is known to alter its coactivation potential, was found in patients harboring idiopathic tyrosinemia-like disorders and may therefore represent one risk factor for their clinical symptoms. Hence, we reinforce the concept that SRC-1 is a central factor in the fine orchestration of multiple pathways of intermediary metabolism, suggesting it as a potential therapeutic target that may be exploitable in human metabolic diseases and cancer. PMID:25148457

  1. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model.

    PubMed

    Szary, Nicholas; Rector, R Scott; Uptergrove, Grace M; Ridenhour, Suzanne E; Shukla, Shivendra D; Thyfault, John P; Koch, Lauren G; Britton, Steven L; Ibdah, Jamal A

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide "metabolic protection" from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  2. High Intrinsic Aerobic Capacity Protects against Ethanol-Induced Hepatic Injury and Metabolic Dysfunction: Study Using High Capacity Runner Rat Model

    PubMed Central

    Szary, Nicholas; Rector, R. Scott; Uptergrove, Grace M.; Ridenhour, Suzanne E.; Shukla, Shivendra D.; Thyfault, John P.; Koch, Lauren G.; Britton, Steven L.; Ibdah, Jamal A.

    2015-01-01

    Rats artificially selected over several generations for high intrinsic endurance/aerobic capacity resulting in high capacity runners (HCR) has been developed to study the links between high aerobic fitness and protection from metabolic diseases (Wisloff et al., Science, 2005). We have previously shown that the HCR strain have elevated hepatic mitochondrial content and oxidative capacity. In this study, we tested if the elevated hepatic mitochondrial content in the HCR rat would provide “metabolic protection” from chronic ethanol-induced hepatic steatosis and injury. The Leiber-Decarli liquid diet with ethanol (7% v/v; HCR-E) and without (HCR-C) was given to HCR rats (n = 8 per group) from 14 to 20 weeks of age that were weight matched and pair-fed to assure isocaloric intake. Hepatic triglyceride (TG) content and macro- and microvesicular steatosis were significantly greater in HCR-E compared with HCR-C (p < 0.05). In addition, hepatic superoxide dismutase activity and glutathione levels were significantly (p < 0.05) reduced in the HCR-E rats. This hepatic phenotype also was associated with reduced total hepatic fatty acid oxidation (p = 0.03) and β-hydroxyacyl-CoA dehydrogenase activity (p = 0.01), and reductions in microsomal triglyceride transfer protein and apoB-100 protein content (p = 0.01) in HCR-E animals. However, despite these documented hepatic alterations, ethanol ingestion failed to induce significant hepatic liver injury, including no changes in hepatic inflammation, or serum alanine amino transferase (ALTs), free fatty acids (FFAs), triglycerides (TGs), insulin, or glucose. High intrinsic aerobic fitness did not reduce ethanol-induced hepatic steatosis, but protected against ethanol-induced hepatic injury and systemic metabolic dysfunction in a high aerobic capacity rat model. PMID:26610588

  3. Direct imaging of the disruption of hepatitis C virus replication complexes by inhibitors of lipid metabolism

    SciTech Connect

    Lyn, Rodney K.; Kennedy, David C.; Sagan, Selena M.; Blais, David R.; Rouleau, Yanouchka; Pegoraro, Adrian F.; Xie, X. Sunney; Stolow, Albert; Pezacki, John Paul

    2009-11-10

    Here we have simultaneously characterized the influence of inhibitors of peroxisome proliferator-activated receptor alpha (PPARalpha) and the mevalonate pathway on hepatocyte lipid metabolism and the subcellular localization of hepatitis C virus (HCV) RNA using two-photon fluorescence (TPF) and coherent anti-Stokes Raman scattering (CARS) microscopy. Using this approach, we demonstrate that modulators of PPARalpha signaling rapidly cause the dispersion of HCV RNA from replication sites and simultaneously induce lipid storage and increases in lipid droplet size. We demonstrate that reductions in the levels of cholesterol resulting from inhibition of the mevalonate pathway upregulates triglyceride levels. We also show that the rate of dispersion of HCV RNA is very rapid when using a PPARalpha antagonist. This occurs with a faster rate to that of direct inhibition of 3-hydroxy-3-methyglutaryl CoA reductase (HMG-CoA reductase) using lovastatin in living cells, demonstrating the potential therapeutic value of modulating host cell pathways as part of a strategy to eliminate chronic HCV infection.

  4. Differentiating mucosal and hepatic metabolism of budesonide by local pretreatment with increasing doses of ketoconazole in the proximal jejunum.

    PubMed

    Seidegård, Janeric; Nyberg, Lars; Borgå, Olof

    2012-08-15

    Many drugs undergo first-pass metabolism both in the gut mucosa and the liver, but little is known about the relative efficiency of these two pathways. The objective of this study was to differentiate between mucosal and hepatic metabolism using budesonide as a probe. After a light breakfast, budesonide, 3mg, was infused locally in the proximal jejunum of eight healthy men on seven occasions, on six occasions after administering the CYP3A4 inhibitor ketoconazole 5 min before in the same jejunal position. The dose range of local inhibitor was 1-128 mg, the highest dose also preceded by an oral dose of 200mg given 12h earlier. Simultaneously with intrajejunal budesonide, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated after LC-MS/MS analysis. Bioavailability of budesonide without inhibition was 27(12-42)%. All ketoconazole doses increased budesonide bioavailability. However, systemic clearance of labelled budesonide was unaffected by ketoconazole doses up to 16 mg but decreased significantly at doses of 64 mg and above. At the two highest doses (128 mg and above) bioavailability approached 100%, showing that budesonide was completely absorbed from jejunum. Ketoconazole doses up to 16 mg appeared to inhibit only mucosal enzymes, while higher doses inhibited also hepatic metabolism. Applying sigmoid E(max)-models of the mean inhibitions in mucosa and liver indicated that, in this study performed under fed conditions, their uninhibited extraction ratios of budesonide were approximately 0.32 and 0.60, respectively. Ketoconazole doses that inhibited half the metabolism were estimated at about 1mg in the mucosa and about 50mg in the liver. In conclusion, this study gave a rough estimate of the relation between mucosal and hepatic first-pass metabolism of budesonide. PMID:22538054

  5. Albumin Supplement Affects the Metabolism and Metabolism-Related Drug-Drug Interaction of Fenoprofen Enantiomers.

    PubMed

    Wang, Nan; Wang, Feng; Meng, Yu; Yang, Guo-Hui; Chen, Ju-Wu; Wang, Jia-Xiang

    2015-07-01

    The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 μM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 μM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction. PMID:26037509

  6. Metabolic differences in temperamental Brahman cattle can affect productivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many factors may adversely affect the growth and productivity of livestock. These include stressors associated with management practices, such as weaning, handling relative to transportation, and vaccination, that can modulate growth through the production of stress-related hormones (i.e., cortisol,...

  7. Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans.

    PubMed

    Shen, Jianwei; Serby, Michael; Reed, Aimee; Lee, Anthony J; Menon, Rajeev; Zhang, Xiaomei; Marsh, Kennan; Wan, Xia; Kavetskaia, Olga; Fischer, Volker

    2016-08-01

    Dasabuvir [also known as ABT-333 or N-(6-(3-(tert-butyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide] is a potent non-nucleoside NS protein 5B polymerase inhibitor of the hepatitis C virus (HCV) and is being developed in combination with paritaprevir/ritonavir and ombitasvir in an oral regimen with three direct-acting antivirals for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of dasabuvir in humans. After administration of a single oral dose of 400-mg [(14)C]dasabuvir (without coadministration of paritaprevir/ritonavir and ombitasvir) to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 96.6%. The recovery from the individual subjects ranged from 90.8% to 103%. Dasabuvir and corresponding metabolites were predominantly eliminated in feces (94.4% of the dose) and minimally through renal excretion (2.2% of the dose). The biotransformation of dasabuvir primarily involves hydroxylation of the tert-butyl group to form active metabolite M1 [N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide], followed by glucuronidation and sulfation of M1 and subsequent secondary oxidation. Dasabuvir was the major circulating component (58% of total radioactivity) in plasma, followed by metabolite M1 (21%). Other minor metabolites represented < 10% each of total circulating radioactivity. Dasabuvir was cleared mainly through cytochrome P450-mediated oxidation metabolism to M1. M1 and its glucuronide and sulfate conjugates were primarily eliminated in feces. Subsequent oxidation of M1 to the tert-butyl acid, followed by formation of the corresponding glucuronide conjugate, plays a secondary role in elimination. Cytochrome P450 profiling indicated that dasabuvir was mainly metabolized by CYP2C8, followed by CYP3A4. In

  8. Downregulation of Mouse Hepatic CYP3A Protein by 3-Methylcholanthrene Does Not Require Cytochrome P450-Dependent Metabolism

    PubMed Central

    Lee, Chunja; Ding, Xinxin

    2013-01-01

    The aryl hydrocarbon receptor (AHR)–dependent induction of cytochromes P450 (P450) such as CYP1A1 by 3-methylcholanthrene (MC) and related polycyclic aromatic hydrocarbons is well characterized. We reported previously that MC treatment triggers a pronounced downregulation, particularly at the protein level, of mouse hepatic Cyp3a11, a counterpart of the key human drug-metabolizing enzyme CYP3A4. To determine whether this effect of MC requires hepatic microsomal P450 activity, we studied liver Cpr-null (LCN) mice with hepatocyte-specific conditional deletion of the NADPH-cytochrome P450 oxidoreductase gene. In vehicle-treated animals, basal levels of CYP3A11 mRNA and CYP3A protein immunoreactivity were elevated by approximately 9-fold in LCN mice compared with wild-type (WT) mice, whereas CYP3A catalytic activity was profoundly compromised in LCN mice. MC treatment caused suppression of CYP3A11 mRNA, CYP3A protein immunoreactivity, and CYP3A catalytic activity in WT mice, and the MC effects at the mRNA and protein levels were maintained in LCN mice. Flavin-containing monooxygenase-3 (Fmo3) induction by MC was suggested previously to occur via an AHR-dependent mechanism requiring conversion of the parent compound to DNA-damaging reactive metabolites; however, hepatic FMO3 mRNA levels were dramatically increased by MC in both WT and LCN mice. MC did not function as a mechanism-based inactivator of CYP3A enzymes in hepatic microsomes prepared from untreated WT mice, under conditions in which 1-aminobenzotriazole caused marked NADPH-dependent loss of total P450 content and CYP3A catalytic activity. These results indicate that MC downregulates mouse hepatic CYP3A protein via a pretranslational mechanism that does not require hepatic microsomal P450-dependent activity. PMID:23846873

  9. The metabolism and disposition of a potent inhibitor of hepatitis C virus NS3/4A protease.

    PubMed

    Monteagudo, E; Fonsi, M; Chu, X; Bleasby, K; Evers, R; Pucci, V; Orsale, M V; Cianetti, S; Ferrara, M; Harper, S; Laufer, R; Rowley, M; Summa, V

    2010-12-01

    Compound A ((1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-8-carboxamide) is a prototype of a series of subnanomolar inhibitors of genotypes 1, 2, and 3 hepatitis C virus (HCV) NS3/4A proteases. HCV NS3/4A protease inhibitors have demonstrated high antiviral effects in patients with chronic HCV infection and are likely to form a key component of future HCV therapy. Compound A showed excellent liver exposure in rats, which is essential for compounds intended to treat HCV. The compound was mainly eliminated intact in bile and showed greater than dose proportional systemic exposure in rats. Compound A demonstrated time- and temperature-dependent uptake into rat and human hepatocytes and proved to be a substrate for rat hepatic uptake transporter Oatp1b2 and for human hepatic uptake transporters OATP1B1 and OATP1B3. The liver selectivity observed for this compound is likely to be due to transporter-mediated hepatic uptake together with moderate passive permeability. Metabolism was mainly CYP3A-mediated and generated a reactive epoxide on the vinylcyclopropyl sulfonamide moiety that could be quenched by glutathione. Similar metabolic profiles of Compound A were obtained in liver microsomes of rats and humans. The oral bioavailability at 5 mg/kg was low due to extensive hepatic first-pass effect but clearly the intestinal absorption was enough to deliver a high amount of the compound to the liver. The metabolism and disposition properties of Compound A are particularly attractive to support its evaluation as a drug candidate for the treatment of hepatitis C. PMID:20925584

  10. Spastin Binds to Lipid Droplets and Affects Lipid Metabolism

    PubMed Central

    Papadopoulos, Chrisovalantis; Orso, Genny; Mancuso, Giuseppe; Herholz, Marija; Gumeni, Sentiljana; Tadepalle, Nimesha; Jüngst, Christian; Tzschichholz, Anne; Schauss, Astrid; Höning, Stefan; Trifunovic, Aleksandra; Daga, Andrea; Rugarli, Elena I.

    2015-01-01

    Mutations in SPAST, encoding spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). HSP is characterized by weakness and spasticity of the lower limbs, owing to progressive retrograde degeneration of the long corticospinal axons. Spastin is a conserved microtubule (MT)-severing protein, involved in processes requiring rearrangement of the cytoskeleton in concert to membrane remodeling, such as neurite branching, axonal growth, midbody abscission, and endosome tubulation. Two isoforms of spastin are synthesized from alternative initiation codons (M1 and M87). We now show that spastin-M1 can sort from the endoplasmic reticulum (ER) to pre- and mature lipid droplets (LDs). A hydrophobic motif comprised of amino acids 57 through 86 of spastin was sufficient to direct a reporter protein to LDs, while mutation of arginine 65 to glycine abolished LD targeting. Increased levels of spastin-M1 expression reduced the number but increased the size of LDs. Expression of a mutant unable to bind and sever MTs caused clustering of LDs. Consistent with these findings, ubiquitous overexpression of Dspastin in Drosophila led to bigger and less numerous LDs in the fat bodies and increased triacylglycerol levels. In contrast, Dspastin overexpression increased LD number when expressed specifically in skeletal muscles or nerves. Downregulation of Dspastin and expression of a dominant-negative variant decreased LD number in Drosophila nerves, skeletal muscle and fat bodies, and reduced triacylglycerol levels in the larvae. Moreover, we found reduced amount of fat stores in intestinal cells of worms in which the spas-1 homologue was either depleted by RNA interference or deleted. Taken together, our data uncovers an evolutionarily conserved role of spastin as a positive regulator of LD metabolism and open up the possibility that dysfunction of LDs in axons may contribute to the pathogenesis of HSP. PMID:25875445

  11. Relationship between murine Ah phenotype and the hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD)

    SciTech Connect

    Shen, E.S.; Olson, J.R.

    1986-03-05

    The Ah receptor has been correlated with the toxic effects of TCDD in C57BL/6J (B6) and DBA/2J (D2) mice. The B6 strain, which has a high affinity cytosolic Ah receptor, is more sensitive to TCDD than the D2 strain, which lacks this receptor. The metabolism of TCDD was studied by incubating /sup 14/C-TCDD (2.2 ..mu..M) with hepatocytes from control and TCDD-pretreated B6 and D2 mice. Mice were pretreated with TCDD at doses that maximally induce ethoxyresorufin-O-deethylase (EROD) activity, a measure of Ah locus responsiveness to TCDD (B6, 3..mu..g/kg, ip;D2, 30..mu..g/kg, ip). Similar cytochrome P-450 content was detected in control B6 and D2 hepatocytes, however, TCDD pretreatment increased P-450 content 400% in B6 and 300% in D2 mice. No difference in hepatic EROD activity was found between control B6 and D2 mice (81.7 and 101.7 pmol/min/nmol P-450, respectively), but EROD activity was increased 17-fold in B6 and 10-fold in D2 mice after TCDD administration. The average rate of hepatic TCDD metabolism over two hours was similar in control B6 and D2 mice (1.103 and 0.945 pmol/hr/mg cell protein, respectively), although some qualitative differences in the metabolites were detected by HPLC. TCDD pretreatment produced no quantitative or qualitative changes in TCDD metabolism. These results suggest that the rate of hepatic TCDD metabolism does not correlate with genetic differences at the Ah locus.

  12. Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice.

    PubMed

    Dawson, Paul Anthony; Gardiner, Brooke; Grimmond, Sean; Markovich, Daniel

    2006-07-12

    Sulfate plays an essential role in human growth and development, and its circulating levels are maintained by the renal Na+-SO42- cotransporter, NaS1. We previously generated a NaS1 knockout (Nas1-/-) mouse, an animal model for hyposulfatemia, that exhibits reduced growth and liver abnormalities including hepatomegaly. In this study, we investigated the hepatic gene expression profile of Nas1-/- mice using oligonucleotide microarrays. The mRNA expression levels of 92 genes with known functional roles in metabolism, cell signaling, cell defense, immune response, cell structure, transcription, or protein synthesis were increased (n = 51) or decreased (n = 41) in Nas1-/- mice when compared with Nas1+/+ mice. The most upregulated transcript levels in Nas1-/- mice were found for the sulfotransferase genes, Sult3a1 (approximately 500% increase) and Sult2a2 (100% increase), whereas the metallothionein-1 gene, Mt1, was among the most downregulated genes (70% decrease). Several genes involved in lipid and cholesterol metabolism, including Scd1, Acly, Gpam, Elov16, Acsl5, Mvd, Insig1, and Apoa4, were found to be upregulated (> or = 30% increase) in Nas1-/- mice. In addition, Nas1-/- mice exhibited increased levels of hepatic lipid (approximately 16% increase), serum cholesterol (approximately 20% increase), and low-density lipoprotein (approximately 100% increase) and reduced hepatic glycogen (approximately 50% decrease) levels. In conclusion, these data suggest an altered lipid and cholesterol metabolism in the hyposulfatemic Nas1-/- mouse and provide new insights into the metabolic state of the liver in Nas1-/- mice. PMID:16621889

  13. Moderate physical activity from childhood contributes to metabolic health and reduces hepatic fat accumulation in adult rats

    PubMed Central

    2013-01-01

    Background Obesity, oxidative stress and inflammation, by triggering insulin resistance, may contribute to the accumulation of hepatic fat, and this accumulation by lipotoxicity can lead the organ to fail. Because obesity is growing at an alarming rate and, worryingly, in a precocious way, the present study aimed to investigate the effects of moderate physical training performed from childhood to adulthood on liver fat metabolism in rats. Methods Twenty rats that were 28 days old were divided into two groups: control (C) and trained (T). The C Group was kept in cages without exercise, and the T group was submitted to swimming exercise for 1 hour/day, 5 days/week from 28 to 90 days of age (8 weeks) at 80% of the anaerobic threshold determined by the lactate minimum test. At the end of the experiment, the body weight gain, insulin sensitivity (glucose disappearance rate during the insulin tolerance test), concentrations of free fatty acids (FFA) and triglycerides (TG) and hepatic lipogenic rate were analyzed. For the statistical analysis, the Student t-test was used with the level of significance preset at 5%. Results The T group showed lower body weight gain, FFA concentrations, fat accumulation, hepatic lipogenic rate and insulin resistance. Conclusion The regular practice of moderate physical exercise from childhood can contribute to the reduction of obesity and insulin resistance and help prevent the development of accumulation of hepatic fat in adulthood. PMID:23496920

  14. Lactobacillus acidophilus NCFM affects vitamin E acetate metabolism and intestinal bile acid signature in monocolonized mice

    PubMed Central

    Roager, Henrik M; Sulek, Karolina; Skov, Kasper; Frandsen, Henrik L; Smedsgaard, Jørn; Wilcks, Andrea; Skov, Thomas H; Villas-Boas, Silas G; Licht, Tine R

    2014-01-01

    Monocolonization of germ-free (GF) mice enables the study of specific bacterial species in vivo. Lactobacillus acidophilus NCFMTM (NCFM) is a probiotic strain; however, many of the mechanisms behind its health-promoting effect remain unknown. Here, we studied the effects of NCFM on the metabolome of jejunum, cecum, and colon of NCFM monocolonized (MC) and GF mice using liquid chromatography coupled to mass-spectrometry (LC-MS). The study adds to existing evidence that NCFM in vivo affects the bile acid signature of mice, in particular by deconjugation. Furthermore, we confirmed that carbohydrate metabolism is affected by NCFM in the mouse intestine as especially the digestion of oligosaccharides (penta- and tetrasaccharides) was increased in MC mice. Additionally, levels of α-tocopherol acetate (vitamin E acetate) were higher in the intestine of GF mice than in MC mice, suggesting that NCFM affects the vitamin E acetate metabolism. NCFM did not digest vitamin E acetate in vitro, suggesting that direct bacterial metabolism was not the cause of the altered metabolome in vivo. Taken together, our results suggest that NCFM affects intestinal carbohydrate metabolism, bile acid metabolism and vitamin E metabolism, although it remains to be investigated whether this effect is unique to NCFM. PMID:24717228

  15. Lactobacillus acidophilus NCFM affects vitamin E acetate metabolism and intestinal bile acid signature in monocolonized mice.

    PubMed

    Roager, Henrik M; Sulek, Karolina; Skov, Kasper; Frandsen, Henrik L; Smedsgaard, Jørn; Wilcks, Andrea; Skov, Thomas H; Villas-Boas, Silas G; Licht, Tine R

    2014-01-01

    Monocolonization of germ-free (GF) mice enables the study of specific bacterial species in vivo. Lactobacillus acidophilus NCFM(TM) (NCFM) is a probiotic strain; however, many of the mechanisms behind its health-promoting effect remain unknown. Here, we studied the effects of NCFM on the metabolome of jejunum, cecum, and colon of NCFM monocolonized (MC) and GF mice using liquid chromatography coupled to mass-spectrometry (LC-MS). The study adds to existing evidence that NCFM in vivo affects the bile acid signature of mice, in particular by deconjugation. Furthermore, we confirmed that carbohydrate metabolism is affected by NCFM in the mouse intestine as especially the digestion of oligosaccharides (penta- and tetrasaccharides) was increased in MC mice. Additionally, levels of α-tocopherol acetate (vitamin E acetate) were higher in the intestine of GF mice than in MC mice, suggesting that NCFM affects the vitamin E acetate metabolism. NCFM did not digest vitamin E acetate in vitro, suggesting that direct bacterial metabolism was not the cause of the altered metabolome in vivo. Taken together, our results suggest that NCFM affects intestinal carbohydrate metabolism, bile acid metabolism and vitamin E metabolism, although it remains to be investigated whether this effect is unique to NCFM. PMID:24717228

  16. The effect of Smallanthus sonchifolius leaf extracts on rat hepatic metabolism.

    PubMed

    Valentová, K; Moncion, A; de Waziers, I; Ulrichová, J

    2004-03-01

    Smallanthus sonchifolius (yacon), originating from South America, has become popular in Japan and in New Zealand for its tubers which contain beta-1,2-oligofructans as the main saccharides. The plant is also successfully cultivated in Central Europe in the Czech Republic in particular. Its aerial part is used in Japan and in Brazil as a component in medicinal teas; while aqueous leaf extracts have been studied for their hypoglycemic activity in normal and diabetic rats. We have already demonstrated the high content of phenolic compounds in yacon leaf extracts and their in vitro antioxidant activity. In this paper, we present the effects of two organic fractions and two aqueous extracts from the leaves of S. sonchifolius on rat hepatocyte viability, on oxidative damage induced by tert-butyl hydroperoxide (t-BH) and allyl alcohol (AA), and on glucose metabolism and their insulin-like effect on the expression of cytochrome P450 (CYP) mRNA. All the extracts tested exhibited strong protective effect against oxidative damage to rat hepatocyte primary cultures in concentrations ranging from 1 to 1000 microg/ml, reduced hepatic glucose production via gluconeogenesis and glycogenolysis at 1000 microg/ml. Moreover, the effects of the organic fractions (200 and 250 microg/ml) and to a lesser extent, the tea infusion (500 microg/ml) on rat CYP2B and CYP2E mRNA expression, were comparable to those observed with insulin. The combination of radical scavenging, cytoprotective and anti-hyperglycemic activity predetermine S. sonchifolius leaves for use in prevention and treatment of chronic diseases involving oxidative stress, particularly diabetes. PMID:15242186

  17. In vivo and in vitro studies of hepatic lipid metabolism in lean and reobese fetal pigs

    SciTech Connect

    Hausman, G.J.; Trusty, C.D.; Martin, R.J.

    1986-03-01

    Fetuses were removed from pregnant (110 days of gestation) sows and 80 to 120 mg liver slices were prepared for two hour incubations with /sup 14/C-palmitate (1 ..mu..Ci/ml) or /sup 3/H/sub 2/O (1 mCi/ml). In vivo studies were conducted by injecting a single bolus of 0.5 or 10 ml of Liposyn (a 10% safflower oil emulsion) into fetuses (umbilical vein). One hour post injection (Liposyn) fetuses were removed from the uterus. Subsequently liver lipids were extracted and gas chromatographic analysis for 16:0, 18:0, 18:1, 18:2 and 20:4 were performed. Incorporation of C/sup 14/-palmitate into total lipids was higher in lean livers whereas incorporation into CO/sub 2/ was independent of fetal strain. Incorporation of /sup 3/H/sub 2/O into triglyceride fatty acids was similar in lean and obese livers. Fatty acid composition of livers indicated strain differences (obese versus lean for 16:0 = 52 vs 27.8%; 18:0 = 20 vs 16.8%; 18:1 = 16.3 vs 32.6%; 20:4 = 8.8 vs 17.6%). There was a similar Liposyn dose dependent increase in the amount of 18:2 in chromatographs of lean (n = 7) and obese (n = 7) livers. Administration of Liposyn caused a significant increase in the amount of 18:1 and 20:4 in lean livers (least squares means +/- SEM, 0 vs 0.5 ml for 20:4 = .31 +/- .03 vs .48 +/- .04) but no increase in preobese livers. These studies illustrate significant alterations in hepatic lipid metabolism in the preobese state.

  18. Metabolism and Disposition of the Hepatitis C Protease Inhibitor Paritaprevir in Humans.

    PubMed

    Shen, Jianwei; Serby, Michael; Reed, Aimee; Lee, Anthony J; Zhang, Xiaomei; Marsh, Kennan; Khatri, Amit; Menon, Rajeev; Kavetskaia, Olga; Fischer, Volker

    2016-08-01

    Paritaprevir (also known as ABT-450), a potent NS3-4A serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with ombitasvir and dasabuvir in a three-direct-acting antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]paritaprevir coadministered with 100 mg of ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2) amide hydrolysis at the acyl cyclopropane-sulfonamide moiety and the pyrazine-2-carboxamide moiety. Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity. Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of paritaprevir were characterized, and the structures of metabolites in circulation and excreta were elucidated. PMID:27179127

  19. Metabolism of glycerophospholipid, bile acid and retinol is correlated with the early outcomes of autoimmune hepatitis.

    PubMed

    Zhou, Chao; Jia, Hong-Mei; Liu, Yue-Tao; Yu, Meng; Chang, Xing; Ba, Yuan-Ming; Zou, Zhong-Mei

    2016-04-26

    Autoimmune hepatitis (AIH) is a complex liver disease with an increasing prevalence in recent years and can develop into the severe or fulminant form if the patients are not diagnosed accurately or treated in time. However, AIH accurate diagnosis, especially at the early stage, is still difficult to perform due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features. To evaluate the biochemical process of AIH at the early stage, we investigated serum metabolic alterations in mice with liver injury induced by concanavalin A (Con A), which closely mimics the immune and inflammatory response of AIH in humans. Metabonomic profiling was performed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC Q-TOF MS). As a result, fourteen metabolites were detected as potential biomarkers related to the early stage of the liver injury, including two bile acids (taurocholic acid (V1) and taurochenodeoxycholic acid (V2)), three long-chain acylcarnitines (tetradecanoylcarnitine (V4), linoleyl carnitine (V8) and l-palmitoylcarnitine (V9)), seven glycerophospholipids (lysoPE (18 : 0/0 : 0) (V3), lysoPC (16 : 0) (V5), lysoPC (18 : 1) (V7), lysoPC (18 : 0) (V10), lysoPC (20 : 1) (V11), lysoPE (22 : 0/0 : 0) (V12) and lysoPC (20 : 0) (V13)), a bilirubin (V14), and a retinyl ester (V6). Moreover, partial least square regression analysis (RLS-RA) showed that metabolism of glycerophospholipids (P2), bile acids (P4) and retinol (P5) was highly correlated with the clinical outcomes, suggesting they played key roles in the early stage of the liver injury. Our results also demonstrated that a metabonomic approach coupled with PLS-RA is a powerful tool with which changes can be characterized in the levels of endogenous metabolites associated with disease progression and to assist in further understanding the molecular mechanism of the disease. PMID

  20. Vitamin C modulates the metabolic and cytokine profiles, alleviates hepatic endoplasmic reticulum stress, and increases the life span of Gulo−/− mice

    PubMed Central

    Aumailley, Lucie; Warren, Alessandra; Garand, Chantal; Dubois, Marie Julie; Paquet, Eric R.; Le Couteur, David G.; Marette, André; Cogger, Victoria C.; Lebel, Michel

    2016-01-01

    Suboptimal intake of dietary vitamin C (ascorbate) increases the risk of several chronic diseases but the exact metabolic pathways affected are still unknown. In this study, we examined the metabolic profile of mice lacking the enzyme gulonolactone oxidase (Gulo) required for the biosynthesis of ascorbate. Gulo−/− mice were supplemented with 0%, 0.01%, and 0.4% ascorbate (w/v) in drinking water and serum was collected for metabolite measurements by targeted mass spectrometry. We also quantified 42 serum cytokines and examined the levels of different stress markers in liver. The metabolic profiles of Gulo−/− mice treated with ascorbate were different from untreated Gulo−/− and normal wild type mice. The cytokine profiles of Gulo−/− mice, in return, overlapped the profile of wild type animals upon 0.01% or 0.4% vitamin C supplementation. The life span of Gulo−/− mice increased with the amount of ascorbate in drinking water. It also correlated significantly with the ratios of serum arginine/lysine, tyrosine/phenylalanine, and the ratio of specific species of saturated/unsaturated phosphatidylcholines. Finally, levels of hepatic phosphorylated endoplasmic reticulum associated stress markers IRE1α and eIF2α correlated inversely with serum ascorbate and life span suggesting that vitamin C modulates endoplasmic reticulum stress response and longevity in Gulo−/− mice. PMID:26922388

  1. Covariation Analysis of Serumal and Urinary Metabolites Suggests Aberrant Glycine and Fatty Acid Metabolism in Chronic Hepatitis B

    PubMed Central

    Yang, Xue; Kong, Xiangliang; Cao, Zhiwei; Zhang, Yongyu; Hu, Yiyang; Tang, Kailin

    2016-01-01

    Background Chronic hepatitis b (CHB) is one of the most serious viral diseases threatening human health by putting patients at lifelong risk of cirrhosis and hepatocellular carcinoma (HCC). Although some proofs of altered metabolites in CHB were accumulated, its metabolic mechanism remains poorly understood. Analyzing covariations between metabolites may provide new hints toward underlying metabolic pathogenesis in CHB patients. Methods The present study collected paired urine and serum samples from the same subjects including 145 CHB and 23 healthy controls. A large-scale analysis of metabolites’ covariation within and across biofluids was systematically done to explore the underlying biological evidences for reprogrammed metabolism in CHB. Randomization and relative ranking difference were introduced to reduce bias caused by different sample size. More importantly, functional indication was interpreted by mapping differentially changed covariations to known metabolic pathways. Results Our results suggested reprogrammed pathways related to glycine metabolism, fatty acids metabolism and TCA cycle in CHB patients. With further improvement, the covariation analysis combined with network association study would pave new alternative way to interpret functional clues in clinical multi-omics data. PMID:27228119

  2. NF-E2-related factor 2 deletion facilitates hepatic fatty acids metabolism disorder induced by high-fat diet via regulating related genes in mice.

    PubMed

    Wang, Xinghe; Li, Chunyan; Xu, Shang; Ishfaq, Muhammad; Zhang, Xiuying

    2016-08-01

    There is increasing evidence that Nrf2 participates in hepatic fatty acid metabolism in non-alcoholic fatty liver disease; however, the mechanism remains unclear. We investigated the role of Nrf2 in hepatic fatty acid metabolism disorder induced by high-fat diet (HFD). Mice fed HFD developed hepatic steatosis and exhibited Nrf2 deficiency. Change of fatty acid composition mediated by Nrf2 deletion was observed predominantly in the liver and not the serum. HFD-induced variations in hepatic 18-carbon and 22-carbon fatty acids were enhanced by Nrf2 deficiency. In the HFD group, Nrf2 deficiency led to increases in the mRNA expression of PPARα, FXR, FAS, LXR and ACC-1, while levels of PGC-1α and Srebp-1c mRNA were decreased. Nrf2 mRNA expression was enhanced in the liver of HFD-induced wild type mice, whereas it was undetectable in Nrf2-null mice. These results suggest that Nrf2 deficiency induced by HFD promoted hepatic fatty acid metabolism disorder by altering 18-carbon and 22-carbon fatty acid composition. Changes in fatty acid content were also associated with alteration of the transcription of genes involved in hepatic fatty acid metabolism. PMID:27311796

  3. Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content.

    PubMed

    Machicao, Fausto; Peter, Andreas; Machann, Jürgen; Königsrainer, Ingmar; Böhm, Anja; Lutz, Stefan Zoltan; Heni, Martin; Fritsche, Andreas; Schick, Fritz; Königsrainer, Alfred; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

    2016-01-01

    Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs' minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk. PMID:26726810

  4. Glucose-Raising Polymorphisms in the Human Clock Gene Cryptochrome 2 (CRY2) Affect Hepatic Lipid Content

    PubMed Central

    Machann, Jürgen; Königsrainer, Ingmar; Böhm, Anja; Lutz, Stefan Zoltan; Heni, Martin; Fritsche, Andreas; Schick, Fritz; Königsrainer, Alfred; Stefan, Norbert; Häring, Hans-Ulrich; Staiger, Harald

    2016-01-01

    Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs’ minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk. PMID:26726810

  5. Comparative effects of cadmium, zinc, and lead in vitro on pulmonary, adrenal, and hepatic microsomal metabolism in the guinea pig

    SciTech Connect

    Colby, H.D.; Johnson, P.B.; Zulkoski, J.S.; Pope, M.R.; Miles, P.R.

    1981-11-01

    The in vitro effects of Cd, Zn, and Pb on pulmonary, adrenal, and hepatic microsomal enzyme activities in guinea pigs were compared. Cd and Zn produced concentration-dependent (20-200 ..mu..M) decreases in benzphetamine demethylase and biphenyl hydrozylase activities in adrenal, liver, and lung. Pb had no significant effect on either enzyme in any of the tissues studied. Adrenal and pulmonary enzymes were more sensitive to the effects of Cd and Zn than were hepatic enzymes. Benzo(a)pyrene hydroxylase and ethoxycoumarin demethylase activities were decreased by Zn, Cd and Pb in adrenal, liver, and lung microsomes. The inhibitory effects on benzo(a)pyrene and ethoxycoumarin methabolism were far greater than those on benzphetamine or biphenyl metabolism. The relative potencies of the metals as inhibitors of xenobiotic metabolism were Zn > Cd > Pb. Cd and Zn also inhibited steroid 21-hydroxylase activity in adrenal microsomes, but Pb had no effect on steroid metabolism. In addition, microsomal epoxide hydratase activity in adrenal, liver, and lung was inhibited by Cd but not by Zn or Pb. The results demonstrate that adrenal and pulmonary microsomal enzyme, like those in liver, are inhibited by various metals. Inhibition of mixed-function oxidases by metals in vitro is apparently not related to changes in cytochrome P-450 levels or substrate binding to cytochrome P-450. In addition, the actions of Cd, Zn, and Pb in each tissue are highly dependent on the substrates employed.

  6. Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism.

    PubMed

    Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-01-01

    Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns. PMID:27502578

  7. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.

    PubMed

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W; Flanders, Kathleen C; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M; Gonzalez, Frank J

    2012-12-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. PMID:23034213

  8. The metabolic responses to hepatitis B virus infection shed new light on pathogenesis and targets for treatment

    PubMed Central

    Li, Hongde; Zhu, Wandi; Zhang, Leike; Lei, Hehua; Wu, Xiangyu; Guo, Lin; Chen, Xinwen; Wang, Yulan; Tang, Huiru

    2015-01-01

    Chronic infection caused by the hepatitis B virus (HBV), is strongly associated with hepatitis, fatty liver and hepatocellular carcinoma. To investigate the underlying mechanisms, we characterize the metabolic features of host cells infected with the virus using systems biological approach. The results show that HBV replication induces systematic metabolic alterations in host cells. HBV infection up-regulates the biosynthesis of hexosamine and phosphatidylcholine by activating glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1) and choline kinase alpha (CHKA) respectively, which were reported for the first time for HBV infection. Importantly suppressing hexosamine biosynthesis and phosphatidylcholine biosynthesis can inhibit HBV replication and expression. In addition, HBV induces oxidative stress and stimulates central carbon metabolism and nucleotide synthesis. Our results also indicate that HBV associated hepatocellular carcinoma could be attributed to GFAT1 activated hexosamine biosynthesis and CHKA activated phosphatidylcholine biosynthesis. This study provides further insights into the pathogenesis of HBV-induced diseases, and sheds new light on drug target for treating HBV infection. PMID:25672227

  9. Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

    PubMed Central

    Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-01-01

    Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns. PMID:27502578

  10. Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism

    NASA Astrophysics Data System (ADS)

    Ke, Zhang-Hong; Pan, Jie-Xue; Jin, Lu-Yang; Xu, Hai-Yan; Yu, Tian-Tian; Ullah, Kamran; Rahman, Tanzil Ur; Ren, Jun; Cheng, Yi; Dong, Xin-Yan; Sheng, Jian-Zhong; Huang, He-Feng

    2016-08-01

    Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 μg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA-exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns.

  11. Iron and the liver. Acute and long-term effects of iron-loading on hepatic haem metabolism.

    PubMed Central

    Bonkowsky, H L; Healey, J F; Sinclair, P R; Sinclair, J F; Pomeroy, J S

    1981-01-01

    We have determined the dose-response curves (100-900 mg of Fe/kg body wt.) and the time course over 84 days for the effects of a single injection of iron-dextran on rat hepatic 5-aminolaevulinate synthetase, cytochrome P-450, iron content, and GSH (reduced glutathione). Porphyrins in liver and urine have also been measured. (1) At 2 days after treatment, a dose of 500 mg of Fe/kg produced a 20-fold increase in iron concentration, which was maintained for 14 days. Total hepatic iron remained constant over 63 days, falling slightly by 84 days. (2) The activity of 5-aminolaevulinate synthetase was maximally increased (6-fold) 12-24 h after iron treatment. By 48 h the activity fell to less than twice the control value and thereafter remained slightly above the control value (1.1-1.5-fold) until 84 days after iron treatment. Liver GSH concentrations were unaffected by iron. Porphyrins in liver and urine were either unchanged or decreased. (3) Hepatic cytochrome P-450 decreased after iron treatment to a minimum (63% of control) at 48 h after iron administration and gradually returned to the control value by 28 days. (4) Iron-dextran potentiated 2 allyl-2-isopropyl-acetamide-induced synthesis of hepatic 5-aminolaevulinate. Potentiation occurred if the drug was given at the same time or 36 h after iron administration, but did not occur if the drug was given 14 or 64 days after iron administration. (5) The results are discussed in relation to proposed mechanisms for the effects of iron on hepatic haem metabolism. PMID:7306080

  12. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice

    PubMed Central

    Sleeman, M. W.; Garcia, K.; Liu, R.; Murray, J. D.; Malinova, L.; Moncrieffe, M.; Yancopoulos, G. D.; Wiegand, S. J.

    2003-01-01

    Obesity plays a central role in the development of insulin resistance and type 2 diabetes. We therefore examined the effects of a modified form of ciliary neurotrophic factor [Axokine, which is hereafter referred to as ciliary neurotrophic factor (CNTF)Ax15], which uses a leptin-like mechanism to reduce body weight, in the db/db murine model of type 2 diabetes. In previous studies, weight loss produced by CNTF treatment could largely be attributed to its effects on food intake. In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone. These beneficial effects, above and beyond those seen in animals controlled for either food restriction or body weight, correlated with the ability of CNTFAx15 to increase metabolic rate and energy expenditure and reduce hepatic steatosis while enhancing hepatic responsiveness to insulin. The hepatic effects were linked to rapid alterations in hepatic gene expression, most notably reduced expression of stearoyl-CoA desaturase 1, a rate-limiting enzyme in the synthesis of complex lipids that is also markedly suppressed by leptin in ob/ob mice. These observations further link the mechanisms of CNTF and leptin action, and they suggest important, beneficial effects for CNTF in diabetes that may be distinct from its ability to decrease food intake; instead, these effects may be more related to its influence on energy expenditure and hepatic gene expression. PMID:14610276

  13. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice.

    PubMed

    Sleeman, M W; Garcia, K; Liu, R; Murray, J D; Malinova, L; Moncrieffe, M; Yancopoulos, G D; Wiegand, S J

    2003-11-25

    Obesity plays a central role in the development of insulin resistance and type 2 diabetes. We therefore examined the effects of a modified form of ciliary neurotrophic factor [Axokine, which is hereafter referred to as ciliary neurotrophic factor (CNTF)Ax15], which uses a leptin-like mechanism to reduce body weight, in the db/db murine model of type 2 diabetes. In previous studies, weight loss produced by CNTF treatment could largely be attributed to its effects on food intake. In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone. These beneficial effects, above and beyond those seen in animals controlled for either food restriction or body weight, correlated with the ability of CNTFAx15 to increase metabolic rate and energy expenditure and reduce hepatic steatosis while enhancing hepatic responsiveness to insulin. The hepatic effects were linked to rapid alterations in hepatic gene expression, most notably reduced expression of stearoyl-CoA desaturase 1, a rate-limiting enzyme in the synthesis of complex lipids that is also markedly suppressed by leptin in ob/ob mice. These observations further link the mechanisms of CNTF and leptin action, and they suggest important, beneficial effects for CNTF in diabetes that may be distinct from its ability to decrease food intake; instead, these effects may be more related to its influence on energy expenditure and hepatic gene expression. PMID:14610276

  14. Synergic hypocholesterolaemic effect of n-3 PUFA and oestrogen by modulation of hepatic cholesterol metabolism in female rats.

    PubMed

    Oh, Yuna; Jin, Youri; Park, Yongsoon

    2015-12-14

    n-3 PUFA such as EPA and DHA as well as oestrogen have been reported to decrease blood levels of cholesterol, but their underlying mechanism is unclear. The purpose of this study was to determine the effects of the combination of n-3 PUFA supplementation and oestrogen injection on hepatic cholesterol metabolism. Rats were fed a modified AIN-93G diet with 0, 1 or 2 % n-3 PUFA (EPA+DHA) relative to the total energy intake for 12 weeks. Rats were surgically ovariectomised at week 8, and, after 1-week recovery, rats were injected with 17β-oestradiol-3-benzoate (E2) or maize oil for the last 3 weeks. Supplementation with n-3 PUFA and E2 injection significantly increased the ratio of the hepatic expression of phosphorylated AMP activated protein kinase (p-AMPK):AMP activated protein kinase (AMPK) and decreased sterol regulatory element-binding protein-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase and proprotein convertase subtilisin/kexin type 9. Supplementation with n-3 PUFA increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP8B1) and sterol 27-hydroxylase (CYP27A1); however, E2 injection decreased CYP7A1 and CYP8B1 but not CYP27A1. Additionally, E2 injection increased hepatic expression of oestrogen receptor-α and β. In conclusion, n-3 PUFA supplementation and E2 injection had synergic hypocholesterolaemic effects by down-regulating hepatic cholesterol synthesis (n-3 PUFA and oestrogen) and up-regulating bile acid synthesis (n-3 PUFA) in ovariectomised rats. PMID:26388416

  15. Effects of guar gum and cellulose on glucose absorption, hormonal release and hepatic metabolism in the pig

    NASA Technical Reports Server (NTRS)

    Nunes, C. S.; Malmlof, K.

    1992-01-01

    Six Large White pigs (mean body-weight 59 (SE 1.7) kg) were surgically fitted with permanent catheters in the portal vein, the brachiocephalic artery and the right hepatic vein, as well as with electromagnetic flow probes around the portal vein and the hepatic artery, and allowed to recover. The non-anaesthetized animals were given a basal non-fibre diet (diet A) alone or together with 60 g guar gum/kg (diet B) or 150 g purified cellulose/kg (diet C) by substitution for mica. The diets were given for weekly periods and according to a replicated 3 x 3 Latin square design. On the last day of each such adaptation period, test meals of 800 g were given before blood sampling. Sampling was continued for 8 h. Guar gum strongly reduced glucose apparent absorption without changing the absorption and the hepatic uptake profiles. Production rates of insulin, gastric inhibitory polypeptide and insulin-like growth factor-1 (IGF-1) were lowest after guar gum ingestion. However, the reductions in peripheral blood insulin levels caused by guar gum were not associated with a change in hepatic insulin extraction. IGF-1 appeared to be strongly secreted by the gut, whereas the liver had a net uptake of the peptide. Ingestion of guar gum increased the hepatic extraction coefficient of gut-produced IGF-1. Guar gum ingestion appeared also to decrease glucagon secretion. Cellulose at the level consumed had very few effects on the variables considered. It is suggested that the modulation of intestinal mechanisms by guar gum was sufficient to mediate the metabolic effects described.

  16. Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

    SciTech Connect

    Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S.; Alegret, Marta; Merlos, Manuel; Roglans, Nuria; Laguna, Juan C.

    2011-02-15

    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. 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

  17. Three Conazoles Increase Hepatic Microsomal Retinoic Acid Metabolism and Decrease Mouse Hepatic Retinoic Acid Levels In Vivo

    EPA Science Inventory

    Conazoles are fungicides used in agriculture and as pharmaceuticals. In a previous toxicogenomic study of triazole-containing conazoles we found gene expression changes consistent with the alteration of the metabolism of all trans-retinoic acid (atRA), a vitamin A metabolite with...

  18. In vitro effects of the citrus flavonoids diosmin, naringenin and naringin on the hepatic drug-metabolizing CYP3A enzyme in human, pig, mouse and fish.

    PubMed

    Burkina, Viktoriia; Zlabek, Vladimir; Halsne, Ruth; Ropstad, Erik; Zamaratskaia, Galia

    2016-06-15

    Flavonoids are known to have effects on cytochrome P450 enzymatic activity. However, little effort has been made to examine species differences and the relevance of studies on mammalian and fish microsomes so that extrapolations can be made to humans. Therefore, the effects of several naturally occurring flavonoids on the activity of CYP3A-dependent 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD) were evaluated in human, pig, mouse, and juvenile rainbow trout sources of hepatic microsomes. Each was exposed to three concentrations (1, 10, and 100μM) of diosmin, naringin, and naringenin. Naringenin competitively inhibited BFCOD activity (Ki values were 24.6μM in human, 15.6μM in pig, and 19.6μM in mouse microsomes). In fish, BFCOD activity was inhibited in a noncompetitive manner (Ki=7μM). Neither diosmin nor naringenin affected BFCOD activity in hepatic microsomes from the studied model organisms. These results suggest that dietary flavonoids potentially inhibit the metabolism of clinical drugs. PMID:27107807

  19. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

    SciTech Connect

    Zhu Baoting Gallo, Michael A. Burger, Conney W.; Meeker, Robert J.; Cai, May Xiaoxin; Xu Shiyao; Conney, Allan H.

    2008-01-15

    We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every 2 weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 {mu}g/kg b.w. once every 2 weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD at a high dose (100 {mu}g/kg b.w.), but not at lower doses (1 or 10 {mu}g/kg b.w.), may have a strong obesity-inducing effect in C3H/HeN mice fed an HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals an HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2- and 4-hydroxylation of 17{beta}-estradiol in animals fed a control diet, but surprisingly not in animals fed an HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD.

  20. 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

  1. Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring

    PubMed Central

    Sabet, Julia A.; Park, Lara K.; Iyer, Lakshmanan K.; Tai, Albert K.; Koh, Gar Yee; Pfalzer, Anna C.; Parnell, Laurence D.; Mason, Joel B.; Liu, Zhenhua; Byun, Alexander J.; Crott, Jimmy W.

    2016-01-01

    Background The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well. Objective In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content. Methods Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden. Results No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring. Conclusions In this animal model, modulation of

  2. Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[18F]fluoro-2-deoxygalactose positron emission tomography.

    PubMed

    Sørensen, Michael; Munk, Ole Lajord; Mortensen, Frank Viborg; Olsen, Aage Kristian; Bender, Dirk; Bass, Ludvik; Keiding, Susanne

    2008-07-01

    Metabolism of galactose is a specialized liver function. The purpose of this PET study was to use the galactose analog 2-[(18)F]fluoro-2-deoxygalactose (FDGal) to investigate hepatic uptake and metabolism of galactose in vivo. FDGal kinetics was studied in 10 anesthetized pigs at blood concentrations of nonradioactive galactose yielding approximately first-order kinetics (tracer only; n = 4), intermediate kinetics (0.5-0.6 mmol galactose/l blood; n = 2), and near-saturation kinetics (>3 mmol galactose/l blood; n = 4). All animals underwent liver C15O PET (blood volume) and FDGal PET (galactose kinetics) with arterial and portal venous blood sampling. Flow rates in the hepatic artery and the portal vein were measured by ultrasound transit-time flowmeters. The hepatic uptake and net metabolic clearance of FDGal were quantified by nonlinear and linear regression analyses. The initial extraction fraction of FDGal from blood-to-hepatocyte was unity in all pigs. Hepatic net metabolic clearance of FDGal, K(FDGal), was 332-481 ml blood.min(-1).l(-1) tissue in experiments with approximately first-order kinetics and 15.2-21.8 ml blood.min(-1).l(-1) tissue in experiments with near-saturation kinetics. Maximal hepatic removal rates of galactose were on average 600 micromol.min(-1).l(-1) tissue (range 412-702), which was in agreement with other studies. There was no significant difference between K(FDGal) calculated with use of the dual tracer input (Kdual(FDGal)) or the single arterial input (Karterial(FDGal)). In conclusion, hepatic galactose kinetics can be quantified with the galactose analog FDGal. At near-saturated kinetics, the maximal hepatic removal rate of galactose can be calculated from the net metabolic clearance of FDGal and the blood concentration of galactose. PMID:18483186

  3. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes

    PubMed Central

    Shi, Chang-Xiang; Zhao, Ming-Xia; Shu, Xiao-Dong; Xiong, Xiao-Qing; Wang, Jue-Jin; Gao, Xing-Ya; Chen, Qi; Li, Yue-Hua; Kang, Yu-Ming; Zhu, Guo-Qing

    2016-01-01

    β-aminoisobutyric acid (BAIBA) is a nature thymine catabolite, and contributes to exercise-induced protection from metabolic diseases. Here we show the therapeutical effects of BAIBA on hepatic endoplasmic reticulum (ER) stress and glucose/lipid metabolic disturbance in diabetes. Type 2 diabetes was induced by combined streptozotocin (STZ) and high-fat diet (HFD) in mice. Oral administration of BAIBA for 4 weeks reduced blood glucose and lipids levels, hepatic key enzymes of gluconeogenesis and lipogenesis expressions, attenuated hepatic insulin resistance and lipid accumulation, and improved insulin signaling in type 2 diabetic mice. BAIBA reduced hepatic ER stress and apoptosis in type 2 diabetic mice. Furthermore, BAIBA alleviated ER stress in human hepatocellular carcinoma (HepG2) cells with glucosamine-induced insulin resistance. Hepatic AMPK phosphorylation was reduced in STZ/HFD mice and glucosamine-treated HepG2 cells, which were restored by BAIBA treatment. The suppressive effects of BAIBA on glucosamine-induced ER stress were reversed by knockdown of AMPK with siRNA. In addition, BAIBA prevented thapsigargin- or tunicamycin-induced ER stress, and tunicamycin–induced apoptosis in HepG2 cells. These results indicate that BAIBA attenuates hepatic ER stress, apoptosis and glucose/lipid metabolic disturbance in mice with type 2 diabetes. AMPK signaling is involved to the role of BAIBA in attenuating ER stress. PMID:26907958

  4. Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats

    PubMed Central

    Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A.; Correig, Xavier; Arola, Lluís; Bladé, Cinta

    2016-01-01

    Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD+) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD+ availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD+ levels. PMID:27102823

  5. Metabolic syndrome - the consequence of lifelong treatment of bipolar affective disorder.

    PubMed

    Dadić-Hero, Elizabeta; Ruzić, Klementina; Grahovac, Tanja; Petranović, Duska; Graovac, Mirjana; Palijan, Tija Zarković

    2010-06-01

    Mood disturbances are characteristic and dominant feature of Mood disorders. Bipolar Affective Disorder (BAD) is a mood disorder which occurs equally in both sexes. BAD may occur in co morbidity with other mental diseases and disorders such as: Anorexia Nervosa, Bulimia Nervosa, Attention Deficit, Panic Disorder and Social Phobia. However, medical disorders (one or more) can also coexist with BAD. Metabolic syndrome is a combination of metabolic disorders that increase the risk of developing cardiovascular disease. A 61-year old female patient has been receiving continuous and systematic psychiatric treatment for Bipolar Affective Disorder for the last 39 years. The first episode was a depressive one and it occurred after a child delivery. Seventeen years ago the patient developed diabetes (diabetes type II), and twelve years ago arterial hypertension was diagnosed. High cholesterol and triglyceride levels as well as weight gain were objective findings. During the last nine years she has been treated for lower leg ulcer. Since metabolic syndrome includes abdominal obesity, hypertension, diabetes mellitus, increased cholesterol and serum triglyceride levels, the aforesaid patient can be diagnosed with Metabolic Syndrome. When treating Bipolar Affective Disorder, the antipsychotic drug choice should be careful and aware of its side-effects in order to avoid the development or aggravation of metabolic syndrome. PMID:20562789

  6. Metabolic issues in patients affected by schizophrenia: clinical characteristics and medical management

    PubMed Central

    Ventriglio, Antonio; Gentile, Alessandro; Stella, Eleonora; Bellomo, Antonello

    2015-01-01

    Patients affected by psychotic disorders are more likely to develop high rates of co-morbidities, such as obesity, type 2 diabetes, dyslipidemias, hypertension, metabolic syndrome, myocardial infarction, stroke etc., in the long-term. These morbidities have a significant impact on the life-expectancy of these patients. Patients with chronic psychoses show a 2–3-fold increased risk of death mostly from cardiovascular and metabolic diseases. Although there may be an independent link, between schizophrenia and metabolic conditions the cardio-metabolic risk is mostly related to an unhealthy lifestyle and the usage of antipsychotic agents (especially Second Generation Antipsychotics or atypical) even when these remain effective treatments in the management of major psychoses. Recently, many international organizations have developed screening and monitoring guidelines for the control of modifiable risk factors in order to reduce the rate of co-morbidity and mortality among patients affected by schizophrenia. This paper is a review of current knowledge about the metabolic issues of patients affected by schizophrenia and describes clinical characteristics and medical management strategies for such conditions. PMID:26388714

  7. Extra-hepatic metabolism of 7-ketocholesterol occurs by esterification to fatty acids via cPLA2α and SOAT1 followed by selective efflux to HDL

    PubMed Central

    Lee, Jung Wha; Huang, Jiahn-Dar; Rodriguez, Ignacio R.

    2015-01-01

    Accumulation of 7-ketocholesterol (7KCh) in tissues has been previously associated with various chronic aging diseases. Orally ingested 7KCh is readily metabolized by the liver and does not pose a toxicity threat. However, 7KCh formed in situ, usually associated with lipoprotein deposits, can adversely affect surrounding tissues by causing inflammation and cytotoxicity. In this study we have investigated various mechanisms for extra-hepatic metabolism of 7KCh (e.g. hydroxylation, sulfation) and found only esterification to fatty acids. The esterification of 7KCh to fatty acids involves the combined action of cytosolic phospholipase A2 alpha (cPLA2α) and sterol O-acyltransferase (SOAT1). Inhibition of either one of these enzymes ablates 7KCh-fatty acid ester (7KFAE) formation. The 7KFAEs are not toxic and do not induce inflammatory responses. However, they can be unstable and re-release 7KCh. The higher the degree of unsaturation, the more unstable the 7KFAE (e.g. 18:0>18:1>18:2>18:3>>20:4). Biochemical inhibition and siRNA knockdown of SOAT1 and cPLA2α ablated the 7KFAE synthesis in cultured ARPE19 cells, but had little effect on the 7KCh-induced inflammatory response. Overexpression of SOAT1 reduced the 7KCh-induced inflammatory response and provided some protection from cell death. This effect is likely due to the increased conversion of 7KCh to 7KFAEs, which reduced the intracellular 7KCh levels. Addition of HDL selectively increased the efflux of 7KFAEs and enhanced the effect of SOAT1 overexpression. Our data suggests an additional function for HDL in aiding extra-hepatic tissues to eliminate 7KCh by returning 7KFAEs to the liver for bile acid formation. PMID:25617738

  8. A Recipe Composed of Chinese Herbal Active Components Regulates Hepatic Lipid Metabolism of NAFLD In Vivo and In Vitro

    PubMed Central

    Meng, Sheng-xi; Liu, Qian; Tang, Ya-jun; Wang, Wen-jing; Zheng, Qing-shan; Tian, Hua-jie; Yao, Dong-sheng; Liu, Lin; Peng, Jing-hua; Zhao, Yu; Hu, Yi-yang; Feng, Qin

    2016-01-01

    This study is to investigate the therapeutic effects of the recipe composed of Atractylodes macrocephala polysaccharide, chlorogenic acid, and geniposide (named ACG) on experimental nonalcoholic fatty liver (NAFL). The research was divided into two parts as screening experiment and verification experiment. In the screening experiment, we used high-fat diet (HFD) induced NAFL rat model and uniform design to get the recipe from five Chinese herbal active components. In the verification experiment, HFD induced fatty liver rat and mouse NAFL models and free fatty acid (FFA) induced HepG2 cell model were used to verify the effects of ACG. According to the multiple regression equation of the hepatic triglyceride (TG) contents of each group in the screening experiment, the recipe ACG was obtained and the doses of Atractylodes macrocephala polysaccharide, chlorogenic acid, and geniposide for rats were 266.67, 3.33, and 45 mg/kg, respectively. The results of verification experiment verified that ACG could significantly reduce hepatic TG contents of NAFL rats and mice, as well as the cellular TG content of FFA-induced HepG2 cells. ACG could also improve HOMA-IR and hepatic mitochondrial ultrastructure of NAFL mice. Our study verified that ACG recipe could regulate lipid metabolism of NAFL in vivo and in vitro. PMID:27069915

  9. The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism.

    PubMed

    Chambel, Sílvia S; Santos-Gonçalves, Andreia; Duarte, Tiago L

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH), which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment. PMID:26120584

  10. Cysteine Sulfinic Acid Decarboxylase Regulation: A Role for FXR and SHP in Murine Hepatic Taurine Metabolism

    PubMed Central

    Kerr, Thomas A.; Matsumoto, Yuri; Matsumoto, Hitoshi; Xie, Yan; Hirschberger, Lawrence L.; Stipanuk, Martha H.; Anakk, Sayeepriyadarshini; Moore, David D.; Watanabe, Mitsuhiro; Kennedy, Susan

    2014-01-01

    Background Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor15/19 (FGF15/19). Because bile acid synthesis involves amino acid conjugation, we hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids. Aims To investigate CSAD regulation by bile acids and CSAD regulatory mechanisms. Methods Mice were fed a control diet or a diet supplemented with either 0.5% cholate or 2% cholestyramine. To gain mechanistic insight into CSAD regulation, we utilized GW4064 (FXR agonist), FGF19, or T-0901317 (LXR agonist) and Shp−/− mice. Tissue mRNA expression was determined by qRT-PCR. Amino acids were measured by HPLC. Results Mice supplemented with dietary cholate exhibited reduced hepatic CSAD mRNA expression while those receiving cholestyramine exhibited increased hepatic CSAD mRNA expression. Activation of FXR suppressed CSAD mRNA expression whereas hepatic CSAD mRNA expression was increased in Shp−/− mice. Hepatic hypotaurine concentration (the product of CSAD) was higher in Shp−/− mice with a corresponding increase in serum (but not hepatic) taurine-conjugated bile acids. FGF19 administration suppressed hepatic CYP7A1 mRNA but did not change CSAD mRNA expression. LXR activation induced CYP7A1 mRNA yet failed to induce CSAD mRNA expression. Conclusion CSAD mRNA expression is physiologically regulated by bile acids in a feedback fashion via mechanisms involving SHP and FXR but not FGF15/19 or LXR. These novel findings implicate bile acids as regulators of CSAD mRNA via mechanisms shared in part with CYP7A1. PMID:24033844

  11. A High Phosphorus Diet Affects Lipid Metabolism in Rat Liver: A DNA Microarray Analysis

    PubMed Central

    Chun, Sunwoo; Bamba, Takeshi; Suyama, Tatsuya; Ishijima, Tomoko; Fukusaki, Eiichiro; Abe, Keiko; Nakai, Yuji

    2016-01-01

    A high phosphorus (HP) diet causes disorders of renal function, bone metabolism, and vascular function. We previously demonstrated that DNA microarray analysis is an appropriate method to comprehensively evaluate the effects of a HP diet on kidney dysfunction such as calcification, fibrillization, and inflammation. We reported that type IIb sodium-dependent phosphate transporter is significantly up-regulated in this context. In the present study, we performed DNA microarray analysis to investigate the effects of a HP diet on the liver, which plays a pivotal role in energy metabolism. DNA microarray analysis was performed with total RNA isolated from the livers of rats fed a control diet (containing 0.3% phosphorus) or a HP diet (containing 1.2% phosphorus). Gene Ontology analysis of differentially expressed genes (DEGs) revealed that the HP diet induced down-regulation of genes involved in hepatic amino acid catabolism and lipogenesis, while genes related to fatty acid β-oxidation process were up-regulated. Although genes related to fatty acid biosynthesis were down-regulated in HP diet-fed rats, genes important for the elongation and desaturation reactions of omega-3 and -6 fatty acids were up-regulated. Concentrations of hepatic arachidonic acid and eicosapentaenoic acid were increased in HP diet-fed rats. These essential fatty acids activate peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor for fatty acid β-oxidation. Evaluation of the upstream regulators of DEGs using Ingenuity Pathway Analysis indicated that PPARα was activated in the livers of HP diet-fed rats. Furthermore, the serum concentration of fibroblast growth factor 21, a hormone secreted from the liver that promotes fatty acid utilization in adipose tissue as a PPARα target gene, was higher (p = 0.054) in HP diet-fed rats than in control diet-fed rats. These data suggest that a HP diet enhances energy expenditure through the utilization of free fatty acids

  12. Characterization of oncogene-induced metabolic alterations in hepatic cells by using ultrahigh performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Tang, Zhi; Cao, Tingting; Lin, Shuhai; Fu, Li; Li, Shangfu; Guan, Xin-Yuan; Cai, Zongwei

    2016-05-15

    Elucidation of altered metabolic pathways by using metabolomics may open new avenues for basic research on disease mechanisms and facilitate the development of novel therapeutic strategies. Here, we report the development of ultrahigh performance liquid chromatography-tandem mass spectrometry-based metabolomics platform with capability of measuring both cationic and anionic intermediates in cellular metabolism. The platform was established based on the hydrophobic ion-pairing interaction chromatography coupled with tandem mass spectrometry in multiple reaction monitoring (MRM) mode. The MRM transitions were created and optimized via energy-resolved collision-induced dissociation experiments, serving as an essential reference point for the quantification and identification. For chromatographic separation, application of hydrophobic ion-pairing interaction led to dramatic enhancement on retention of water-soluble metabolites and provision of good peak shapes. Two volatile ion-pairing reagents, namely heptafluorobutyric acid and tributylamine, were used with dedicated C18 columns as complementary separation systems coupled with the MRM analysis, allowing measurement of the metabolites of interest at nanomolar levels. The developed platform was successfully applied to investigate the altered metabolism in hepatic cells with over-expression of an oncogene, thus can provide important information on the rewired metabolism. PMID:26992502

  13. Anaerococcus urinomassiliensis sp. nov., isolated from a urine sample of a 17-year-old boy affected by autoimmune hepatitis and membranoproliferative glomerulonephritis.

    PubMed

    Morand, A; Cornu, F; Tsimaratos, M; Lagier, J-C; Cadoret, F; Fournier, P-E; Raoult, D

    2016-09-01

    We report the main characteristics of 'Anaerococcus urinomassiliensis' strain FC4(T) (CSURP2143) that was isolated from a urine sample of a 17-year-old boy affected by autoimmune hepatitis and membranoproliferative glomerulonephritis. PMID:27408746

  14. Developmental Profile and effects of perinatal PBDE exposure in Hepatic Phase I, II, III and deiodinase I gene expression involved in thyroid hormone metabolism in male rat pups

    EPA Science Inventory

    Previous studies demonstrated that perinatal exposure to PBDEs, a major class of brominated flame retardants, may affect thyroid hormone (TH) concentrations by inducing hepatic uridinediphosphate-glucoronosyltransferases (UGTs). This study further examines effects of the commerc...

  15. Microbiota-Dependent Hepatic Lipogenesis Mediated by Stearoyl CoA Desaturase 1 (SCD1) Promotes Metabolic Syndrome in TLR5-Deficient Mice.

    PubMed

    Singh, Vishal; Chassaing, Benoit; Zhang, Limin; San Yeoh, Beng; Xiao, Xia; Kumar, Manish; Baker, Mark T; Cai, Jingwei; Walker, Rachel; Borkowski, Kamil; Harvatine, Kevin J; Singh, Nagendra; Shearer, Gregory C; Ntambi, James M; Joe, Bina; Patterson, Andrew D; Gewirtz, Andrew T; Vijay-Kumar, Matam

    2015-12-01

    The gut microbiota plays a key role in host metabolism. Toll-like receptor 5 (TLR5), a flagellin receptor, is required for gut microbiota homeostasis. Accordingly, TLR5-deficient (T5KO) mice are prone to develop microbiota-dependent metabolic syndrome. Here we observed that T5KO mice display elevated neutral lipids with a compositional increase of oleate [C18:1 (n9)] relative to wild-type littermates. Increased oleate contribution to hepatic lipids and liver SCD1 expression were both microbiota dependent. Analysis of short-chain fatty acids (SCFAs) and (13)C-acetate label incorporation revealed elevated SCFA in ceca and hepatic portal blood and increased liver de novo lipogenesis in T5KO mice. Dietary SCFAs further aggravated metabolic syndrome in T5KO mice. Deletion of hepatic SCD1 not only prevented hepatic neutral lipid oleate enrichment but also ameliorated metabolic syndrome in T5KO mice. Collectively, these results underscore the key role of the gut microbiota-liver axis in the pathogenesis of metabolic diseases. PMID:26525535

  16. Antidiabetic efficacy of citronellol, a citrus monoterpene by ameliorating the hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.

    PubMed

    Srinivasan, Subramani; Muruganathan, Udaiyar

    2016-04-25

    Diabetes mellitus is a clinically complex disease characterized by chronic hyperglycemia with metabolic disturbances. During diabetes, endogenous hepatic glucose production is increased as a result of impaired activities of the key enzymes of carbohydrate metabolism. The purpose of the present study was to evaluate the antidiabetic efficacy of citronellol, a citrus monoterpene in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w). STZ induced diabetic rats received citronellol orally at the doses of 25, 50, and 100 mg/kg b.w for 30 days. In this study the levels of plasma glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA1C), glycogen, and the activities of carbohydrate metabolic enzymes, liver and kidney markers were evaluated. Oral administration of citronellol (50 mg/kg) for 30 days dose dependently improved the levels of insulin, Hb and hepatic glycogen with significant decrease in glucose and HbA1C levels. The altered activities of carbohydrate metabolic enzymes, hepatic and kidney markers were restored to near normal. Citronellol supplement was found to be effective in preserving the normal histological appearance of hepatic cells and insulin-positive β-cells in STZ-rats. Our results suggest that administration of citronellol attenuates the hyperglycemia in the STZ-induced diabetic rats by ameliorating the key carbohydrate metabolic enzymes and could be developed as a functional and nutraceutical ingredient in combating diabetes mellitus. PMID:26944432

  17. Hepatic metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat and guinea pig

    SciTech Connect

    Wroblewski, V.J.; Olson, J.R.

    1985-11-01

    Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the rat having an LD/sub 50/ about 25-fold greater than the guinea pig. The metabolism of TCDD was examined by incubating hepatocytes isolated from these animals with purified (/sup 14/C)TCDD (2.2 microM) for 8 hr. Over the 8-hr incubation, cytochrome P-450 content and ethoxyresorufin O-deethylase and benzphetamine N-demethylase activities were well maintained, indicating the functional viability of the hepatocytes. Quantitative differences were observed in the rate of (/sup 14/C)TCDD metabolism, with hepatocytes from control rats metabolizing TCDD at a rate 2.8-fold greater than hepatocytes from control guinea pigs. The role of the hepatic cytochrome P-450-448-dependent monooxygenase system in the metabolism of TCDD was examined through the use of hepatocytes isolated from animals pretreated with either TCDD or phenobarbital. The rate of (/sup 14/C)TCDD metabolite formation in hepatocytes from TCDD pretreated guinea pigs (0.26 +/- 0.14 pmol mg cell protein-1 hr-1) was unchanged from the control rate, while the rate in hepatocytes from TCDD pretreated rats was 3.2-fold greater than control and nine times greater than in hepatocytes from TCDD-pretreated guinea pigs. On the other hand, phenobarbital pretreatment produced little change in the rate of (/sup 14/C)TCDD metabolism in rat hepatocytes. These results suggest that TCDD may be metabolized by a TCDD inducible form of cytochrome P-448 which is expressed in the rat but not in the guinea pig.

  18. Stretching Your Energetic Budget: How Tendon Compliance Affects the Metabolic Cost of Running

    PubMed Central

    Uchida, Thomas K.; Hicks, Jennifer L.; Dembia, Christopher L.; Delp, Scott L.

    2016-01-01

    Muscles attach to bones via tendons that stretch and recoil, affecting muscle force generation and metabolic energy consumption. In this study, we investigated the effect of tendon compliance on the metabolic cost of running using a full-body musculoskeletal model with a detailed model of muscle energetics. We performed muscle-driven simulations of running at 2–5 m/s with tendon force–strain curves that produced between 1 and 10% strain when the muscles were developing maximum isometric force. We computed the average metabolic power consumed by each muscle when running at each speed and with each tendon compliance. Average whole-body metabolic power consumption increased as running speed increased, regardless of tendon compliance, and was lowest at each speed when tendon strain reached 2–3% as muscles were developing maximum isometric force. When running at 2 m/s, the soleus muscle consumed less metabolic power at high tendon compliance because the strain of the tendon allowed the muscle fibers to operate nearly isometrically during stance. In contrast, the medial and lateral gastrocnemii consumed less metabolic power at low tendon compliance because less compliant tendons allowed the muscle fibers to operate closer to their optimal lengths during stance. The software and simulations used in this study are freely available at simtk.org and enable examination of muscle energetics with unprecedented detail. PMID:26930416

  19. Xylitol affects the intestinal microbiota and metabolism of daidzein in adult male mice.

    PubMed

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group) and those fed a 0.05% daidzein-containing control diet (CD group) for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05). Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05). The fecal lipid contents (% dry weight) were significantly greater in the XD group than in the CD group (p < 0.01). The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05). This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health. PMID:24336061

  20. Xylitol Affects the Intestinal Microbiota and Metabolism of Daidzein in Adult Male Mice

    PubMed Central

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group) and those fed a 0.05% daidzein-containing control diet (CD group) for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05). Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05). The fecal lipid contents (% dry weight) were significantly greater in the XD group than in the CD group (p < 0.01). The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05). This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health. PMID:24336061

  1. The Hepatitis B Virus Genotype Affects the Persistence of Viral Replication in Immunodeficient NOG Mice

    PubMed Central

    Yokoyama, Yoshinobu; Miyagi, Takuya; Hikita, Hayato; Yoshioka, Teppei; Mukai, Kaori; Nawa, Takatoshi; Sakamori, Ryotaro; Ohkawa, Kazuyoshi; Hiramatsu, Naoki; Takahashi, Takeshi; Suemizu, Hiroshi; Ryo, Akihide; Tatsumi, Tomohide; Takehara, Tetsuo

    2015-01-01

    Background & Aims At least eight genotypes of Hepatitis B virus (HBV) have been identified. HBV genotype C is the most common genotype in Japan, although the incidence of HBV genotype A is increasing. The reason underlying the differences in viral multiplication of the HBV genotypes is unclear, especially in vivo. The purpose of this study was to elucidate the differences in HBV load and the persistence of viremia in vivo between genotypes A and C. Methods Immunodeficient NOG mice were transfected by hydrodynamic injection with the HBV expression plasmids pHBA1.2 or pHBC1.2, which contain overlength (1.2-mer) copies of the genomes of HBV genotype A or C, respectively. Results One day after transfection, the number of HBcAg-positive hepatocytes and serum HBV DNA levels were similar between mice transfected with pHBA1.2 and pHBC1.2. Serum levels of HBV DNA, HBsAg and HBeAg in mice transfected with pHBA1.2 were maintained over 5 months. In contrast, those in mice with pHBC1.2 gradually decreased over time and reached undetectable levels within 3 months after transfection. HBcAg-stained hepatocytes were detected in mice transfected with pHBA1.2, but not pHBC1.2, 5 months post-transfection. Double-staining immunohistochemistry revealed that the number of cleaved caspase3-stained, HBcAg-positive hepatocytes in the pHBC1.2-transfected mice was higher than in the pHBA1.2-transfected mice 3 days post-transfection. Moreover, the plasmid DNA and covalently closed circular DNA levels were decreased in the livers of pHBC1.2-transfected mice. These results suggested that hepatocytes expressing HBV genotype C were eliminated by apoptosis in the absence of immune cells more often than in hepatocytes expressing HBV genotype A. Conclusions Immunodeficient mice transfected with HBV genotype A develop persistent viremia, whereas those transfected with HBV genotype C exhibit transient viremia accompanied by apoptosis of HBV-expressing hepatocytes. This differences may affect the

  2. Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro.

    PubMed

    Manwaring, John; Rothe, Helga; Obringer, Cindy; Foltz, David J; Baker, Timothy R; Troutman, John A; Hewitt, Nicola J; Goebel, Carsten

    2015-09-01

    Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis-Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte Km and Vmax values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and Cmax was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers. PMID:26028483

  3. The Flower Tea Coreopsis tinctoria Increases Insulin Sensitivity and Regulates Hepatic Metabolism in Rats Fed a High-Fat Diet.

    PubMed

    Jiang, Baoping; Le, Liang; Wan, Wenting; Zhai, Wei; Hu, Keping; Xu, Lijia; Xiao, Peigen

    2015-06-01

    An infusion of Coreopsis tinctoria (CT) flowering tops is traditionally used in Portugal to control hyperglycemia; however, the effects of CT protection against high-fat diet (HFD)-induced hepatic insulin resistance have not been systematically studied and the precise mechanism of action is not clear. The metabolomic profiles of insulin-resistant rats fed a HFD and a CT-supplemented diet (HFD supplemented with CT drinking) for 8 weeks were investigated. Serum samples for clinical biochemistry and liver samples for histopathology and liquid chromatography-mass spectrometry-based metabolomic research were collected. Western blot and quantitative real-time PCR analyses were further used to measure the expression of several relevant enzymes together with perturbed metabolic pathways. Using analysis software, the CT treatment was found to significantly ameliorate the disturbance in 10 metabolic pathways. Combined metabolomic, Western blot, and quantitative real-time PCR analyses revealed that CT treatment significantly improved the glucose homeostasis by, on the one hand, through inhibiting the expression of gluconeogenic pathway key proteins glucose-6-phosphatase and phosphoenolpyruvate carboxykinase and, on the other hand, via regulating the mRNA or protein levels of the Krebs cycle critical enzymes (citrate synthase, succinate dehydrogenase complex, subunit A, flavoprotein, and dihydrolipoamide S-succinyltransferase). These results provide metabolic evidence of the complex pathogenic mechanism involved in hepatic insulin resistance and that the supplementation with CT improves insulin resistance at a global scale. Liquid chromatography-mass spectrometry-based metabolomics approaches are helpful to further understand diabetes-related mechanisms. PMID:25774555

  4. Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation.

    PubMed

    Lord, Caleb C; Ferguson, Daniel; Thomas, Gwynneth; Brown, Amanda L; Schugar, Rebecca C; Burrows, Amy; Gromovsky, Anthony D; Betters, Jenna; Neumann, Chase; Sacks, Jessica; Marshall, Stephanie; Watts, Russell; Schweiger, Martina; Lee, Richard G; Crooke, Rosanne M; Graham, Mark J; Lathia, Justin D; Sakaguchi, Takuya F; Lehner, Richard; Haemmerle, Guenter; Zechner, Rudolf; Brown, J Mark

    2016-07-26

    Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes. PMID:27396333

  5. Transcription Interference and ORF Nature Strongly Affect Promoter Strength in a Reconstituted Metabolic Pathway

    PubMed Central

    Carquet, Marie; Pompon, Denis; Truan, Gilles

    2015-01-01

    Fine tuning of individual enzyme expression level is necessary to alleviate metabolic imbalances in synthetic heterologous pathways. A known approach consists of choosing a suitable combination of promoters, based on their characterized strengths in model conditions. We questioned whether each step of a multiple-gene synthetic pathway could be independently tunable at the transcription level. Three open reading frames, coding for enzymes involved in a synthetic pathway, were combinatorially associated to different promoters on an episomal plasmid in Saccharomyces cerevisiae. We quantified the mRNA levels of the three genes in each strain of our generated combinatorial metabolic library. Our results evidenced that the ORF nature, position, and orientation induce strong discrepancies between the previously reported promoters’ strengths and the observed ones. We conclude that, in the context of metabolic reconstruction, the strength of usual promoters can be dramatically affected by many factors. Among them, transcriptional interference and ORF nature seem to be predominant. PMID:25767795

  6. In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes

    PubMed Central

    Crowell, S.R.; Hanson-Drury, S.; Williams, D.E.; Corley, R.A.

    2014-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and often carcinogenic contaminants released into the environment during natural and anthropogenic combustion processes. Benzo[a]pyrene (B[a]P) is the prototypical carcinogenic PAH, and dibenzo[def,p]chrysene (DBC) is a less prevalent, but highly potent transplacental carcinogenic PAH. Both are metabolically activated by isoforms of the cytochrome P450 enzyme superfamily to form reactive carcinogenic and cytotoxic metabolites. Metabolism of B[a]P and DBC was studied in hepatic microsomes of male Sprague-Dawley rats, naïve and pregnant female B6129SF1/J mice, and female humans, corresponding to available pharmacokinetic data. Michaelis–Menten saturation kinetic parameters including maximum rates of metabolism (VMAX, nmol/min/mg microsomal protein), affinity constants (KM, μM), and rates of intrinsic clearance (CLINT, ml/min/kg body weight) were calculated from substrate depletion data. CLINT was also estimated from substrate depletion data using the alternative in vitro half-life method. VMAX and CLINT were higher for B[a]P than DBC, regardless of species. Clearance for both B[a]P and DBC was highest in naïve female mice and lowest in female humans. Clearance rates of B[a]P and DBC in male rat were more similar to female human than to female mice. Clearance of DBC in liver microsomes from pregnant mice was reduced compared to naïve mice, consistent with reduced active P450 protein levels and elevated tissue concentrations and residence times for DBC observed in previous in vivo pharmacokinetic studies. These findings suggest that rats are a more appropriate model organism for human PAH metabolism, and that pregnancy's effects on metabolism should be further explored. PMID:24769260

  7. Cardiac Metabolic Pathways Affected in the Mouse Model of Barth Syndrome

    PubMed Central

    Huang, Yan; Powers, Corey; Madala, Satish K.; Greis, Kenneth D.; Haffey, Wendy D.; Towbin, Jeffrey A.; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W.; Khuchua, Zaza

    2015-01-01

    Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS. PMID:26030409

  8. Cardiac metabolic pathways affected in the mouse model of barth syndrome.

    PubMed

    Huang, Yan; Powers, Corey; Madala, Satish K; Greis, Kenneth D; Haffey, Wendy D; Towbin, Jeffrey A; Purevjav, Enkhsaikhan; Javadov, Sabzali; Strauss, Arnold W; Khuchua, Zaza

    2015-01-01

    Cardiolipin (CL) is a mitochondrial phospholipid essential for electron transport chain (ETC) integrity. CL-deficiency in humans is caused by mutations in the tafazzin (Taz) gene and results in a multisystem pediatric disorder, Barth syndrome (BTHS). It has been reported that tafazzin deficiency destabilizes mitochondrial respiratory chain complexes and affects supercomplex assembly. The aim of this study was to investigate the impact of Taz-knockdown on the mitochondrial proteomic landscape and metabolic processes, such as stability of respiratory chain supercomplexes and their interactions with fatty acid oxidation enzymes in cardiac muscle. Proteomic analysis demonstrated reduction of several polypeptides of the mitochondrial respiratory chain, including Rieske and cytochrome c1 subunits of complex III, NADH dehydrogenase alpha subunit 5 of complex I and the catalytic core-forming subunit of F0F1-ATP synthase. Taz gene knockdown resulted in upregulation of enzymes of folate and amino acid metabolic pathways in heart mitochondria, demonstrating that Taz-deficiency causes substantive metabolic remodeling in cardiac muscle. Mitochondrial respiratory chain supercomplexes are destabilized in CL-depleted mitochondria from Taz knockdown hearts resulting in disruption of the interactions between ETC and the fatty acid oxidation enzymes, very long-chain acyl-CoA dehydrogenase and long-chain 3-hydroxyacyl-CoA dehydrogenase, potentially affecting the metabolic channeling of reducing equivalents between these two metabolic pathways. Mitochondria-bound myoglobin was significantly reduced in Taz-knockdown hearts, potentially disrupting intracellular oxygen delivery to the oxidative phosphorylation system. Our results identify the critical pathways affected by the Taz-deficiency in mitochondria and establish a future framework for development of therapeutic options for BTHS. PMID:26030409

  9. Glycolipid Metabolism Disorder in the Liver of Obese Mice Is Improved by TUDCA via the Restoration of Defective Hepatic Autophagy

    PubMed Central

    Guo, Qinyue; Shi, Qindong; Li, Huixia; Liu, Jiali; Wu, Shufang; Sun, Hongzhi; Zhou, Bo

    2015-01-01

    Objective. Tauroursodeoxycholic acid (TUDCA) has been considered an important regulator of energy metabolism in obesity. However, the mechanism underlying how TUDCA is involved in insulin resistance is not fully understood. We tested the effects of TUDCA on autophagic dysfunction in obese mice. Material and Methods. 500 mg/kg of TUDCA was injected into obese mice, and metabolic parameters, autophagy markers, and insulin signaling molecular were assessed by Western blotting and real-time PCR. Results. The TUDCA injections in the obese mice resulted in a reduced body weight gain, lower blood glucose, and improved insulin sensitivity compared with obese mice that were injected with vehicle. Meanwhile, TUDCA treatment not only reversed autophagic dysfunction and endoplasmic reticulum stress, but also improved the impaired insulin signaling in the liver of obese mice. Additionally, the same results obtained with TUDCA were evident in obese mice treated with the adenoviral Atg7. Conclusions. We found that TUDCA reversed abnormal autophagy, reduced ER stress, and restored insulin sensitivity in the liver of obese mice and that glycolipid metabolism disorder was also improved via the restoration of defective hepatic autophagy. PMID:26681941

  10. Peculiarities of One-Carbon Metabolism in the Strict Carnivorous Cat and the Role in Feline Hepatic Lipidosis

    PubMed Central

    Verbrugghe, Adronie; Bakovic, Marica

    2013-01-01

    Research in various species has indicated that diets deficient in labile methyl groups (methionine, choline, betaine, folate) produce fatty liver and links to steatosis and metabolic syndrome, but also provides evidence of the importance of labile methyl group balance to maintain normal liver function. Cats, being obligate carnivores, rely on nutrients in animal tissues and have, due to evolutionary pressure, developed several physiological and metabolic adaptations, including a number of peculiarities in protein and fat metabolism. This has led to specific and unique nutritional requirements. Adult cats require more dietary protein than omnivorous species, maintain a consistently high rate of protein oxidation and gluconeogenesis and are unable to adapt to reduced protein intake. Furthermore, cats have a higher requirement for essential amino acids and essential fatty acids. Hastened use coupled with an inability to conserve certain amino acids, including methionine, cysteine, taurine and arginine, necessitates a higher dietary intake for cats compared to most other species. Cats also seemingly require higher amounts of several B-vitamins compared to other species and are predisposed to depletion during prolonged inappetance. This carnivorous uniqueness makes cats more susceptible to hepatic lipidosis. PMID:23877091

  11. Embryonic Protein Undernutrition by Albumen Removal Programs the Hepatic Amino Acid and Glucose Metabolism during the Perinatal Period in an Avian Model

    PubMed Central

    Willems, Els; Hu, Tjing-Tjing; Soler Vasco, Laura; Buyse, Johan; Decuypere, Eddy; Arckens, Lutgarde; Everaert, Nadia

    2014-01-01

    Different animal models have been used to study the effects of prenatal protein undernutrition and the mechanisms by which these occur. In mammals, the maternal diet is manipulated, exerting both direct nutritional and indirect hormonal effects. Chicken embryos develop independent from the hen in the egg. Therefore, in the chicken, the direct effects of protein deficiency by albumen removal early during incubation can be examined. Prenatal protein undernutrition was established in layer-type eggs by the partial replacement of albumen by saline at embryonic day 1 (albumen-deprived group), compared to a mock-treated sham and a non-treated control group. At hatch, survival of the albumen-deprived group was lower compared to the control and sham group due to increased early mortality by the manipulation. No treatment differences in yolk-free body weight or yolk weight could be detected. The water content of the yolk was reduced, whereas the water content of the carcass was increased in the albumen-deprived group, compared to the control group, indicating less uptake of nutrients from the yolk. At embryonic day 16, 20 and at hatch, plasma triiodothyronine (T3), corticosterone, lactate or glucose concentrations and hepatic glycogen content were not affected by treatment. At embryonic day 20, the plasma thyroxine (T4) concentrations of the albumen-deprived embryos was reduced compared to the control group, indicating a decreased metabolic rate. Screening for differential protein expression in the liver at hatch using two-dimensional difference gel electrophoresis revealed not only changed abundance of proteins important for amino acid metabolism, but also of enzymes related to energy and glucose metabolism. Interestingly, GLUT1, a glucose transporter, and PCK2 and FBP1, two out of three regulatory enzymes of the gluconeogenesis were dysregulated. No parallel differences in gene expressions causing the differences in protein abundance could be detected pointing to post

  12. Leucine metabolism regulates TRI6 expression and affects deoxynivalenol production and virulence in Fusarium graminearum.

    PubMed

    Subramaniam, Rajagopal; Narayanan, Swara; Walkowiak, Sean; Wang, Li; Joshi, Manisha; Rocheleau, Hélène; Ouellet, Thérèse; Harris, Linda J

    2015-11-01

    TRI6 is a positive regulator of the trichothecene gene cluster and the production of trichothecene mycotoxins [deoxynivalenol (DON)] and acetylated forms such as 15-Acetyl-DON) in the cereal pathogen Fusarium graminearum. As a global transcriptional regulator, TRI6 expression is modulated by nitrogen-limiting conditions, sources of nitrogen and carbon, pH and light. However, the mechanism by which these diverse environmental factors affect TRI6 expression remains underexplored. In our effort to understand how nutrients affect TRI6 regulation, comparative digital expression profiling was performed with a wild-type F. graminearum and a Δtri6 mutant strain, grown in nutrient-rich conditions. Analysis showed that TRI6 negatively regulates genes of the branched-chain amino acid (BCAA) metabolic pathway. Feeding studies with deletion mutants of MCC, encoding methylcrotonyl-CoA-carboxylase, one of the key enzymes of leucine metabolism, showed that addition of leucine specifically down-regulated TRI6 expression and reduced 15-ADON accumulation. Constitutive expression of TRI6 in the Δmcc mutant strain restored 15-ADON production. A combination of cellophane breach assays and pathogenicity experiments on wheat demonstrated that disrupting the leucine metabolic pathway significantly reduced disease. These findings suggest a complex interaction between one of the primary metabolic pathways with a global regulator of mycotoxin biosynthesis and virulence in F. graminearum. PMID:26248604

  13. Bromochloromethane, a Methane Analogue, Affects the Microbiota and Metabolic Profiles of the Rat Gastrointestinal Tract

    PubMed Central

    Yang, Yu-Xiang; Mu, Chun-Long; Luo, Zhen

    2015-01-01

    Bromochloromethane (BCM), an inhibitor of methanogenesis, has been used in animal production. However, little is known about its impact on the intestinal microbiota and metabolic patterns. The present study aimed to investigate the effect of BCM on the colonic bacterial community and metabolism by establishing a Wistar rat model. Twenty male Wistar rats were randomly divided into two groups (control and treated with BCM) and raised for 6 weeks. Bacterial fermentation products in the cecum were determined, and colonic methanogens and sulfate-reducing bacteria (SRB) were quantified. The colonic microbiota was analyzed by pyrosequencing of the 16S rRNA genes, and metabolites were profiled by gas chromatography and mass spectrometry. The results showed that BCM did not affect body weight and feed intake, but it did significantly change the intestinal metabolic profiles. Cecal protein fermentation was enhanced by BCM, as methylamine, putrescine, phenylethylamine, tyramine, and skatole were significantly increased. Colonic fatty acid and carbohydrate concentrations were significantly decreased, indicating the perturbation of lipid and carbohydrate metabolism by BCM. BCM treatment decreased the abundance of methanogen populations, while SRB were increased in the colon. BCM did not affect the total colonic bacterial counts but significantly altered the bacterial community composition by decreasing the abundance of actinobacteria, acidobacteria, and proteobacteria. The results demonstrated that BCM treatment significantly altered the microbiotic and metabolite profiles in the intestines, which may provide further information on the use of BCM in animal production. PMID:26567308

  14. Developmental changes in hepatic glucose metabolism in a newborn piglet model: A comparative analysis for suckling period and early weaning period.

    PubMed

    Xie, Chunyan; Wang, Qinhua; Wang, Jing; Tan, Bie; Fan, Zhiyong; Deng, Ze-yuan; Wu, Xin; Yin, Yulong

    2016-02-19

    The liver glucose metabolism, supplying sufficient energy for glucose-dependent tissues, is important in suckling or weaned animals, although there are few studies with piglet model. To better understand the development of glucose metabolism in the piglets during suckling period and early weaning period, we determined the hepatic glycogen content, and investigated the relative protein expression of key enzymes of glucogenesis (GNG) and mRNA levels of some glucose metabolism-related genes. During suckling period, the protein level of G6Pase in the liver of suckling piglets progressively declined with day of age compared with that of newborn piglets (at 1 day of age), whereas the PEPCK level stabilized until day 21 of age, indicating that hepatic GNG capacity gradually weakened in suckling piglets. The synthesis of hepatic glycogen, which was consistent with the fluctuation of glycolytic key genes PFKL and PKLR that gradually decreased after birth and was more or less steady during latter suckling period, although both the mRNA levels of GCK and key glucose transporter GLUT2 presented uptrend in suckling piglets. However, early weaning significantly suppressed the hepatic GNG in the weaned piglets, especially at d 3-5 of weaning period, then gradually recovered at d 7 of weaning period. Meanwhile, PFKL, PKLR and GLUT2 showed the similar trend during weaning period. On the contrast, the hepatic glycogen reached the maximum value when the G6Pase and PEPCK protein expression were at the lowest level, although the GCK level maintained increasing through 7 days of weaning period. Altogether, our study provides evidence that hepatic GNG and glycolysis in newborn piglets were more active than other days during suckling period, and early weaning could significantly suppressed glucose metabolism in liver, but this inhibition would progressively recover at day 7 after weaning. PMID:26802463

  15. [THE ANALYSIS OF INDICATORS OF MINERAL METABOLISM IN PATIENTS WITH DEGENERATIVE DYSTROPHIC AFFECTIONS OF JOINTS].

    PubMed

    Gasanova, A G; Matveeva, E L; Spirkina, E S

    2015-12-01

    The analysis of indicators of mineral metabolism in patients with degenerative dystrophic affections of joints demonstrated that under development of osteoarthrosis process the alteration of indicators of concentration of electrolytes in blood serum, urine and synovial fluid occurs. The stage II of process is characterized by maximal alterations of indicators. The indicator of relationship between concentration of phosphate-ion and index of phosphatases of blood serum turned out the significant coefficient of correlation. PMID:27032248

  16. Oleanolic acid and ursolic acid affect peptidoglycan metabolism in Listeria monocytogenes.

    PubMed

    Kurek, Anna; Grudniak, Anna M; Szwed, Magdalena; Klicka, Anna; Samluk, Lukasz; Wolska, Krystyna I; Janiszowska, Wirginia; Popowska, Magdalena

    2010-01-01

    The plant pentacyclic triterpenoids, oleanolic and ursolic acids, inhibit the growth and survival of many bacteria, particularly Gram-positive species, including pathogenic ones. The effect of these compounds on the facultative human pathogen Listeria monocytogenes was examined. Both acids affected cell morphology and enhanced autolysis of the bacterial cells. Autolysis of isolated cell walls was inhibited by oleanolic acid, but the inhibitory activity of ursolic acid was less pronounced. Both compounds inhibited peptidoglycan turnover and quantitatively affected the profile of muropeptides obtained after digestion of peptidoglycan with mutanolysin. These results suggest that peptidoglycan metabolism is a cellular target of oleanolic and ursolic acids. PMID:19894138

  17. 1-deoxynojirimycin isolated from Bacillus subtilis improves hepatic lipid metabolism and mitochondrial function in high-fat-fed mice.

    PubMed

    Do, Hyun Ju; Chung, Ji Hyung; Hwang, Ji Won; Kim, Oh Yoen; Lee, Jae-Yeon; Shin, Min-Jeong

    2015-01-01

    The aim of this study was to determine whether 1-deoxynojirimycin (DNJ) isolated from Bacillus subtilis MORI beneficially influences lipid metabolism and mitochondrial function in the liver of mice fed a high-fat diet in addition to the anti-obesity properties of DNJ. Male C57BL/6 mice (n = 29; 5 weeks old) were randomly assigned to three groups: normal control diet (CTL, n = 10), high-fat diet (HF, n = 10), and high-fat diet supplemented with DNJ (DNJ, n = 9). After 12 weeks, the HF group exhibited higher overall weight gain, of the liver, and of various fat pads than the CTL and DNJ groups did. The HF group also showed greater expression of C/EBPα and CD36 mRNA in the liver than that in the CTL and/or DNJ groups. In addition, mRNA expressions of AAC and FAS were lower, while mRNA expression of PGC-1β was higher in the liver of the DNJ group than that of the HF group. The hepatic expression of p-AMPK/AMPK was higher in the DNJ group than in the HF group. This study provides novel insight into the protective effect of DNJ supplementation against obesity-induced hepatic lipid abnormalities and mitochondrial dysfunction. PMID:25445511

  18. Effects of feeding dehydroepiandrosterone (DHEA) on the hepatic metabolism of 7,12-dimethylbenzanthracene (DMBA) in rats

    SciTech Connect

    Prasanna, H.R.; Schwartz, A.; Hacobian, N.; Magee, P.N.

    1987-05-01

    The possibility that the anticarcinogenic action of the naturally occurring steroid DHEA could arise from its interference in the metabolic activation of DMBA was investigated. Young mature male Sprague Dawley rats were fed for 14 days with a diet containing a nontoxic dose of DHEA in the diet. Control rats were pairfed and received the same diet except DHEA. The animals were given interperitoneally 120 ..mu..Ci of (/sup 3/H)DMBA in DMSO. After 48 hours the rats were sacrificed. Liver weights at sacrifice were 11.7 +/- 0.9 g and 7.1 g +/- 0.6 g for DHEA fed and control animals respectively. Protein content of whole liver and hepatic microsomal protein was significantly higher in DHEA fed animals. Binding of DMBA to hepatic DNA was 6688 +/- 1308 and 4070 +/- 890 dpm/mg DNA for control and DHEA fed animals respectively. Furthermore the excretion of DMBA derived radioactivity in urine was 2.3 fold more in DHEA fed animals. These results suggest that DHEA could protect rats from the carcinogenic manifestations of DMBA by interfering at the biotransformation step of the carcinogen.

  19. Premarital screening programmes for haemoglobinopathies, HIV and hepatitis viruses: review and factors affecting their success.

    PubMed

    Alswaidi, Fahad M; O'Brien, Sarah J

    2009-01-01

    This literature review is a comprehensive summary of premarital (prenuptial) screening programmes for the most prevalent hereditary haemoglobinopathies, namely thalassaemia and sickle cell disease, and the important infections HIV (human immunodeficiency virus) and hepatitis viruses B and C (HBV and HCV). It describes the background to premarital screening programmes and their value in countries where these diseases are endemic. The use of premarital screening worldwide is critically evaluated, including recent experiences in Saudi Arabia, followed by discussion of the outcomes of such programmes. Despite its many benefits, premarital testing is not acceptable in some communities for various legal and religious reasons, and other educational and cultural factors may prevent some married couples following the advice given by counsellors. The success of these programmes therefore depends on adequate religious support, government policy, education and counselling. In contrast to premarital screening for haemoglobinopathies, premarital screening for HIV and the hepatitis viruses is still highly controversial, both in terms of ethics and cost-effectiveness. In wealthy countries, premarital hepatitis and HIV testing could become mandatory if at-risk, high-prevalence populations are clearly identified and all ethical issues are adequately addressed. PMID:19349527

  20. 27-Hydroxycholesterol modulation of low density lipoprotein metabolism in cultured human hepatic and extrahepatic cells.

    PubMed

    Bellosta, S; Corsini, A; Bernini, F; Granata, A; Didoni, G; Mazzotti, M; Fumagalli, R

    1993-10-11

    27-Hydroxycholesterol**, 25-hydroxycholesterol and cholesterol suppressed LDL uptake and degradation in human extrahepatic and hepatic cell lines in a concentration-dependent manner. Cholesterol was the least potent, and the inhibitory effect of oxysterols was more pronounced in skin fibroblasts and in endothelial cell line EAhy 926 than in hepatoma HepG2 cells. Shorter incubations were required for oxysterols to achieve 50% inhibition of LDL uptake and degradation in all cultured cells. The inhibition of LDL catabolism in extrahepatic cells by 27-hydroxycholesterol occurred at concentrations close to those observed in human plasma (0.2-0.6 microM). The results support a possible role of 27-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis in non-hepatic tissues. PMID:8405424

  1. Induction of hepatic drug metabolizing enzymes by coal fly ash in rats

    SciTech Connect

    Srivastava, P.K.; Singh, Y.; Tyagi, S.R.; Misra, U.K.

    1987-12-01

    The effect of intratracheal administration of fly ash, its benzene-extracted residue and the benzene extract has been studied on the activities of hepatic mixed-function oxidases in the rat. Fly ash and its fractions significantly increased the levels of cytochrome P-450, cytochrome b/sub 5/, cytochrome b/sub 5/ reductase, NADPH-cytochrome c reductase, aminopyrine N-demethylase, aniline hydroxylase, and glutathione S-transferase in a dose-dependent manner. Phenobarbital or 3-methylcholanthrene treatment along with the administration of fly ash or its fractions showed an additive effect on the activities of the mixed-function oxidases. The observed effects were due to chemical component, i.e., organic and inorganic fractions of fly ash, and not due to its particulate nature. This was shown by the administration of glass beads, which did not cause any alteration in the activities of hepatic mixed-function oxidases.

  2. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis

    PubMed Central

    Lee, Jung Hoon; Wada, Taira; Febbraio, Maria; He, Jinhan; Matsubara, Tsutomu; Lee, Min Jae; Gonzalez, Frank J.; Xie, Wen

    2010-01-01

    Background & Aims The aryl hydrocarbon receptor (AhR) is a PAS domain transcription factor previously known as the “dioxin receptor” or “xenobiotic receptor.” The goal of this study is to determine the endobiotic role of AhR in hepatic steatosis. Methods Wild type, constitutively activated AhR (CA-AhR) transgenic, AhR null (AhR-/-), and fatty acid translocase CD36/FAT null (CD36-/-) mice were used to investigate the role of AhR in steatosis and the involvement of CD36 in the steatotic effect of AhR. The promoters of the mouse and human CD36 genes were cloned and their regulation by AhR was analyzed. Results Activation of AhR induced spontaneous hepatic steatosis characterized by the accumulation of triglycerides. The steatotic effect of AhR is likely due to the combined upregulation of CD36 and fatty acid transport proteins (FATPs), suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, increase in peripheral fat mobilization, and increased hepatic oxidative stress. Promoter analysis established CD36 as a novel transcriptional target of AhR. Activation of AhR in liver cells induced CD36 gene expression and enhanced fatty acid uptake. The steatotic effect of an AhR agonist was inhibited in CD36-/- mice. Conclusions Our study reveals a novel link between AhR-induced steatosis and the expression of CD36. Industrial or military exposures to dioxin and related compounds have been linked to increased prevalence of fatty liver in humans. Results from this study may help to establish AhR and its target CD36 as novel therapeutic and preventive targets for fatty liver disease. PMID:20303349

  3. Mechanism of chloroform-induced renal toxicity: Non-involvement of hepatic cytochrome P450-dependent metabolism

    SciTech Connect

    Fang Cheng; Behr, Melissa; Xie Fang; Lu Shijun; Doret, Meghan; Luo Hongxiu; Yang Weizhu; Aldous, Kenneth; Ding Xinxin; Gu Jun

    2008-02-15

    Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.

  4. Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro

    SciTech Connect

    Manwaring, John; Rothe, Helga; Obringer, Cindy; Foltz, David J.; Baker, Timothy R.; Troutman, John A.; Hewitt, Nicola J.; Goebel, Carsten

    2015-09-01

    Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis–Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte K{sub m} and V{sub max} values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and C{sub max} was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers. - Highlights: • An entirely in silico/in vitro approach to predict in vivo exposure to dermally applied hair dyes • Skin penetration and epidermal conversion assessed in human

  5. Absence of cumulus cells during in vitro maturation affects lipid metabolism in bovine oocytes.

    PubMed

    Auclair, Sylvain; Uzbekov, Rustem; Elis, Sébastien; Sanchez, Laura; Kireev, Igor; Lardic, Lionel; Dalbies-Tran, Rozenn; Uzbekova, Svetlana

    2013-03-15

    Cumulus cells (CC) surround the oocyte and are coupled metabolically through regulation of nutrient intake. CC removal before in vitro maturation (IVM) decreases bovine oocyte developmental competence without affecting nuclear meiotic maturation. The objective was to investigate the influence of CC on oocyte cytoplasmic maturation in relation to energy metabolism. IVM with either cumulus-enclosed (CEO) or -denuded (DO) oocytes was performed in serum-free metabolically optimized medium. Transmission electron microscopy revealed different distribution of membrane-bound vesicles and lipid droplets between metaphase II DO and CEO. By Nile Red staining, a significant reduction in total lipid level was evidenced in DO. Global transcriptomic analysis revealed differential expression of genes regulating energy metabolism, transcription, and translation between CEO and DO. By Western blot, fatty acid synthase (FAS) and hormone-sensitive phospholipase (HSL) proteins were detected in oocytes and in CC, indicating a local lipogenesis and lypolysis. FAS protein was significantly less abundant in DO that in CEO and more highly expressed in CC than in the oocytes. On the contrary, HSL protein was more abundant in oocytes than in CC. In addition, active Ser⁵⁶³-phosphorylated HSL was detected in the oocytes only after IVM, and its level was similar in CEO and DO. In conclusion, absence of CC during IVM affected lipid metabolism in the oocyte and led to suboptimal cytoplasmic maturation. Thus, CC may influence the oocyte by orienting the consumption of nutritive storage via regulation of local fatty acid synthesis and lipolysis to provide energy for maturation. PMID:23321473

  6. Effect of Sofosbuvir and Ribavirin Treatment on Peripheral and Hepatic Lipid Metabolism in Chronic HCV, Genotype-1 Infected Patients

    PubMed Central

    Meissner, Eric G.; Lee, Yu-Jin; Osinusi, Anu; Sims, Zayani; Qin, Jing; Sturdevant, Dan; McHutchison, John; Subramanian, Mani; Sampson, Maureen; Naggie, Susanna; Patel, Keyur; Remaley, Alan T.; Masur, Henry; Kottilil, Shyam

    2014-01-01

    Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance, which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype-1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end of treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response (SVR), n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n= 17 SVR, n=8 relapse). Serum LDL concentration and particle size increased early in therapy, while triglyceride concentration and very low density lipoprotein (VLDL) particle size decreased concomitantly, irrespective of treatment outcome. While LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. Conclusion Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis. PMID:25203718

  7. Metabolism and Disposition of Pan-Genotypic Inhibitor of Hepatitis C Virus NS5A Ombitasvir in Humans.

    PubMed

    Shen, Jianwei; Serby, Michael; Surber, Bruce; Lee, Anthony J; Ma, Junli; Badri, Prajakta; Menon, Rajeev; Kavetskaia, Olga; de Morais, Sonia M; Sydor, Jens; Fischer, Volker

    2016-08-01

    Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [(14)C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [(14)C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steady-state concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug. PMID:27179128

  8. Perinatal Exposure to Perfluorooctane Sulfonate Affects Glucose Metabolism in Adult Offspring

    PubMed Central

    Wan, Hin T.; Zhao, Yin G.; Leung, Pik Y.; Wong, Chris K. C.

    2014-01-01

    Perfluoroalkyl acids (PFAAs) are globally present in the environment and are widely distributed in human populations and wildlife. The chemicals are ubiquitous in human body fluids and have a long serum elimination half-life. The notorious member of PFAAs, perfluorooctane sulfonate (PFOS) is prioritized as a global concerning chemical at the Stockholm Convention in 2009, due to its harmful effects in mammals and aquatic organisms. PFOS is known to affect lipid metabolism in adults and was found to be able to cross human placenta. However the effects of in utero exposure to the susceptibility of metabolic disorders in offspring have not yet been elucidated. In this study, pregnant CD-1 mice (F0) were fed with 0, 0.3 or 3 mg PFOS/kg body weight/day in corn oil by oral gavage daily throughout gestational and lactation periods. We investigated the immediate effects of perinatal exposure to PFOS on glucose metabolism in both maternal and offspring after weaning (PND 21). To determine if the perinatal exposure predisposes the risk for metabolic disorder to the offspring, weaned animals without further PFOS exposure, were fed with either standard or high-fat diet until PND 63. Fasting glucose and insulin levels were measured while HOMA-IR index and glucose AUCs were reported. Our data illustrated the first time the effects of the environmental equivalent dose of PFOS exposure on the disturbance of glucose metabolism in F1 pups and F1 adults at PND 21 and 63, respectively. Although the biological effects of PFOS on the elevated levels of fasting serum glucose and insulin levels were observed in both pups and adults of F1, the phenotypes of insulin resistance and glucose intolerance were only evident in the F1 adults. The effects were exacerbated under HFD, highlighting the synergistic action at postnatal growth on the development of metabolic disorders. PMID:24498028

  9. In vitro and in vivo temperature modulation of hepatic metabolism and DNA adduction of aflatoxin B1 in rainbow trout.

    PubMed

    Carpenter, H M; Zhang, Q; el Zahr, C; Selivonchick, D P; Brock, D E; Curtis, L R

    1995-02-01

    Alterations in membrane lipid composition during temperature acclimation of poikilotherms is hypothesized to compensate for direct effects of temperature on membrane fluidity. Temperature also influences disposition and actions of some xenobiotics. This suggests the potential for complex interactions between temperature and metabolism of chemical carcinogens. Whole livers and hepatic microsomes from rainbow trout acclimated at 18 degrees C have more saturated fatty acids and less mono- and polyunsaturated fatty acids than those from fish acclimated at 10 degrees C. Such changes are consistent with a role for membrane lipid fluidity in temperature compensation. When 10 and 18 degrees C acclimated fish are ip injected with 0.4 mg/kg [3H]aflatoxin B1 (AFB1) at their respective acclimation temperatures, hepatic disposition of AFB1, DNA adduction, and biliary metabolites are similar. An acute shift of 18 degrees C acclimated trout to 14 degrees C reduces [3H]AFB-DNA adduct formation, while [3H]AFB1 adduction after acute shift of 10 degrees C acclimated fish to 14 degrees C is no different than in non-shifted fish. Hepatic microsomes isolated from 10 or 18 degrees C acclimated trout, incubated with 10 microM [3H]AFB1 and calf thymus DNA between 6 and 22 degrees C exhibit no differences in the "break points" of Arrhenius plots (16 degrees C in both groups). There is, however, more in vitro DNA adduction of [3H]AFB1 by microsomes from 18 degrees C acclimated fish, a difference abolished by 0.5 mM alpha-naphthoflavone (ANF). These results suggest that temperature acclimation of trout differentially modifies activities of cytochrome P-450 isozymes. When assayed at respective acclimation temperatures, hepatic cytosol from 18 degrees C fish produces more aflatoxicol, a detoxication product of AFB1, than cytosol from 10 degree C fish. Therefore, this soluble enzyme does not exhibit ideal temperature compensation. Such temperature-induced differences in microsomal cytochrome P

  10. Human hepatic metabolism of the anti-osteoporosis drug eldecalcitol involves sterol C4-methyl oxidase

    PubMed Central

    Yasuda, Kaori; Iwanaga, Yuasa; Ogawa, Kazuaki; Mano, Hiroki; Ueno, Sera; Kimoto, Shutaro; Ohta, Miho; Kamakura, Masaki; Ikushiro, Shinichi; Sakaki, Toshiyuki

    2015-01-01

    The metabolism of eldecalcitol (ED-71), a 2β-hydroxypropoxylated analog of the active form of vitamin D3 was investigated by using in vitro systems. ED-71 was metabolized to 1α,2β,25-trihydroxyvitamin D3 (1α,2β,25(OH)3D3) in human small intestine and liver microsomes. To identify the enzymes involved in this metabolism, we examined NADPH-dependent metabolism by recombinant P450 isoforms belonging to the CYP1, 2, and 3 families, and revealed that CYP3A4 had the activity. However, the CYP3A4 -specific inhibitor, ketoconazole, decreased the activity in human liver microsomes by only 36%, suggesting that other enzymes could be involved in ED-71 metabolism. Because metabolism was dramatically inhibited by cyanide, we assumed that sterol C4-methyl oxidase like gene product (SC4MOL) might contribute to the metabolism of ED-71. It is noted that SC4MOL is physiologically essential for cholesterol synthesis. Recombinant human SC4MOL expressed in COS7, Saccharomyces cerevisiae, or Escherichia coli cells converted ED-71 to 1α,2β,25(OH)3D3. Furthermore, we evaluated the metabolism of ED-71 by recombinant CYP24A1, which plays an important role in the metabolism of the active form of vitamin D3 (1α,25(OH)2D3) and its analogs. The kcat/Km value for 24- or 23-hydroxylation of ED-71 was only 3% of that for 1α,25(OH)2D3, indicating that ED-71 was resistant to CYP24A1-dependent catabolism. Among the three enzymes catalyzing ED-71, SC4MOL appears to be most important in the metabolism of ED-71. To the best of our knowledge, this is the first study showing that SC4MOL can function as a drug-metabolizing enzyme. The yeast and E. coli expression systems for SC4MOL could be useful for structure-function analyses of SC4MOL. PMID:26038696

  11. Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

    PubMed

    Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

    2016-01-01

    Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. PMID:27137487

  12. In vitro differentiation of unrestricted somatic stem cells into functional hepatic-like cells displaying a hepatocyte-like glucose metabolism.

    PubMed

    Waclawczyk, Simon; Buchheiser, Anja; Flögel, Ulrich; Radke, Teja F; Kögler, Gesine

    2010-11-01

    The hepatic-like phenotype resulting from in vitro differentiation of unrestricted somatic stem cells (USSC) derived from human umbilical cord blood (CB) was analyzed with regard to functional and metabolic aspects. USSC can be differentiated into cells of all three germ layers in vitro and in vivo and, although they share many features with mesenchymal stroma cells (MSC), can be distinguished from these by their expression of DLK1 as well as a restricted adipogenic differentiation potential. For the differentiation procedure described herein, a novel three-stage differentiation protocol resembling embryonic developmental processes of hepatic endoderm was applied. Hepatic pre-induction was performed by activinA and FGF4 resulting in enhanced SOX17 and FOXA2 expression. Further differentiation was achieved sequentially by retinoic acid, FGF4, HGF, EGF, and OSM resulting in a hepatic endodermal identity, characterized by the expression of AFP and HNF1alpha. Thereafter, expression of G6PC, ARG1, FBP1, and HNF4alpha was observed, thus indicating progressive differentiation. Functional studies concerning albumin secretion, urea formation, and cytochrome-p450-3A4 (CYP3A4) enzyme activity confirmed the hepatic-like phenotype. In order to characterize the differentiated cells at a metabolic level, USSC were incubated with [1-(13)C]glucose. By tracing the fate of the molecule's label via isotopomer analysis using (13)C NMR spectroscopy, formation of both glycogen and some gluconeogenetic activity could be observed providing evidence of a hepatocyte-like glucose metabolism in differentiated USSC. In conclusion, the results of the present study indicate that USSC represent a stem cell source with a substantial hepatic differentiation capacity which hold the potential for clinical applications. PMID:20458755

  13. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Ni, Xunjun; Wang, Haiyan

    2016-01-01

    Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment. PMID:27158393

  14. Hepatic Atypical Protein Kinase C: An Inherited Survival-Longevity Gene that Now Fuels Insulin-Resistant Syndromes of Obesity, the Metabolic Syndrome and Type 2 Diabetes Mellitus

    PubMed Central

    Farese, Robert V.; Lee, Mackenzie C.; Sajan, Mini P.

    2014-01-01

    This review focuses on how insulin signals to metabolic processes in health, why this signaling is frequently deranged in Western/Westernized societies, how these derangements lead to, or abet development of, insulin-resistant states of obesity, the metabolic syndrome and type 2 diabetes mellitus, and what our options are for restoring insulin signaling, and glucose/lipid homeostasis. A central theme in this review is that excessive hepatic activity of an archetypal protein kinase enzyme, “atypical” protein kinase C (aPKC), plays a critically important role in the development of impaired glucose metabolism, systemic insulin resistance, and excessive hepatic production of glucose, lipids and proinflammatory factors that underlie clinical problems of glucose intolerance, obesity, hepatosteatosis, hyperlipidemia, and, ultimately, type 2 diabetes. The review suggests that normally inherited genes, in particular, the aPKC isoforms, that were important for survival and longevity in times of food scarcity are now liabilities in times of over-nutrition. Fortunately, new knowledge of insulin signaling mechanisms and how an aberration of excessive hepatic aPKC activation is induced by over-nutrition puts us in a position to target this aberration by diet and/or by specific inhibitors of hepatic aPKC. PMID:26237474

  15. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD)

    PubMed Central

    Ni, Xunjun; Wang, Haiyan

    2016-01-01

    Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment. PMID:27158393

  16. Similarities and Differences in the Expression of Drug-Metabolizing Enzymes between Human Hepatic Cell Lines and Primary Human HepatocytesS⃞

    PubMed Central

    Guo, Lei; Dial, Stacey; Shi, Leming; Branham, William; Liu, Jie; Fang, Jia-Long; Green, Bridgett; Deng, Helen; Kaput, Jim

    2011-01-01

    In addition to primary human hepatocytes, hepatoma cell lines, and transfected nonhepatoma, hepatic cell lines have been used for pharmacological and toxicological studies. However, a systematic evaluation and a general report of the gene expression spectra of drug-metabolizing enzymes and transporters (DMETs) in these in vitro systems are not currently available. To fill this information gap and to provide references for future studies, we systematically characterized the basal gene expression profiles of 251 drug-metabolizing enzymes in untreated primary human hepatocytes from six donors, four commonly used hepatoma cell lines (HepG2, Huh7, SK-Hep-1, and Hep3B), and one transfected human liver epithelial cell line. A large variation in DMET expression spectra was observed between hepatic cell lines and primary hepatocytes, with the complete absence or much lower abundance of certain DMETs in hepatic cell lines. Furthermore, the basal DMET expression spectra of five hepatic cell lines are summarized, providing references for researchers to choose carefully appropriate in vitro models for their studies of drug metabolism and toxicity, especially for studies with drugs in which toxicities are mediated through the formation of reactive metabolites. PMID:21149542

  17. Prognostic factors affecting local control of hepatic tumors treated by stereotactic body radiation therapy

    PubMed Central

    2012-01-01

    Purpose Robotic Stereotactic Body Radiation Therapy with real-time tumor tracking has shown encouraging results for hepatic tumors with good efficacy and low toxicity. We studied the factors associated with local control of primary or secondary hepatic lesions post-SBRT. Methods and materials Since 2007, 153 stereotactic liver treatments were administered to 120 patients using the CyberKnife® System. Ninety-nine liver metastases (72 patients), 48 hepatocellular carcinomas (42 patients), and six cholangiocarcinomas were treated. On average, three to four sessions were delivered over 12 days. Twenty-seven to 45 Gy was prescribed to the 80% isodose line. Margins consisted of 5 to 10 mm for clinical target volume (CTV) and 3 mm for planning target volume (PTV). Results Median size was 33 mm (range, 5–112 mm). Median gross tumor volume (GTV) was 32.38 cm3 (range, 0.2–499.5 cm3). Median total dose was 45 Gy in three fractions. Median minimum dose was 27 Gy in three fractions. With a median follow-up of 15.0 months, local control rates at one and two years were 84% and 74.6%, respectively. The factors associated with better local control were lesion size < 50 mm (p = 0.019), GTV volume (p < 0.05), PTV volume (p < 0.01) and two treatment factors: a total dose of 45 Gy and a dose–per-fraction of 15 Gy (p = 0.019). Conclusions Dose, tumor diameter and volume are prognostic factors for local control when a stereotactic radiation therapy for hepatic lesions is considered. These results should be considered in order to obtain a maximum therapeutic efficacy. PMID:23050794

  18. Silver nanoparticles affect glucose metabolism in hepatoma cells through production of reactive oxygen species

    PubMed Central

    Lee, Mi Jin; Lee, Seung Jun; Yun, Su Jin; Jang, Ji-Young; Kang, Hangoo; Kim, Kyongmin; Choi, In-Hong; Park, Sun

    2016-01-01

    The silver nanoparticle (AgNP) is a candidate for anticancer therapy because of its effects on cell survival and signaling. Although numerous reports are available regarding their effect on cell death, the effect of AgNPs on metabolism is not well understood. In this study, we investigated the effect of AgNPs on glucose metabolism in hepatoma cell lines. Lactate release from both HepG2 and Huh7 cells was reduced with 5 nm AgNPs as early as 1 hour after treatment, when cell death did not occur. Treatment with 5 nm AgNPs decreased glucose consumption in HepG2 cells but not in Huh7 cells. Treatment with 5 nm AgNPs reduced nuclear factor erythroid 2-like 2 expression in both cell types without affecting its activation at the early time points after AgNPs’ treatment. Increased reactive oxygen species (ROS) production was detected 1 hour after 5 nm AgNPs’ treatment, and lactate release was restored in the presence of an ROS scavenger. Our results suggest that 5 nm AgNPs affect glucose metabolism by producing ROS. PMID:26730190

  19. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster

    PubMed Central

    Wagner, Anika E.; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-01-01

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies. PMID:26375250

  20. Evidence that high pCO2 affects protein metabolism in tropical reef corals.

    PubMed

    Edmunds, Peter J; Wall, Christopher B

    2014-08-01

    Early life stages of the coral Seriatopora caliendrum were used to test the hypothesis that the depression of dark respiration in coral recruits by high pCO2 is caused by perturbed protein metabolism. First, the contribution of protein anabolism to respiratory costs under high pCO2 was evaluated by measuring the aerobic respiration of S. caliendrum recruits with and without the protein synthesis inhibitor emetine following 1 to 4 days at 45 Pa versus 77 Pa pCO2. Second, protein catabolism under high pCO2 was evaluated by measuring the flux of ammonium (NH4 (+)) from juvenile colonies of S. caliendrum incubated in darkness at 47 Pa and 90 Pa pCO2. Two days after settlement, respiration of recruits was affected by an interaction between emetine and pCO2, with emetine reducing respiration 63% at 45 Pa pCO2 and 27% at 77 Pa pCO2. The interaction disappeared 5 days after settlement, when respiration was reduced 27% by emetine under both pCO2 conditions. These findings suggest that protein anabolism accounted for a large proportion of metabolic costs in coral recruits and was affected by high pCO2, with consequences detected in aerobic respiration. Juvenile S. caliendrum showed net uptake of NH4 (+) at 45 Pa pCO2 but net release of NH4 (+) at 90 Pa pCO2, indicating that protein catabolism, NH4 (+) recycling, or both were affected by high pCO2. Together, these results are consistent with the hypothesis that high pCO2 affects protein metabolism in corals. PMID:25216504

  1. Ubiquinol affects the expression of genes involved in PPARα signalling and lipid metabolism without changes in methylation of CpG promoter islands in the liver of mice

    PubMed Central

    Schmelzer, Constance; Kitano, Mitsuaki; Hosoe, Kazunori; Döring, Frank

    2012-01-01

    Coenzyme Q10 is an essential cofactor in the respiratory chain and serves as a potent antioxidant in biological membranes. Recent studies in vitro and in vivo provide evidence that Coenzyme Q10 is involved in inflammatory processes and lipid metabolism via gene expression. To study these effects at the epigenomic level, C57BL6J mice were supplemented for one week with reduced Coenzyme Q10 (ubiquinol). Afterwards, gene expression signatures and DNA promoter methylation patterns of selected genes were analysed. Genome-wide transcript profiling in the liver identified 1112 up-regulated and 571 down-regulated transcripts as differentially regulated between ubiquinol-treated and control animals. Text mining and GeneOntology analysis revealed that the ”top 20” ubiquinol-regulated genes play a role in lipid metabolism and are functionally connected by the PPARα signalling pathway. With regard to the ubiquinol-induced changes in gene expression of about +3.14-fold (p≤0.05), +2.18-fold (p≤0.01), and −2.13-fold (p≤0.05) for ABCA1, ACYP1, and ACSL1 genes, respectively, hepatic DNA methylation analysis of 282 (sense orientation) and 271 (antisense) CpG units in the respective promoter islands revealed no significant effect of ubiquinol. In conclusion, ubiquinol affects the expression of genes involved in PPARα signalling and lipid metabolism without changing the promoter DNA methylation status in the liver of mice. PMID:22448092

  2. Benzo(a)pyrene (B(a)P) metabolism and in vitro formation of B(a)P-DNA adducts by hepatic microsomes from rats fed diets containing corn and menhaden oils

    SciTech Connect

    Dharwadkar, S.; Bellow, J.; Ramanathan, R.; Wade, A.

    1986-03-01

    Dietary unsaturated fat is required for maximum induction of hepatic mixed function oxidases responsible for activating carcinogens which may bind covalently to DNA. The aim of this study was to assess the influence of dietary fat type on in vitro B(a)P metabolism and B(a)P-DNA adduct formation. Male rats were starved 2 days and refed diet devoid of fat, or containing 20% corn oil (CO) or 20% menhaden oil (MO) for 4 days. Both dietary fats increased Vmax for B(a)P hydroxylation without affecting Km. Phenobarbital (PB) administration increased Vmax in all animals but Km was increased only in rats fed the fat diets. PB resulted in decreased B(a)P metabolism when conducted at 15 =M only in rats fed the two fat diets even in the presence of increased cytochrome P-450 (P-450). This effect was due to a decrease in B(a)P metabolism at low substrate concentrations in PB treated fat-fed animals. Binding of B(a)P to calf-thymus DNA was increased in animals fed both fats which was enhanced further by PB only in rats fed the CO and MO diets. When the data are calculated as B(a)P metabolized per unit of P-450, PB seems to induce a P-450 in fat-fed animals having lower affinity and capacity for B(a)P metabolism and activation.

  3. Food chain transport of nanoparticles affects behaviour and fat metabolism in fish.

    PubMed

    Cedervall, Tommy; Hansson, Lars-Anders; Lard, Mercy; Frohm, Birgitta; Linse, Sara

    2012-01-01

    Nano-sized (10(-9)-10(-7) m) particles offer many technical and biomedical advances over the bulk material. The use of nanoparticles in cosmetics, detergents, food and other commercial products is rapidly increasing despite little knowledge of their effect on organism metabolism. We show here that commercially manufactured polystyrene nanoparticles, transported through an aquatic food chain from algae, through zooplankton to fish, affect lipid metabolism and behaviour of the top consumer. At least three independent metabolic parameters differed between control and test fish: the weight loss, the triglycerides∶cholesterol ratio in blood serum, and the distribution of cholesterol between muscle and liver. Moreover, we demonstrate that nanoparticles bind to apolipoprotein A-I in fish serum in-vitro, thereby restraining them from properly utilising their fat reserves if absorbed through ingestion. In addition to the metabolic effects, we show that consumption of nanoparticle-containing zooplankton affects the feeding behaviour of the fish. The time it took the fish to consume 95% of the food presented to them was more than doubled for nanoparticle-exposed compared to control fish. Since many nano-sized products will, through the sewage system, end up in freshwater and marine habitats, our study provides a potential bioassay for testing new nano-sized material before manufacturing. In conclusion, our study shows that from knowledge of the molecular composition of the protein corona around nanoparticles it is possible to make a testable molecular hypothesis and bioassay of the potential biological risks of a defined nanoparticle at the organism and ecosystem level. PMID:22384193

  4. Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases.

    PubMed

    Ruchat, Stephanie-May; Houde, Andrée-Anne; Voisin, Grégory; St-Pierre, Julie; Perron, Patrice; Baillargeon, Jean-Patrice; Gaudet, Daniel; Hivert, Marie-France; Brisson, Diane; Bouchard, Luigi

    2013-09-01

    Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring's methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24-28 weeks of pregnancy. DNA methylation was measured at>485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10(-06); none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10(-13)metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming. PMID:23975224

  5. The ameliorating effects of vitamin E on hepatic antioxidant system and xenobiotic-metabolizing enzymes in fenvalerate-exposed iodine-deficient rats.

    PubMed

    Kocer-Gumusel, Belma; Erkekoglu, Pinar; Caglayan, Aydan; Hincal, Filiz

    2016-07-01

    This study investigated the effects of vitamin E (VE) on hepatic antioxidant system and drug-metabolizing enzymes in fenvalerate (FEN)-exposed iodine-deficient (ID) Wistar rats. ID was produced by perchlorate containing drinking water. VE was introduced by a loading dose of 100 mg/kg/d, i.g. for the first three days in the last week of feeding period; then with a single maintenance dose of 40 mg/kg on the 4th day. During last week, FEN groups (F) received 100 mg/kg/d, i.p. FEN. VE alone did not significantly affect thyroid hormones and antioxidant parameters; however, significantly increased total cytochrome P450 (38%) and cytochrome b5 levels (36%). In all ID groups, plasma thyroid-stimulating hormone (TSH) levels increased markedly, but remained at control level in vitamin E plus FEN receiving iodine-deficient group (IDVF) group. Glutathione peroxidase activity showed marked increases in F (19%) and FEN-exposed iodine-deficient group (IDF, 48%) groups. FEN treatment significantly increased total cytochrome P450 (28%) and thiobarbituric acid reactive substance levels (36%), as well as 7-ethoxyresorufin O-deethylase (120%), 7-penthoxyresorufin O-deethylase (139%) and glutathione S-transferase (15%) activities and decreased total glutathione concentrations (28%) versus control. Overall results suggest that vitamin E has ameliorating effects on the measured parameters in ID and/or FEN exposure. PMID:26446907

  6. Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo

    PubMed Central

    da Silva, Robin P.; Nissim, Itzhak; Brosnan, Margaret E.; Brosnan, John T.

    2009-01-01

    Since creatinine excretion reflects a continuous loss of creatine and creatine phosphate, there is a need for creatine replacement, from the diet and/or by de novo synthesis. Creatine synthesis requires three amino acids, methionine, glycine, and arginine, and two enzymes, l-arginine:glycine amidinotransferase (AGAT), which produces guanidinoacetate acid (GAA), and guanidinoacetate methyltransferase (GAMT), which methylates GAA to produce creatine. In the rat, high activities of AGAT are found in the kidney, whereas high activities of GAMT occur in the liver. Rat hepatocytes readily convert GAA to creatine; this synthesis is stimulated by the addition of methionine, which increases cellular S-adenosylmethionine concentrations. These same hepatocytes are unable to produce creatine from methionine, arginine, and glycine. 15N from 15NH4Cl is readily incorporated into urea but not into creatine. Hepatic uptake of GAA is evident in vivo by livers of rats fed a creatine-free diet but not when rats were fed a creatine-supplemented diet. Rats fed the creatine-supplemented diet had greatly decreased renal AGAT activity and greatly decreased plasma [GAA] but no decrease in hepatic GAMT or in the capacity of hepatocytes to produce creatine from GAA. These studies indicate that hepatocytes are incapable of the entire synthesis of creatine but are capable of producing it from GAA. They also illustrate the interplay between the dietary provision of creatine and its de novo synthesis and point to the crucial role of renal AGAT expression in regulating creatine synthesis in the rat. PMID:19017728

  7. Hepatic Isoprenoid Metabolism in a Rat Model of Smith-Lemli-Opitz Syndrome

    PubMed Central

    Keller, R. Kennedy; Mitchell, David A.; Goulah, Christopher C.

    2013-01-01

    Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths. PMID:23361583

  8. Hepatic energy metabolism correlated with pathology score in rats chronically fed ethanol

    SciTech Connect

    Takahasi, H.; Geoffrion, Y.; Butler, K.W.; French, S.W. )

    1989-02-09

    We repeatedly measured in vivo levels of hepatic phosphorylated metabolites in alcohol-fed rats using non-invasive 31P MRS to evaluate their relation to the severity of the pathologic changes of alcoholic liver disease (ALD). Five pairs of Wister rats were pair-fed with a liquid diet plus ethanol or an isocaloric amount of dextrose via an implanted intragastric tube for up to 6 months (mo). For MRS, the rats were sedated, air was provided by a face mask, and the diet was infused to maintain high blood alcohol levels. {sup 31}P MRS spectra were obtained using a CYCLOPS pulse-acquire sequence, 200 scans, and a 2s recycle delay. The inorganic phosphate (Pi)/ATP peak area ratio was found to be consistently higher in the alcohol-fed rats (E) compared to the pair-fed controls (C). The sugar phosphate/ATP ratio tended to be higher in E when compared to C. Cytosolic pH measured by the chemical shift of the Pi peak showed no significant differences between E and C. The monthly liver biopsies from E showed more severe steatosis, necrosis, and fibrosis with time of feeding and the Pi/ATP ratio was positively correlated with the scored histological changes. These results suggest that a low hepatic energetic state is associated with the progression of ALD pathology.

  9. The essential functions of endoplasmic reticulum chaperones in hepatic lipid metabolism.

    PubMed

    Zhang, LiChun; Wang, Hong-Hui

    2016-07-01

    The endoplasmic reticulum (ER) is an essential organelle for protein and lipid synthesis in hepatocytes. ER homeostasis is vital to maintain normal hepatocyte physiology. Perturbed ER functions causes ER stress associated with accumulation of unfolded protein in the ER that activates a series of adaptive signalling pathways, termed unfolded protein response (UPR). The UPR regulates ER chaperone levels to preserve ER protein-folding environment to protect the cell from ER stress. Recent findings reveal an array of ER chaperones that alter the protein-folding environment in the ER of hepatocytes and contribute to dysregulation of hepatocyte lipid metabolism and liver disease. In this review, we will discuss the specific functions of these chaperones in regulation of lipid metabolism, especially de novo lipogenesis and lipid transport and demonstrate their homeostatic role not only for ER-protein synthesis but also for lipid metabolism in hepatocyte. PMID:27133206

  10. Multi-TGDR, a multi-class regularization method, identifies the metabolic profiles of hepatocellular carcinoma and cirrhosis infected with hepatitis B or hepatitis C virus

    PubMed Central

    2014-01-01

    Background Over the last decade, metabolomics has evolved into a mainstream enterprise utilized by many laboratories globally. Like other “omics” data, metabolomics data has the characteristics of a smaller sample size compared to the number of features evaluated. Thus the selection of an optimal subset of features with a supervised classifier is imperative. We extended an existing feature selection algorithm, threshold gradient descent regularization (TGDR), to handle multi-class classification of “omics” data, and proposed two such extensions referred to as multi-TGDR. Both multi-TGDR frameworks were used to analyze a metabolomics dataset that compares the metabolic profiles of hepatocellular carcinoma (HCC) infected with hepatitis B (HBV) or C virus (HCV) with that of cirrhosis induced by HBV/HCV infection; the goal was to improve early-stage diagnosis of HCC. Results We applied two multi-TGDR frameworks to the HCC metabolomics data that determined TGDR thresholds either globally across classes, or locally for each class. Multi-TGDR global model selected 45 metabolites with a 0% misclassification rate (the error rate on the training data) and had a 3.82% 5-fold cross-validation (CV-5) predictive error rate. Multi-TGDR local selected 48 metabolites with a 0% misclassification rate and a 5.34% CV-5 error rate. Conclusions One important advantage of multi-TGDR local is that it allows inference for determining which feature is related specifically to the class/classes. Thus, we recommend multi-TGDR local be used because it has similar predictive performance and requires the same computing time as multi-TGDR global, but may provide class-specific inference. PMID:24707821

  11. Guar gum effects on plasma low-density lipoprotein and hepatic cholesterol metabolism in guinea pigs fed low- and high-cholesterol diets: a dose-response study.

    PubMed

    Fernandez, M L; Sun, D M; Tosca, M; McNamara, D J

    1995-01-01

    Guinea pigs were fed semipurified diets containing either 0% or 12.5% guar gum (GG) with 0.04% cholesterol or increasing concentrations of GG (0%, 2.5%, 5%, 7.5%, 10%, and 12.5%) with 0.25% cholesterol (by wt). Compared to the 0% GG diet with 0.04% cholesterol, intake of the 12.5% GG diet with 0.04% cholesterol lowered plasma low-density-lipoprotein (LDL) concentrations, the ratio of LDL cholesteryl ester to protein, hepatic cholesterol concentrations, and the activity of acyl-CoA:cholesterol acyltransferase (ACAT), and increased 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and hepatic apo B/E receptor number (P < 0.01). Intake of GG by animals fed 0.25% cholesterol diets resulted in modest effects on hepatic cholesterol pools and plasma LDL concentrations; however, significant negative correlations were found between both plasma LDL cholesterol and hepatic free cholesterol concentrations with the amount of dietary GG (P < 0.05). Hepatic HMG-CoA reductase was suppressed by the 0.25% cholesterol intake, and GG did not reverse this suppression. In contrast, ACAT activity was negatively correlated with the amount of dietary GG (P < 0.05), and GG intake increased the number of hepatic apo B/E receptors at all intakes with the 0.25% cholesterol diets. These results demonstrate that intake of GG significantly alters endogenous cholesterol metabolism by decreasing hepatic cholesterol pools, altering hepatic cholesterol homeostasis, and reducing plasma LDL concentrations. PMID:7825524

  12. A New Metabolism-Related Index Correlates with the Degree of Liver Fibrosis in Hepatitis C Virus-Positive Patients

    PubMed Central

    Aizawa, Nobuhiro; Takata, Ryo; Sakai, Yoshiyuki; Iwata, Yoshinori; Tanaka, Hironori; Ikeda, Naoto; Hasegawa, Kunihiro; Yoh, Kazunori; Hashimoto, Kenji; Ishii, Akio; Takashima, Tomoyuki; Saito, Masaki; Imanishi, Hiroyasu; Iijima, Hiroko; Nishiguchi, Shuhei

    2015-01-01

    Background. Only a few biomarkers based on metabolic parameters for evaluating liver fibrosis have been reported. The aim of this study was to investigate the relevance of an index obtained from three metabolic variables (glycated albumin: GA, glycated hemoglobin: HbA1c, and branched-chain amino acids to tyrosine ratio: BTR) to the degree of liver fibrosis in hepatitis C virus virus- (HCV-) positive patients. Methods. A total of 394 HCV-positive patients were assessed based on the values of a new index (GA/HbA1c/BTR). The index findings were used to investigate the relationship with the degree of liver fibrosis. Results. The new index showed an association with the stage of fibrosis (METAVIR scores: F0-1: 0.42 ± 0.10, F2: 0.48 ± 0.15, F3: 0.56 ± 0.22, and F4: 0.71 ± 0.30). The index was negatively correlated with three variables of liver function: the prothrombin time percentage (P < 0.0001), albumin level (P < 0.0001), and cholinesterase level (P < 0.0001). The new index showed a higher correlation related to liver function than FIB-4 and the APRI did. In addition, the index showed a higher AUROC value than that of FIB-4 and the APRI for prediction of liver cirrhosis. Conclusion. The new metabolism-related index, GA/HbA1c/BTR value, is shown to relate to the degree of liver fibrosis in HCV-positive patients. PMID:25861264

  13. Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

    PubMed Central

    Nagiec, Marek M.; Skepner, Adam P.; Negri, Joseph; Eichhorn, Michelle; Kuperwasser, Nicolas; Comer, Eamon; Muncipinto, Giovanni; Subramanian, Aravind; Clish, Clary; Musunuru, Kiran; Duvall, Jeremy R.; Foley, Michael; Perez, Jose R.; Palmer, Michelle A. J.

    2015-01-01

    Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging. PMID:25811180

  14. Oral ingestion of aloe vera phytosterols alters hepatic gene expression profiles and ameliorates obesity-associated metabolic disorders in zucker diabetic fatty rats.

    PubMed

    Misawa, Eriko; Tanaka, Miyuki; Nomaguchi, Kouji; Nabeshima, Kazumi; Yamada, Muneo; Toida, Tomohiro; Iwatsuki, Keiji

    2012-03-21

    We investigated the effects of the oral administration of lophenol (Lo) and cycloartanol (Cy), two kinds of antidiabetic phytosterol isolated from Aloe vera , on glucose and lipid metabolism in Zucker diabetic fatty (ZDF) rats. We demonstrated that the administrations of Lo and Cy suppressed random and fasting glucose levels and reduced visceral fat weights significantly. It was also observed that treatments with Lo and Cy decreased serum and hepatic lipid concentrations (triglyceride, nonesterified fatty acid, and total cholesterol). Additionally, Lo and Cy treatments resulted in a tendency for reduction in serum monocyte chemotactic protein-1 (MCP-1) level and an elevation in serum adiponectin level. Furthermore, the expression levels of hepatic genes encoding gluconeogenic enzymes (G6 Pase, PEPCK), lipogenic enzymes (ACC, FAS), and SREBP-1 were decreased significantly by the administrations of aloe sterols. In contrast, Lo and Cy administration increased mRNA levels of glycolysis enzyme (GK) in the liver. It was also observed that the hepatic β-oxidation enzymes (ACO, CPT1) and PPARα expressions tended to increase in the livers of the Lo- and Cy-treated rats compared with those in ZDF-control rats. We therefore conclude that orally ingested aloe sterols altered the expressions of genes related to glucose and lipid metabolism, and ameliorated obesity-associated metabolic disorders in ZDF rats. These findings suggest that aloe sterols could be beneficial in preventing and improving metabolic disorders with obesity and diabetes in rats. PMID:22352711

  15. The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator.

    PubMed

    Tavares, Clint D J; Sharabi, Kfir; Dominy, John E; Lee, Yoonjin; Isasa, Marta; Orozco, Jose M; Jedrychowski, Mark P; Kamenecka, Theodore M; Griffin, Patrick R; Gygi, Steven P; Puigserver, Pere

    2016-05-13

    Methionine is an essential sulfur amino acid that is engaged in key cellular functions such as protein synthesis and is a precursor for critical metabolites involved in maintaining cellular homeostasis. In mammals, in response to nutrient conditions, the liver plays a significant role in regulating methionine concentrations by altering its flux through the transmethylation, transsulfuration, and transamination metabolic pathways. A comprehensive understanding of how hepatic methionine metabolism intersects with other regulatory nutrient signaling and transcriptional events is, however, lacking. Here, we show that methionine and derived-sulfur metabolites in the transamination pathway activate the GCN5 acetyltransferase promoting acetylation of the transcriptional coactivator PGC-1α to control hepatic gluconeogenesis. Methionine was the only essential amino acid that rapidly induced PGC-1α acetylation through activating the GCN5 acetyltransferase. Experiments employing metabolic pathway intermediates revealed that methionine transamination, and not the transmethylation or transsulfuration pathways, contributed to methionine-induced PGC-1α acetylation. Moreover, aminooxyacetic acid, a transaminase inhibitor, was able to potently suppress PGC-1α acetylation stimulated by methionine, which was accompanied by predicted alterations in PGC-1α-mediated gluconeogenic gene expression and glucose production in primary murine hepatocytes. Methionine administration in mice likewise induced hepatic PGC-1α acetylation, suppressed the gluconeogenic gene program, and lowered glycemia, indicating that a similar phenomenon occurs in vivo These results highlight a communication between methionine metabolism and PGC-1α-mediated hepatic gluconeogenesis, suggesting that influencing methionine metabolic flux has the potential to be therapeutically exploited for diabetes treatment. PMID:27022023

  16. ENANTIOSELECTIVE IN VITRO METABOLISM OF THE TRIAZOLE FUNGICIDES BROMUCONAZOLE AND TRIADIMEFON USING RAT HEPATIC MICROSOMES

    EPA Science Inventory

    We report on the in vitro metabolism of the enantiomers of two triazole fungicides: triadimefon [two enantiomers; 1-(4-chlorophneoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one] and bromuconazole {two diastereomers, each having two enantiomers; 1-[(2RS,4RS:2RS,4SR)-4-brom...

  17. The influence of starvation upon hepatic drug metabolism in rats, mice, and guinea pigs.

    NASA Technical Reports Server (NTRS)

    Furner, R. L.; Feller, D. D.

    1971-01-01

    Male rats, mice, and guinea pigs were starved for 1, 2, or 3 days, and the metabolism of ethylmorphine, p-nitroanisole, and aniline was studied. Results suggest that the oxidative enzyme systems studied are not interdependent, and the pathways studied appear to be species dependent.

  18. A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.

    PubMed

    Iverson, Sonya V; Eriksson, Sofi; Xu, Jianqiang; Prigge, Justin R; Talago, Emily A; Meade, Tesia A; Meade, Erin S; Capecchi, Mario R; Arnér, Elias S J; Schmidt, Edward E

    2013-10-01

    Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage. PMID:23743293

  19. A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification

    PubMed Central

    Iverson, Sonya V.; Eriksson, Sofi; Xu, Jianqiang; Prigge, Justin R.; Talago, Emily A.; Meade, Tesia A.; Meade, Erin S.; Capecchi, Mario R.; Arnér, Elias S.J.; Schmidt, Edward E.

    2013-01-01

    Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug-metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however their constitutive metabolic state supported more robust GSH biosynthesis-, glutathionylation-, and glucuronidation-systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage. PMID:23743293

  20. Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    New generation lipid emulsions comprised of fish oil or blends of soybean/fish/medium chain triglyceride/olive oil are emerging that result in favorable clinical metabolic outcomes in pediatric populations. Our aim was to characterize the lipidodomic, metabolomic, and transcriptomic profiles these ...

  1. Gender and Species Differences in Triadimefon Metabolism by Rodent Hepatic Microsomes

    EPA Science Inventory

    Understanding the potential differences in metabolic capacity and kinetics between various common laboratory species as well as between genders is an important facet of chemical risk assessment that is often overlooked, particularly for chemicals which undergo non-cytochrome P450...

  2. Starvation induced alterations in hepatic lysine metabolism in different families of rainbow trout (Oncorhynchus mykiss)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lysine is the second limiting amino acid in fish meal based diets, second only to methionine. However, little is known about lysine metabolism in rainbow trout (RBT). Therefore, lysine catabolism by the lysine alpha-ketoglutarate reductase (LKR) pathway was studied. Additionally, since genetically i...

  3. Hepatic Xenobiotic Metabolizing Enzyme Gene Expression Through the Life Stages of the Mouse

    EPA Science Inventory

    BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). No comprehensive analysis of the mRNA expression of XMETs has been ca...

  4. Hepatic Encephalopathy

    PubMed Central

    Bleibel, Wissam; Al-Osaimi, Abdullah M. S.

    2012-01-01

    Chronic liver disease and cirrhosis affect hundreds of millions of patients all over the world. The majority of patients with cirrhosis will eventually develop complications related to portal hypertension. One of these recurrent and difficult to treat complications is hepatic encephalopathy. Studies have indicated that overt hepatic encephalopathy affects 30 to 45% of patients with cirrhosis and a higher percentage may be affected by minimal degree of encephalopathy. All of these factors add to the impact of hepatic encephalopathy on the healthcare system and presents a major challenge to the gastroenterologist, hospitalist and primary care physician. PMID:23006457

  5. Continual feeding of two types of microalgal biomass affected protein digestion and metabolism in laying hens.

    PubMed

    Ekmay, R D; Chou, K; Magnuson, A; Lei, X G

    2015-01-01

    A 14-wk study was conducted to determine the nutritional efficacy and ssmetabolic impact of 2 types of microalgal biomass as alternative protein sources in laying hen diets. Shaver hens (total = 150 and 26 wk old) were fed 1 of 5 diets: a control or a defatted green microalgal biomass (DG; Desmodesmus spp.) at 25% and a full-fatted diatom biomass (FD; Staurosira spp.) at 11.7% inclusion with or without protease. This experiment consisted of 5 replicates per treatment and each replicate contained 6 hens individually reared in cages (1 hen for biochemical data/replicate). Despite decreased ADFI (P = 0.03), hens fed DG or FD had final BW, overall hen-day egg production, and egg quality similar to the controls. Feeding DG or FD did not alter plasma concentrations of insulin, glutamine, and uric acid or alkaline phosphatase activity at wk 8 or 14 but decreased plasma 3-methyhistine concentrations (P = 0.03) and tartrate-resistant acid phosphatase (TRAP) activities (P < 0.001) at wk 14 and improved (P = 0.002) ileal total AA digestibility. Although DG or FD exhibited moderate effects on intestinal brush border protease activities and mRNA levels of duodenal transporters Pept1, Lat1, and Cat1, both substantially enhanced (P < 0.05) phosphorylation of hepatic protein synthesis key regulator S6 ribosomal protein (S6) and the ratio of phospho-S6 to S6 in the liver of hens. However, DG and FD manifested with different impacts on weights of egg and egg albumen, proteolytic activity of jejunal digesta, plasma TRAP activity, ileal total AA digestibility, and several intestinal genes and hepatic proteins. Supplemental protease in the DG and FD diets produced mixed effects on a number of measures. In conclusion, our findings revealed the feasibility of including greater levels of microalgal biomass as a source of feed protein for laying hens and a novel potential of the biomass in improving dietary protein digestion and body protein metabolism than previously perceived. PMID

  6. Insulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock.

    PubMed

    Dang, Fabin; Sun, Xiujie; Ma, Xiang; Wu, Rong; Zhang, Deyi; Chen, Yaqiong; Xu, Qian; Wu, Yuting; Liu, Yi

    2016-01-01

    Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms. PMID:27576939

  7. Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism.

    PubMed

    Galbo, Thomas; Olsen, Grith Skytte; Quistorff, Bjørn; Nishimura, Erica

    2011-01-01

    In type 2 Diabetes (T2D) free fatty acids (FFAs) in plasma are increased and hepatic insulin resistance is "selective", in the sense that the insulin-mediated decrease of glucose production is blunted while insulin's effect on stimulating lipogenesis is maintained. We investigated the molecular mechanisms underlying this pathogenic paradox. Primary rat hepatocytes were exposed to palmitate for twenty hours. To establish the physiological relevance of the in vitro findings, we also studied insulin-resistant Zucker Diabetic Fatty (ZDF) rats. While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1) was inhibited in palmitate-exposed cells. Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. In contrast, similar to findings in human T2D, the ability of insulin to induce triglyceride (TG) accumulation and transcription of the enzymes that catalyze de novo lipogenesis and TG assembly was unaffected. Insulin-induction of these genes could, however, be blocked by inhibition of the atypical PKCs (aPKCs). The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A) was increased in the insulin-resistant cells. Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity. PMID:22087313

  8. Effects of L-tryptophan and D,L-. beta. -(1-naphthyl)alanine on rat hepatic protein metabolism

    SciTech Connect

    Sidransky, H.; Verney, E.; Kurl, R.N. )

    1990-02-26

    Earlier studies have reported that the administration of L-tryptophan (TRP) caused increases in polyribosomal aggregation, protein synthesis and cytoplasmic poly(A)mRNA in rat liver. This study was concerned with the effects of a TRP analog, D,L-{beta}-(1-naphthyl)alanine ({beta}NA), in comparison with those of TRP. Both {beta}NA and TRP bound to the TRP receptor protein and increased poly(A)polymerase and nucleoside triphosphatase activities of hepatic nuclei as reported earlier with TRP. However, only TRP, but not {beta}NA, revealed increases in release of labeled nuclear RNA (in vitro), in protein synthesis, in polyribosomal aggregation, and in glycosylation ({sup 14}C-glucosamine incorporation into proteins) of rat liver. These results indicate that although {beta}NA affects hepatic nuclei (binding and enzyme levels), it does not stimulate nucleocytoplasmic translocation of mRNA and concomitantly protein synthesis as occurs with TRP. Thus, one may speculate that the TRP-induced stimulation of glycosylation may play an important role in the overall enhancement of protein synthesis due to TRP.

  9. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance

    PubMed Central

    Caron, Alexandre; Labbé, Sébastien M.; Mouchiroud, Mathilde; Huard, Renaud; Richard, Denis

    2016-01-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. PMID:27097662

  10. Nectar resource limitation affects butterfly flight performance and metabolism differently in intensive and extensive agricultural landscapes.

    PubMed

    Lebeau, Julie; Wesselingh, Renate A; Van Dyck, Hans

    2016-05-11

    Flight is an essential biological ability of many insects, but is energetically costly. Environments under rapid human-induced change are characterized by habitat fragmentation and may impose constraints on the energy income budget of organisms. This may, in turn, affect locomotor performance and willingness to fly. We tested flight performance and metabolic rates in meadow brown butterflies (Maniola jurtina) of two contrasted agricultural landscapes: intensively managed, nectar-poor (IL) versus extensively managed, nectar-rich landscapes (EL). Young female adults were submitted to four nectar treatments (i.e. nectar quality and quantity) in outdoor flight cages. IL individuals had better flight capacities in a flight mill and had lower resting metabolic rates (RMR) than EL individuals, except under the severest treatment. Under this treatment, RMR increased in IL individuals, but decreased in EL individuals; flight performance was maintained by IL individuals, but dropped by a factor 2.5 in EL individuals. IL individuals had more canalized (i.e. less plastic) responses relative to the nectar treatments than EL individuals. Our results show significant intraspecific variation in the locomotor and metabolic response of a butterfly to different energy income regimes relative to the landscape of origin. Ecophysiological studies help to improve our mechanistic understanding of the eco-evolutionary impact of anthropogenic environments on rare and widespread species. PMID:27147100

  11. Cannibalism Affects Core Metabolic Processes in Helicoverpa armigera Larvae-A 2D NMR Metabolomics Study.

    PubMed

    Vergara, Fredd; Shino, Amiu; Kikuchi, Jun

    2016-01-01

    Cannibalism is known in many insect species, yet its impact on insect metabolism has not been investigated in detail. This study assessed the effects of cannibalism on the metabolism of fourth-instar larvae of the non-predatory insect Helicoverpa armigera (Lepidotera: Noctuidea). Two groups of larvae were analyzed: one group fed with fourth-instar larvae of H. armigera (cannibal), the other group fed with an artificial plant diet. Water-soluble small organic compounds present in the larvae were analyzed using two-dimensional nuclear magnetic resonance (NMR) and principal component analysis (PCA). Cannibalism negatively affected larval growth. PCA of NMR spectra showed that the metabolic profiles of cannibal and herbivore larvae were statistically different with monomeric sugars, fatty acid- and amino acid-related metabolites as the most variable compounds. Quantitation of ¹H-(13)C HSQC (Heteronuclear Single Quantum Coherence) signals revealed that the concentrations of glucose, glucono-1,5-lactone, glycerol phosphate, glutamine, glycine, leucine, isoleucine, lysine, ornithine, proline, threonine and valine were higher in the herbivore larvae. PMID:27598144

  12. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.

    PubMed

    Caron, Alexandre; Labbé, Sébastien M; Mouchiroud, Mathilde; Huard, Renaud; Richard, Denis; Laplante, Mathieu

    2016-06-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. PMID:27097662

  13. Factors affecting human heterocyclic amine intake and the metabolism of PhIP.

    PubMed

    Knize, Mark G; Kulp, Kristen S; Salmon, Cynthia P; Keating, Garrett A; Felton, James S

    2002-09-30

    We are working to understand possible human health effects from exposure to heterocyclic amines that are formed in meat during cooking. Laboratory-cooked beef, pork, and chicken are capable of producing tens of nanograms of MeIQx, IFP, and PhIP per gram of meat and smaller amounts of other heteroyclic amines. Well-done restaurant-cooked beef, pork, and chicken may contain PhIP and IFP at concentrations as high as tens of nanograms per gram and MeIQx at levels up to 3 ng/g. Although well-done chicken breast prepared in the laboratory may contain large amounts of PhIP, a survey of flame-grilled meat samples cooked in private homes showed PhIP levels in beef steak and chicken breast are not significantly different (P=0.36). The extremely high PhIP levels reported in some studies of grilled chicken are not seen in home-cooked samples.Many studies suggest individuals may have varying susceptibility to carcinogens and that diet may influence metabolism, thus affecting cancer susceptibility. To understand the human metabolism of PhIP, we examined urinary metabolites of PhIP in volunteers following a single well-done meat exposure. Using solid-phase extraction and LC/MS/MS, we quantified four major PhIP metabolites in human urine. In addition to investigating individual variation, we examined the interaction of PhIP with a potentially chemopreventive food. In a preliminary study of the effect of broccoli on PhIP metabolism, we fed chicken to six volunteers before and after eating steamed broccoli daily for 3 days. Preliminary results suggest that broccoli, which contains isothiocyanates shown to induce Phases I and II metabolism in vitro, may affect both the rate of metabolite excretion and the metabolic products of a dietary carcinogen. This newly developed methodology will allow us to assess prevention strategies that reduce the possible risks associated with PhIP exposure. PMID:12351155

  14. Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation

    PubMed Central

    Lee, Jae Ho; Lee, Gha Young; Jang, Hagoon; Choe, Sung Sik; Koo, Seung-Hoi; Kim, Jae Bum

    2014-01-01

    Sterol regulatory element binding protein1c (SREBP1c) is a key transcription factor for de novo lipogenesis during the postprandial state. During nutritional deprivation, hepatic SREBP1c is rapidly suppressed by fasting signals to prevent lipogenic pathways. However, the molecular mechanisms that control SREBP1c turnover in response to fasting status are not thoroughly understood. To elucidate which factors are involved in the inactivation of SREBP1c, we attempted to identify SREBP1c-interacting proteins by mass spectrometry analysis. Since we observed that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of SREBP1c-interacting proteins, we hypothesized that fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this work, we demonstrate that RNF20 physically interacts with SREBP1c, leading to degradation of SREBP1c via ubiquitination. In accordance with these findings, RNF20 represses the transcriptional activity of SREBP1c and turns off the expression of lipogenic genes that are targets of SREBP1c. In contrast, knockdown of RNF20 stimulates the expression of SREBP1c and lipogenic genes and induces lipogenic activity in primary hepatocytes. Furthermore, activation of protein kinase A (PKA) with glucagon or forskolin enhances the expression of RNF20 and potentiates the ubiquitination of SREBP1c via RNF20. In wild-type and db/db mice, adenoviral overexpression of RNF20 markedly suppresses FASN promoter activity and reduces the level of hepatic triglycerides, accompanied by a decrease in the hepatic lipogenic program. Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation. Conclusion: RNF20 acts as a negative regulator of hepatic fatty acid metabolism through degradation of SREBP1c upon PKA activation. Knowledge regarding this process enhances our understanding of how SREBP1c is able to turn off hepatic lipid metabolism during nutritional deprivation

  15. Do the noncaffeine ingredients of energy drinks affect metabolic responses to heavy exercise?

    PubMed

    Pettitt, Robert W; Niemeyer, JoLynne D; Sexton, Patrick J; Lipetzky, Amanda; Murray, Steven R

    2013-07-01

    Energy drinks (EDs) such as Red Bull (RB) are marketed to enhance metabolism. Secondary ingredients of EDs (e.g., taurine) have been purported to improve time trial performance; however, little research exists on how such secondary ingredients affect aerobic metabolism during heavy exercise. The purpose of this study was to investigate the effect of the secondary ingredients of RB on aerobic metabolism during and subsequent to heavy exercise. In double-blind, counterbalanced, and crossover fashion, 8 recreationally trained individuals completed a graded exercise test to determine the gas exchange threshold (GET). Subjects returned on 2 separate occasions and ingested either a 245 ml serving of RB or a control (CTRL) drink with the equivalent caffeine before engaging in two 10-minute constant-load cycling bouts, at an intensity equivalent to GET, with 3 minutes of rest between bouts. Accumulated liters of O2 (10 minutes) were higher for the first bout (17.1 ± 3.5 L) vs. the second bout (16.7 ± 3.5 L) but did not differ between drinks. Similarly, excess postexercise oxygen consumption was higher after the initial bout (RB mean, 2.6 ± 0.85 L; CTRL mean, 2.9 ± 0.90 L) vs. the second bout (RB mean, 1.5 ± 0.85 L; CTRL mean, 1.9 ± 0.87 L) but did not differ between drinks. No differences occurred between drinks for measures of heart rate or rating of perceived exertion. These results indicate that the secondary ingredients contained in a single serving of RB do not augment aerobic metabolism during or subsequent to heavy exercise. PMID:23037611

  16. Oxygen Affects Gut Bacterial Colonization and Metabolic Activities in a Gnotobiotic Cockroach Model

    PubMed Central

    Tegtmeier, Dorothee; Thompson, Claire L.; Schauer, Christine

    2015-01-01

    The gut microbiota of termites and cockroaches represents complex metabolic networks of many diverse microbial populations. The distinct microenvironmental conditions within the gut and possible interactions among the microorganisms make it essential to investigate how far the metabolic properties of pure cultures reflect their activities in their natural environment. We established the cockroach Shelfordella lateralis as a gnotobiotic model and inoculated germfree nymphs with two bacterial strains isolated from the guts of conventional cockroaches. Fluorescence microscopy revealed that both strains specifically colonized the germfree hindgut. In diassociated cockroaches, the facultatively anaerobic strain EbSL (a new species of Enterobacteriaceae) always outnumbered the obligately anaerobic strain FuSL (a close relative of Fusobacterium varium), irrespective of the sequence of inoculation, which showed that precolonization by facultatively anaerobic bacteria does not necessarily favor colonization by obligate anaerobes. Comparison of the fermentation products of the cultures formed in vitro with those accumulated in situ indicated that the gut environment strongly affected the metabolic activities of both strains. The pure cultures formed the typical products of mixed-acid or butyrate fermentation, whereas the guts of gnotobiotic cockroaches accumulated mostly lactate and acetate. Similar shifts toward more-oxidized products were observed when the pure cultures were exposed to oxygen, which corroborated the strong effects of oxygen on the metabolic fluxes previously observed in termite guts. Oxygen microsensor profiles of the guts of germfree, gnotobiotic, and conventional cockroaches indicated that both gut tissue and microbiota contribute to oxygen consumption and suggest that the oxygen status influences the colonization success. PMID:26637604

  17. Oxygen Affects Gut Bacterial Colonization and Metabolic Activities in a Gnotobiotic Cockroach Model.

    PubMed

    Tegtmeier, Dorothee; Thompson, Claire L; Schauer, Christine; Brune, Andreas

    2016-02-01

    The gut microbiota of termites and cockroaches represents complex metabolic networks of many diverse microbial populations. The distinct microenvironmental conditions within the gut and possible interactions among the microorganisms make it essential to investigate how far the metabolic properties of pure cultures reflect their activities in their natural environment. We established the cockroach Shelfordella lateralis as a gnotobiotic model and inoculated germfree nymphs with two bacterial strains isolated from the guts of conventional cockroaches. Fluorescence microscopy revealed that both strains specifically colonized the germfree hindgut. In diassociated cockroaches, the facultatively anaerobic strain EbSL (a new species of Enterobacteriaceae) always outnumbered the obligately anaerobic strain FuSL (a close relative of Fusobacterium varium), irrespective of the sequence of inoculation, which showed that precolonization by facultatively anaerobic bacteria does not necessarily favor colonization by obligate anaerobes. Comparison of the fermentation products of the cultures formed in vitro with those accumulated in situ indicated that the gut environment strongly affected the metabolic activities of both strains. The pure cultures formed the typical products of mixed-acid or butyrate fermentation, whereas the guts of gnotobiotic cockroaches accumulated mostly lactate and acetate. Similar shifts toward more-oxidized products were observed when the pure cultures were exposed to oxygen, which corroborated the strong effects of oxygen on the metabolic fluxes previously observed in termite guts. Oxygen microsensor profiles of the guts of germfree, gnotobiotic, and conventional cockroaches indicated that both gut tissue and microbiota contribute to oxygen consumption and suggest that the oxygen status influences the colonization success. PMID:26637604

  18. Nonsense mutations in the human. beta. -globin gene affect mRNA metabolism

    SciTech Connect

    Baserga, S.J.; Benz, E.J. Jr. )

    1988-04-01

    A number of premature translation termination mutations (nonsense mutations) have been described in the human {alpha}- and {beta}-globin genes. Studies on mRNA isolated from patients with {beta}{sup 0}-thalassemia have shown that for both the {beta}-17 and the {beta}-39 mutations less than normal levels of {beta}-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human {beta}-globin mRNA). In vitro studies using the cloned {beta}-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. The authors have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, they have studied the effect of five nonsense mutations and two missense mutations on the expression of human {beta}-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.

  19. Litter Environment Affects Behavior and Brain Metabolic Activity of Adult Knockout Mice

    PubMed Central

    Crews, David; Rushworth, David; Gonzalez-Lima, Francisco; Ogawa, Sonoko

    2009-01-01

    In mammals, the formative environment for social and anxiety-related behaviors is the family unit; in the case of rodents, this is the litter and the mother-young bond. A deciding factor in this environment is the sex ratio of the litter and, in the case of mice lacking functional copies of gene(s), the ratio of the various genotypes in the litter. Both Sex and Genotype ratios of the litter affect the nature and quality of the individual's behavior later in adulthood, as well as metabolic activity in brain nuclei that underlie these behaviors. Mice were raised in litters reconstituted shortly after to birth to control for sex ratio and genotype ratio (wild type pups versus pups lacking a functional estrogen receptor α). In both males and females, the Sex and Genotype of siblings in the litter affected aggressive behaviors as well as patterns of metabolic activity in limbic nuclei in the social behavior network later in adulthood. Further, this pattern in males varied depending upon the Genotype of their brothers and sisters. Principal Components Analysis revealed two components comprised of several amygdalar and hypothalamic nuclei; the VMH showed strong correlations in both clusters, suggesting its pivotal nature in the organization of two neural networks. PMID:19707539

  20. A RARE of hepatic Gck promoter interacts with RARα, HNF4α and COUP-TFII that affect retinoic acid- and insulin-induced Gck expression.

    PubMed

    Li, Rui; Zhang, Rui; Li, Yang; Zhu, Bing; Chen, Wei; Zhang, Yan; Chen, Guoxun

    2014-09-01

    The expression of hepatic glucokinase gene (Gck) is regulated by hormonal and nutritional signals. How these signals integrate to regulate the hepatic Gck expression is unclear. We have shown that the hepatic Gck expression is affected by Vitamin A status and synergistically induced by insulin and retinoids in primary rat hepatocytes. We hypothesized that this is mediated by a retinoic acid responsive element (RARE) in the hepatic Gck promoter. Here, we identified the RARE in the hepatic Gck promoter using standard molecular biology techniques. The single nucleotide mutations affecting the promoter activation by retinoic acid (RA) were also determined for detail analysis of protein and DNA interactions. We have optimized experimental conditions for performing electrophoresis mobility shift assay and demonstrated the interactions of the retinoic acid receptor α (RARα), retinoid X receptor α (RXRα), hepatocyte nuclear factor 4α (HNF4α) and chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) in the rat nuclear extract with this RARE, suggesting their roles in the regulation of Gck expression. Chromatin immunoprecipitation assays demonstrated that recombinant adenovirus-mediated overexpression of RARα, HNF4α and COUP-TFII, but not RXRα, significantly increased their occupancy in the hepatic Gck promoter in primary rat hepatocytes. Overexpression of RARα, HNF4α and COUP-TFII, but not RXRα, also affected the RA- and insulin-mediated Gck expression in primary rat hepatocytes. In summary, this hepatic Gck promoter RARE interacts with RARα, HNF4α and COUP-TFII to integrate Vitamin A and insulin signals. PMID:24973045

  1. High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids.

    PubMed

    Lee, Jae-Young; Kim, Sang-Bum; Chun, Jaemoo; Song, Kwang Ho; Kim, Yeong Shik; Chung, Suk-Jae; Cho, Hyun-Jong; Yoon, In-Soo; Kim, Dae-Duk

    2016-04-01

    Alantolactone (ALA) is a major bioactive sesquiterpene lactone present in the roots of Inula helenium L. (Asteraceae) which has been used widely in traditional medicine against various diseases such as asthma, cancer and tuberculosis. The pharmacologic activities of alantolactone have been well characterized, yet information on the physicochemical and pharmacokinetic properties of alantolactone and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of alantolactone and their relevant mechanisms. Log P values of alantolactone ranged from 1.52 to 1.84, and alantolactone was unstable in biological samples such as plasma, urine, bile, rat liver microsomes (RLM) and simulated gastrointestinal fluids. The metabolic rate of alantolactone was markedly higher in rat liver homogenates than in the other tissue homogenates. A saturable and concentration-dependent metabolic rate profile of alantolactone was observed in RLM, and rat cytochrome P450 (CYP) 1 A, 2C, 2D and 3 A subfamilies were significantly involved in its hepatic metabolism. Based on the well-stirred model, the hepatic extraction ratio (HER) was estimated to be 0.890-0.933, classifying alantolactone as a drug with high HER. Moreover, high total body clearance (111 ± 41 ml/min/kg) and low oral bioavailability (0.323%) of alantolactone were observed in rats. Taken together, the present study demonstrates that the extensive hepatic metabolism, at least partially mediated by CYP, is primarily responsible for the high total body clearance of alantolactone, and that the low oral bioavailability of alantolactone could be attributed to its low stability in gastrointestinal fluids and a hepatic first-pass effect in rats. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26861967

  2. Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease

    PubMed Central

    Church, Stephanie J.; Begley, Paul; Kureishy, Nina; McHarg, Selina; Bishop, Paul N.; Bechtold, David A.; Unwin, Richard D.; Cooper, Garth J.S.

    2015-01-01

    Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue. PMID:25797622

  3. Tissue lipid metabolism and hepatic metabolomic profiling in response to supplementation of fermented cottonseed meal in the diets of broiler chickens.

    PubMed

    Nie, Cun-xi; Zhang, Wen-ju; Wang, Yong-qiang; Liu, Yan-feng; Ge, Wen-xia; Liu, Jian-cheng

    2015-06-01

    This study investigated the effects of fermented cottonseed meal (FCSM) on lipid metabolites, lipid metabolism-related gene expression in liver tissues and abdominal adipose tissues, and hepatic metabolomic profiling in broiler chickens. One hundred and eighty 21-d-old broiler chickens were randomly divided into three diet groups with six replicates of 10 birds in each group. The three diets consisted of a control diet supplemented with unfermented cottonseed meal, an experimental diet of cottonseed meal fermented by Candida tropicalis, and a second experimental diet of cottonseed meal fermented by C. tropicalis plus Saccharomyces cerevisae. The results showed that FCSM intake significantly decreased the levels of abdominal fat and hepatic triglycerides (P<0.05 for both). Dietary FCSM supplementation down-regulated the mRNA expression of fatty acid synthase and acetyl CoA carboxylase in liver tissues and the lipoprotein lipase expression in abdominal fat tissues (P<0.05 for both). FCSM intake resulted in significant metabolic changes of multiple pathways in the liver involving the tricarboxylic acid cycle, synthesis of fatty acids, and the metabolism of glycerolipid and amino acids. These findings indicated that FCSM regulated lipid metabolism by increasing or decreasing the expression of the lipid-related gene and by altering multiple endogenous metabolites. Lipid metabolism regulation is a complex process, this discovery provided new essential information about the effects of FCSM diets in broiler chickens and demonstrated the great potential of nutrimetabolomics in researching complex nutrients added to animal diets. PMID:26055906

  4. Ethanol affects hepatitis C pathogenesis: humanized SCID Alb-uPA mouse model.

    PubMed

    Osna, Natalia A; Kharbanda, Kusum K; Sun, Yimin; Simpson, Ronda L; Poluektova, Larisa E; Ganesan, Murali; Wisecarver, James L; Mercer, David F

    2014-07-18

    Alcohol consumption exacerbates the course of hepatitis C viral (HCV) infection, worsens outcomes and contributes to the development of chronic infection that exhibits low anti-viral treatment efficiency. The lack of suitable in vivo models makes HCV-ethanol studies very difficult. Here, we examine whether chimeric SCID Alb-uPA mice transplanted with human hepatocytes and infected with HCV develop worsening pathology when fed ethanol. After 5 weeks of feeding, such mice fed chow+water (control) or chow+20% ethanol in water (EtOH) diets mice developed oxidative stress, decreased proteasome activity and increased steatosis. Importantly, HCV(+) mice in the control group cleared HCV RNA after 5 weeks, while the infection persisted in EtOH-fed mice at the same or even higher levels compared with pre-feeding HCV RNA. We conclude that in chimeric SCID Alb-uPA mice, EtOH exposure causes the complex biochemical and histological changes typical for alcoholic liver injury. In addition, ethanol feeding delays the clearance of HCV RNA thereby generating persistent infection and promoting liver injury. Overall, this model is appropriate for conducting HCV-ethanol studies. PMID:24953695

  5. Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study[S

    PubMed Central

    Clugston, Robin D.; Jiang, Hongfeng; Lee, Man Xia; Piantedosi, Roseann; Yuen, Jason J.; Ramakrishnan, Rajasekhar; Lewis, Michael J.; Gottesman, Max E.; Huang, Li-Shin; Goldberg, Ira J.; Berk, Paul D.; Blaner, William S.

    2011-01-01

    Chronic alcohol consumption is associated with fatty liver disease in mammals. The object of this study was to gain an understanding of dysregulated lipid metabolism in alcohol-fed C57BL/6 mice using a targeted lipidomic approach. Liquid chromatography tandem mass spectrometry was used to analyze several lipid classes, including free fatty acids, fatty acyl-CoAs, fatty acid ethyl esters, sphingolipids, ceramides, and endocannabinoids, in plasma and liver samples from control and alcohol-fed mice. The interpretation of lipidomic data was augmented by gene expression analyses for important metabolic enzymes in the lipid pathways studied. Alcohol feeding was associated with i) increased hepatic free fatty acid levels and decreased fatty acyl-CoA levels associated with decreased mitochondrial fatty acid oxidation and decreased fatty acyl-CoA synthesis, respectively; ii) increased hepatic ceramide levels associated with higher levels of the precursor molecules sphingosine and sphinganine; and iii) increased hepatic levels of the endocannabinoid anandamide associated with decreased expression of its catabolic enzyme fatty acid amide hydrolase. The unique combination of lipidomic and gene expression analyses allows for a better mechanistic understanding of dysregulated lipid metabolism in the development of alcoholic fatty liver disease. PMID:21856784

  6. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.

    PubMed

    Jung, Un Ju; Cho, Yun-Young; Choi, Myung-Sook

    2016-01-01

    Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver. PMID:27213439

  7. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice

    PubMed Central

    Jung, Un Ju; Cho, Yun-Young; Choi, Myung-Sook

    2016-01-01

    Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver. PMID:27213439

  8. Chronic hepatitis B infection is not associated with increased risk of vascular mortality while having an association with metabolic syndrome.

    PubMed

    Katoonizadeh, Aezam; Ghoroghi, Shima; Sharafkhah, Maryam; Khoshnia, Masoud; Mirzaei, Samaneh; Shayanrad, Amaneh; Poustchi, Hossein; Malekzadeh, Reza

    2016-07-01

    This study aimed to assess the association of chronic hepatitis B (CHB) with vascular mortality and metabolic syndrome (MS) using data from a large population-based cohort study in Iran. A total of 12,781 participants (2249 treatment-naïve CHB and 10,532 without CHB) were studied. Logistic regression model was used to assess the association between MS and CHB with adjustment for age, ALT, PLT, alcohol intake, smoking, exercise, and socioeconomic status. MS was defined according to the ATPIII guidelines. Cox proportional hazards model was used to assess the hazard ratios for overall and vascular related mortality. There was a significant association between CHB infection and overall mortality (hazard ratio (95%CI) of 1.44 (1.16-1.79), P < 0.001) after adjusting for other confounders. However, we found no association between CHB infection and mortality from vascular events (hazard ratio (95%CI) of 1.31 (0.93-1.84), P = 0.124) even after subgroup analysis by ALT. Furthermore, increased risk of overall mortality in CHB infected individuals was not related to MS and vice versa (P for interaction = 0.06). We noted a significant direct association between CHB infection and MS in women (OR (95%CI); 1.23 (1.07-1.42), P < 0.004). However, CHB was inversely associated with MS in men (OR (95%CI), 0.85 (0.79-0.99). This gender dependent association was related to high BP levels in women. In this study no association between CHB infection and mortality from vascular events was found. Further longitudinal studies should be done to investigate the exact impact of HBV infection on metabolic parameters and vascular pathology. PMID:26742819

  9. A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats.

    PubMed

    Stanimirovic, Julijana; Obradovic, Milan; Jovanovic, Aleksandra; Sudar-Milovanovic, Emina; Zafirovic, Sonja; Pitt, Samantha J; Stewart, Alan J; Isenovic, Esma R

    2016-04-01

    Men and women differ substantially with regard to the severity of insulin resistance (IR) but the underlying mechanism(s) of how this occurs is poorly characterized. We investigated whether a high fat (HF) diet resulted in sex-specific differences in nitrite/nitrate production and lipid metabolism and whether these variances may contribute to altered obesity-induced IR. Male and female Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. The level of plasma nitrite/nitrate, as well as free fatty acid (FFA), in both plasma and liver lysates were assessed. The levels of inducible nitric oxide (NO) synthase (iNOS), p65 subunit of NFκB, total and phosphorylated forms of Akt, mTOR and PDK-1 in lysates, and the levels of glucose transporter 2 (Glut-2) and fatty acid translocase/cluster of differentiation 36 (FAT/CD36) in plasma membrane fractions of liver were assessed. HF-fed male rats exhibited a significant increase in plasma nitrite/nitrate, and hepatic FFA and FAT/CD36 levels compared with controls. They also displayed a relative decrease in iNOS and Glut-2 levels in the liver. Phosphorylation of Akt (at Ser(473) and Thr(308)), mTOR and PDK-1 was also reduced. HF-fed female rats exhibited increased levels of NFκB-p65 in liver compared with controls, while levels of Glut-2, FAT/CD36 and Akt phosphorylation at Thr(308) and PDK-1 were decreased. Our results reveal that altered lipid and glucose metabolism in obesity, lead to altered iNOS expression and nitrite/nitrate production. It is likely that this mechanism contributes to sex-specific differences in the development of IR. PMID:26924725

  10. The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1.

    PubMed

    Han, Jinbo; Li, Erwei; Chen, Liqun; Zhang, Yuanyuan; Wei, Fangchao; Liu, Jieyuan; Deng, Haiteng; Wang, Yiguo

    2015-08-13

    Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity. PMID:26147081

  11. Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs.

    PubMed

    van Beusekom, C D; Schipper, L; Fink-Gremmels, J

    2010-12-01

    This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities associated with CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A were measured. Cat liver microsomes metabolized all substrates selected for the assessment of cytochrome P450 activity. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Substrate selectivity could be demonstrated by inhibition studies with α-naphthoflavone (CYP1A), tranylcypromine/quercetine (CYP2C), quinidine (CYP2D), diethyldithiocarbamic acid (CYP2E) and ketoconazole (CYP3A) respectively. Other prototypical inhibitors used for characterization of human CYP activities such as furafylline (CYP1A), tranylcypromine (CYP2B) and sulfaphenazole (CYP2C) did not show significant effects in cat and dog liver microsomes. Moreover, IC50-values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. Gender differences were observed in the oxidation of 7-ethoxy-4-trifluoromethylcoumarin (CYP2B) and 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D), which were significantly higher in male cats than in females. Conversely, oxidation of the substrates dibenzylfluorescein (CYP2C) and 7-methoxy-4-trifluoromethylcoumarin (CYP2E) showed significant higher activities in females than in male cats. Overall CYP-activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B. The presented difference between feline and canine CYP-activities are useful to establish dose corrections for feline patients of intensively metabolized drugs licensed for dogs or humans. PMID:21062303

  12. Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein.

    PubMed

    Evans, David C; O'Connor, Desmond; Lake, Brian G; Evers, Raymond; Allen, Christopher; Hargreaves, Richard

    2003-07-01

    "Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity. PMID:12814962

  13. Multiphoton microscopy can visualize zonal damage and decreased cellular metabolic activity in hepatic ischemia-reperfusion injury in rats

    NASA Astrophysics Data System (ADS)

    Thorling, Camilla A.; Liu, Xin; Burczynski, Frank J.; Fletcher, Linda M.; Gobe, Glenda C.; Roberts, Michael S.

    2011-11-01

    Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery. In orthotopic transplantation, the donor liver is exposed to periods of ischemia and when oxygenated blood is reintroduced to the liver, oxidative stress may develop and lead to graft failure. The aim of this project was to investigate whether noninvasive multiphoton and fluorescence lifetime imaging microscopy, without external markers, were useful in detecting early liver damage caused by I/R injury. Localized hepatic ischemia was induced in rats for 1 h followed by 4 h reperfusion. Multiphoton and fluorescence lifetime imaging microscopy was conducted prior to ischemia and up to 4 h of reperfusion and compared to morphological and biochemical assessment of liver damage. Liver function was significantly impaired at 2 and 4 h of reperfusion. Multiphoton microscopy detected liver damage at 1 h of reperfusion, manifested by vacuolated cells and heterogeneous spread of damage over the liver. The damage was mainly localized in the midzonal region of the liver acinus. In addition, fluorescence lifetime imaging showed a decrease in cellular metabolic activity. Multiphoton and fluorescence lifetime imaging microscopy detected evidence of early I/R injury both structurally and functionally. This provides a simple noninvasive technique useful for following progressive liver injury without external markers.

  14. Effect of roxarsone inclusion in the diet on the performance and hepatic lipid metabolism of laying Tsaiya duck.

    PubMed

    Chen, K L; Wu, C P; Chiou, P W

    2000-07-01

    1. The aim of this study was to examine the effects of roxarsone (3-nitro-4-hydroxyphenylarsonic acid) inclusion in the diet on the performance, liver function and lipid metabolism in the liver of laying Brown Tsaiya ducks. 2. Sixty 36-week-old laying ducks were selected and allocated at random into 4 dietary treatments with 3 replications for each treatment. Feeding was for 7 weeks with 3 weeks of experimental diets followed by a 4 week withdrawal period. The experimental diets were supplemented with 0, 50, 100 and 300 mg/kg roxarsone, respectively 3. Dietary inclusion of 50 or 100 mg/kg roxarsone did not significantly promote performance. Inclusion of 300 mg/kg significantly depressed (P<0.05) performance, liver weight and content, serum triacylglycerol (TG), serum nonesterified fatty acid (NEFA) and increased (P<0.05) cholesterol, creatine kinase (CK) and aspartate aminotransferase (AST) in the serum at the end of 3 weeks on the experimental diet. 4. Laying characteristics returned to normal 4 weeks after withdrawal of roxarsone. The liver weight, fat and TG in the liver and serum concentrations of TG, NEFA, high density lipoprotein (HDL) and AST increased significantly (P<0.05), while the level of very low density lipoprotein (VLDL) decreased (P<0.05) at the end of the withdrawal period. More prominent vacuolised hepatic fatty cells were observed in laying ducks treated with 300 mg/kg of roxarsone. PMID:11081432

  15. Role of hepatic blood flow and metabolism in the pharmacokinetics of ten drugs in lean, aged and obese rats.

    PubMed

    Subramanian, Murali; Kurawattimath, Vishwanath; Pocha, Krishna; Freeden, Chris; Rao, Indranil; Mariappan, T Thanga; Marathe, Punit H; Vikramadithyan, Reeba K; Abraham, Pamela; Kulkarni, Chetan P; Katnapally, Prasanna; Nutakki, Ravikumar; Paruchury, Sundeep; Bhutani, Priyadeep; Mandlekar, Sandhya

    2014-12-01

    1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats. PMID:24947446

  16. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport.

    PubMed

    Yeung, Catherine K; Shen, Danny D; Thummel, Kenneth E; Himmelfarb, Jonathan

    2014-03-01

    The pharmacokinetics of non-renally cleared drugs in patients with chronic kidney disease is often unpredictable. Some of this variability may be due to alterations in the expression and activity of extra renal drug-metabolizing enzymes and transporters, primarily localized in the liver and intestine. Studies conducted in rodent models of renal failure have shown decreased mRNA and protein expression of many members of the cytochrome P450 enzyme (CYP) gene family and the ATP-binding cassette (ABC) and solute carrier (SLC) gene families of drug transporters. Uremic toxins interfere with transcriptional activation, cause downregulation of gene expression mediated by proinflammatory cytokines, and directly inhibit the activity of the cytochrome P450s and drug transporters. While much has been learned about the effects of kidney disease on non-renal drug disposition, important questions remain regarding the mechanisms of these effects, as well as the interplay between drug-metabolizing enzymes and drug transporters in the uremic milieu. In this review, we have highlighted the existing gaps in our knowledge and understanding of the impact of chronic kidney disease on non-renal drug clearance, and identified areas of opportunity for future research. PMID:24132209

  17. Increasing Phosphatidylinositol (4,5)-Bisphosphate Biosynthesis Affects Basal Signaling and Chloroplast Metabolism in Arabidopsis thaliana

    PubMed Central

    Im, Yang Ju; Smith, Caroline M.; Phillippy, Brian Q.; Strand, Deserah; Kramer, David M.; Grunden, Amy M.; Boss, Wendy F.

    2014-01-01

    One challenge in studying the second messenger inositol(1,4,5)-trisphosphate (InsP3) is that it is present in very low amounts and increases only transiently in response to stimuli. To identify events downstream of InsP3, we generated transgenic plants constitutively expressing the high specific activity, human phosphatidylinositol 4-phosphate 5-kinase Iα (HsPIPKIα). PIP5K is the enzyme that synthesizes phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2); this reaction is flux limiting in InsP3 biosynthesis in plants. Plasma membranes from transgenic Arabidopsis expressing HsPIPKIα had 2–3 fold higher PIP5K specific activity, and basal InsP3 levels in seedlings and leaves were >2-fold higher than wild type. Although there was no significant difference in photosynthetic electron transport, HsPIPKIα plants had significantly higher starch (2–4 fold) and 20% higher anthocyanin compared to controls. Starch content was higher both during the day and at the end of dark period. In addition, transcripts of genes involved in starch metabolism such as SEX1 (glucan water dikinase) and SEX4 (phosphoglucan phosphatase), DBE (debranching enzyme), MEX1 (maltose transporter), APL3 (ADP-glucose pyrophosphorylase) and glucose-6-phosphate transporter (Glc6PT) were up-regulated in the HsPIPKIα plants. Our results reveal that increasing the phosphoinositide (PI) pathway affects chloroplast carbon metabolism and suggest that InsP3 is one component of an inter-organelle signaling network regulating chloroplast metabolism. PMID:27135490

  18. Potato snakin-1 gene silencing affects cell division, primary metabolism, and cell wall composition.

    PubMed

    Nahirñak, Vanesa; Almasia, Natalia Inés; Fernandez, Paula Virginia; Hopp, Horacio Esteban; Estevez, José Manuel; Carrari, Fernando; Vazquez-Rovere, Cecilia

    2012-01-01

    Snakin-1 (SN1) is an antimicrobial cysteine-rich peptide isolated from potato (Solanum tuberosum) that was classified as a member of the Snakin/Gibberellic Acid Stimulated in Arabidopsis protein family. In this work, a transgenic approach was used to study the role of SN1 in planta. Even when overexpressing SN1, potato lines did not show remarkable morphological differences from the wild type; SN1 silencing resulted in reduced height, which was accompanied by an overall reduction in leaf size and severe alterations of leaf shape. Analysis of the adaxial epidermis of mature leaves revealed that silenced lines had 70% to 90% increases in mean cell size with respect to wild-type leaves. Consequently, the number of epidermal cells was significantly reduced in these lines. Confocal microscopy analysis after agroinfiltration of Nicotiana benthamiana leaves showed that SN1-green fluorescent protein fusion protein was localized in plasma membrane, and bimolecular fluorescence complementation assays revealed that SN1 self-interacted in vivo. We further focused our study on leaf metabolism by applying a combination of gas chromatography coupled to mass spectrometry, Fourier transform infrared spectroscopy, and spectrophotometric techniques. These targeted analyses allowed a detailed examination of the changes occurring in 46 intermediate compounds from primary metabolic pathways and in seven cell wall constituents. We demonstrated that SN1 silencing affects cell division, leaf primary metabolism, and cell wall composition in potato plants, suggesting that SN1 has additional roles in growth and development beyond its previously assigned role in plant defense. PMID:22080603

  19. Metabolic syndrome affects breast cancer risk in postmenopausal women: National Cancer Institute of Naples experience.

    PubMed

    Capasso, Immacolata; Esposito, Emanuela; Pentimalli, Francesca; Crispo, Anna; Montella, Maurizio; Grimaldi, Maria; De Marco, MariaRosaria; Cavalcanti, Ernestina; D'Aiuto, Massimiliano; Fucito, Alfredo; Frasci, Giuseppe; Maurea, Nicola; Esposito, Giuseppe; Pedicini, Tonino; Vecchione, Aldo; D'Aiuto, Giuseppe; Giordano, Antonio

    2010-12-15

    Postmenopausal women show the highest incidence of breast cancer in the female population and are often affected by metabolic syndrome. Metabolic syndrome (MS)--characterized by central adiposity, insulin resistance, low serum high-density lipoprotein cholesterol (HDL-C), high serum triglyceride and high blood pressure--seems to be strictly correlated to breast carcinogenesis. We enrolled 777 healthy women and women with breast cancer in our nested case-control study to evaluate the association between MS and breast cancer, analyzing anthropometric parameters (weight, height, BMI, waist and hip circumference), blood pressure, serum HDL-C, triglyceride, fasting plasma glucose, insulin, testosterone and uric acid levels and administering a questionnaire about physical activity, food intake, tobacco use, alcohol abuse, personal and familial history of disease. We found an higher prevalence of metabolic syndrome (30%) in postmenopausal breast cancer patients compared to healthy women (19%). None of the individual MS features was strong enough to be considered responsible for breast carcinogenesis alone. However, of the 63 postmenopausal breast cancer cases associated to MS, 30% presented three or more MS features, suggesting that the activation of multiple molecular pathways underlying MS might contribute to tumorigenesis. Our data support the hypothesis that MS may be an indicator of breast cancer risk in postmenopausal women. The unsettlement of the hormonal arrangement in postmenopausal, along with an increase in visceral adiposity, probably favour the hormone-dependent cell proliferation, which drives tumorigenesis. Adjustments in lifestyle with physical activity intensification and healthy diet could represent modifiable factors for the primary prevention of sporadic breast cancer. PMID:20935521

  20. Factors affecting carisoprodol metabolism in pain patients using urinary excretion data.

    PubMed

    Tse, Stephanie A; Atayee, Rabia S; Ma, Joseph D; Best, Brookie M

    2014-04-01

    Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ∼47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy. PMID:24488112

  1. Plasma content of B6 vitamers and its relationship to hepatic vitamin B6 metabolism.

    PubMed

    Lumeng, L; Lui, A; Li, T K

    1980-10-01

    The plasma content of B6 vitamers is governed by, among other factors, dietary supply and metabolic interconversion. This study examines the effect of pyridoxine supplementation on the plasma content of B6 vitamers and pyridoxic acid in man, and the metabolic conversion and release of B6 compounds in isolated rat hepatocytes. Six healthy human subjects were given 100 mg pyridoxine-HCl/d orally for 1--3 wk. Before pyridoxine supplementation, the mean total plasma level of B6 vitamers was 114 +/- 9 nM; and pyridoxal-P, pyridoxamine-P, pyridoxal, pyridoxine, and pyridoxamine accounted for 54, 3, 11, 27, and 5%, respectively. Plasma level of pyridoxic acid was 40 +/- 7 nM. Thus, pyridoxal-P is the principal B6 vitamer in plasma. During pyridoxine supplementation, mean plasma levels of the B6 vitamers and pyridoxic acid increased to 655 +/- 122 and 222 +/- 55 nM, respectively. The plasma content of pyridoxal-P and pyridoxic acid increased 6--7-fold and that of pyridoxal, 12-fold, but the pyridoxine level did not increase. Isolated hepatocytes, 1 g/15 ml, were incubated for 2 h with 3.33 microM [14C]pyridoxine (6 microCi/mumol). At zero time, the cells contained about 35 nmol pyridoxal-P and 25 nmol pyridoxamine-P. After 2 h incubation, the cellular content of pyridoxal-P and pyridoxamine-P did not change significantly, but the medium contained 5.9 nmol pyridoxal-P, 0.3 nmol pyridoxamine-P, 7.2 nmol pyridoxal, 26.6 nmol pyridoxine, 0.3 nmol pyridoxamine, and 7.5 nmol pyridoxic acid. Whereas the specific radioactivity of pyridoxal-P, pyridoxal, and pyridoxic acid in the medium approached that of [14C]pyridoxine, the specific radioactivity of cellular pyridoxal-P and pyridoxamine-P was only 20% of that of pyridoxine. Thus, newly synthesized pyridoxal-P is not freely exchangeable with endogenous pyridoxal-P, but is preferentially released or degraded to pyridoxal and pyridoxic acid. The latter B6 compounds are also released. These results suggest that orally ingested

  2. Plasma content of B6 vitamers and its relationship to hepatic vitamin B6 metabolism.

    PubMed Central

    Lumeng, L; Lui, A; Li, T K

    1980-01-01

    The plasma content of B6 vitamers is governed by, among other factors, dietary supply and metabolic interconversion. This study examines the effect of pyridoxine supplementation on the plasma content of B6 vitamers and pyridoxic acid in man, and the metabolic conversion and release of B6 compounds in isolated rat hepatocytes. Six healthy human subjects were given 100 mg pyridoxine-HCl/d orally for 1--3 wk. Before pyridoxine supplementation, the mean total plasma level of B6 vitamers was 114 +/- 9 nM; and pyridoxal-P, pyridoxamine-P, pyridoxal, pyridoxine, and pyridoxamine accounted for 54, 3, 11, 27, and 5%, respectively. Plasma level of pyridoxic acid was 40 +/- 7 nM. Thus, pyridoxal-P is the principal B6 vitamer in plasma. During pyridoxine supplementation, mean plasma levels of the B6 vitamers and pyridoxic acid increased to 655 +/- 122 and 222 +/- 55 nM, respectively. The plasma content of pyridoxal-P and pyridoxic acid increased 6--7-fold and that of pyridoxal, 12-fold, but the pyridoxine level did not increase. Isolated hepatocytes, 1 g/15 ml, were incubated for 2 h with 3.33 microM [14C]pyridoxine (6 microCi/mumol). At zero time, the cells contained about 35 nmol pyridoxal-P and 25 nmol pyridoxamine-P. After 2 h incubation, the cellular content of pyridoxal-P and pyridoxamine-P did not change significantly, but the medium contained 5.9 nmol pyridoxal-P, 0.3 nmol pyridoxamine-P, 7.2 nmol pyridoxal, 26.6 nmol pyridoxine, 0.3 nmol pyridoxamine, and 7.5 nmol pyridoxic acid. Whereas the specific radioactivity of pyridoxal-P, pyridoxal, and pyridoxic acid in the medium approached that of [14C]pyridoxine, the specific radioactivity of cellular pyridoxal-P and pyridoxamine-P was only 20% of that of pyridoxine. Thus, newly synthesized pyridoxal-P is not freely exchangeable with endogenous pyridoxal-P, but is preferentially released or degraded to pyridoxal and pyridoxic acid. The latter B6 compounds are also released. These results suggest that orally ingested

  3. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

    PubMed Central

    Rivory, L P; Slaviero, K A; Clarke, S J

    2002-01-01

    Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C20min measure and the recently proposed 1/TMAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1β, TNFα and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg l−1, n=26) had reduced metabolism as measured with the erythromycin breath test 1/TMAX (Kruskal–Wallis Anova, P=0.0062) as compared to controls (C-reactive protein ⩽10 mg l−1, n=14). Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=−0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population. British Journal of Cancer (2002) 87, 277–280. doi:10.1038/sj.bjc.6600448 www.bjcancer.com © 2002 Cancer Research UK PMID:12177794

  4. Overexpression of miR-155 in the Liver of Transgenic Mice Alters the Expression Profiling of Hepatic Genes Associated with Lipid Metabolism

    PubMed Central

    Li, Wei; Wang, Xiaoyan; Wei, Jieqiong; Lin, Xia; Zeng, Hui; Yao, Longping; Chen, Xuebing; Zhuang, Jingshen; Weng, Jie; Liu, Yu; Lin, Jihong; Wu, Qinghong; Wang, Wanshan; Yao, Kaitai; Xu, Kang; Xiao, Dong

    2015-01-01

    Hepatic expression profiling has revealed miRNA changes in liver diseases, while hepatic miR-155 expression was increased in murine non-alcoholic fatty liver disease, suggesting that miR-155 might regulate the biological process of lipid metabolism. To illustrate the effects of miR-155 gain of function in transgenic mouse liver on lipid metabolism, transgenic mice (i.e., Rm155LG mice) for the conditional overexpression of mouse miR-155 transgene mediated by Cre/lox P system were firstly generated around the world in this study. Rm155LG mice were further crossed to Alb-Cre mice to realize the liver-specific overexpression of miR-155 transgene in Rm155LG/Alb-Cre double transgenic mice which showed the unaltered body weight, liver weight, epididymal fat pad weight and gross morphology and appearance of liver. Furthermore, liver-specific overexpression of miR-155 transgene resulted in significantly reduced levels of serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL), as well as remarkably decreased contents of hepatic lipid, TG, HDL and free fatty acid in Rm155LG/Alb-Cre transgenic mice. More importantly, microarray data revealed a general downward trend in the expression profile of hepatic genes with functions typically associated with fatty acid, cholesterol and triglyceride metabolism, which is likely at least partially responsible for serum cholesterol and triglyceride lowering observed in Rm155LG/Alb-Cre mice. In this study, we demonstrated that hepatic overexpression of miR-155 alleviated nonalcoholic fatty liver induced by a high-fat diet. Additionally, carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) was identified as a direct miR-155 target gene that is potentially responsible for the partial liver phenotypes observed in Rm155LG/Alb-Cre mice. Taken together, these data from miR-155 gain of function study suggest, for what we believe is the first time, the altered lipid metabolism and provide new insights into the metabolic

  5. Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature

    PubMed Central

    Norambuena, Fernando; Morais, Sofia; Emery, James A.; Turchini, Giovanni M.

    2015-01-01

    Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n-3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10°C or 20°C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the β-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparα -transcription factor in lipid metabolism, including β-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for β-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Δ5fad–time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature

  6. Obesity and Metabolic Phenotypes (Metabolically Healthy and Unhealthy Variants) Are Significantly Associated with Prevalence of Elevated C-Reactive Protein and Hepatic Steatosis in a Large Healthy Brazilian Population

    PubMed Central

    Shaharyar, Sameer; Roberson, Lara L.; Jamal, Omar; Younus, Adnan; Blaha, Michael J.; Ali, Shozab S.; Zide, Kenneth; Agatston, Arthur A.; Blumenthal, Roger S.; Conceição, Raquel D.; Santos, Raul D.; Nasir, Khurram

    2015-01-01

    Background. Among the obese, the so-called metabolically healthy obese (MHO) phenotype is thought to confer a lower CVD risk as compared to obesity with typical associated metabolic changes. The present study aims to determine the relationship of different subtypes of obesity with inflammatory-cardiometabolic abnormalities. Methods. We evaluated 5,519 healthy, Brazilian subjects (43 ± 10 years, 78% males), free of known cardiovascular disease. Those with <2 metabolic risk factors (MRF) were considered metabolically healthy, and those with BMI ≥ 25 kg/m2 and/or waist circumference meeting NCEP criteria for metabolic syndrome as overweight/obese (OW). High sensitivity C reactive protein (hsCRP) was measured to assess underlying inflammation and hepatic steatosis (HS) was determined via abdominal ultrasound. Results. Overall, 40% of OW individuals were metabolically healthy, and 12% normal-weight had ≥2 MRF. The prevalence of elevated CRP (≥3 mg/dL) and HS in MHO versus normal weight metabolically healthy group was 22% versus 12%, and 40% versus 8% respectively (P < 0.001). Both MHO individuals and metabolically unhealthy normal weight (MUNW) phenotypes were associated with elevated hsCRP and HS. Conclusion. Our study suggests that MHO and MUNW phenotypes may not be benign and physicians should strive to treat individuals in these subgroups to reverse these conditions. PMID:25838943

  7. Hepatic metabolic response of Holstein cows in early and mid lactation is altered by nutrient supply and lipopolysaccharide in vitro.

    PubMed

    Garcia, M; Bequette, B J; Moyes, K M

    2015-10-01

    The metabolic response of the liver during periods of inflammation is poorly understood. The objective of this study was to characterize the effects of nutrient supply and lipopolysaccharide (LPS) challenge on hepatic intermediate metabolism of early- and mid-lactation cows by employing gas chromatography-mass spectrometry with stable isotope tracer. Twelve multiparous Holstein-Friesian cows in early (n = 6; 12 ± 4.2 d in milk) and mid (n = 6; 115 ± 13.5 d in milk) lactation were used for this study. Liver biopsies were performed on all cows. Liver slices (40-60 mg) were incubated in a 37°C water bath for 2 h with either control (phosphate buffered saline), pyruvate (PYR; 1mM unlabeled pyruvate and 1mM [(13)C3]pyruvate), pyruvate + propionate (PYR+PRO; 1mM unlabeled pyruvate, 1mM [(13)C3]pyruvate, and 2mM sodium propionate), or pyruvate + AA (PYR+AA; 1mM unlabeled pyruvate, 1mM [(13)C3]pyruvate, and 2mM AA solution), and LPS (0.0 or 0.2 μg/mL) was added to flasks per treatment. Enrichment of isotopomers in metabolic equilibrium with Krebs cycle intermediates was assessed. Pyruvate fluxes and the enzymatic activity of pyruvate carboxylase (PC) versus pyruvate dehydrogenase (PDH) and phosphoenol pyruvate carboxykinase (PEPCK) were calculated. Media were analyzed for concentrations of tumor necrosis factor-α (TNF-α), glucose, and haptoglobin. Data were analyzed as randomized block (stage of lactation) design in a factorial arrangement of nutrient treatments by LPS dose. Challenge with LPS increased the mRNA abundance of TNF-α, haptoglobin, and serum amyloid A 2, and the concentration of TNF-α in media. Challenge with LPS increased mRNA abundance of PC but reduced the enrichment of (13)C1[M1] and (13)C2[M2]alanine and tended to reduce the enzymatic activity of PEPCK. Incubation with PYR+PRO and PYR+AA increased the flux of pyruvate to acetyl CoA. However, only PYR+PRO increased the enzymatic activity of PEPCK and PDH versus PC and decreased the mRNA abundance

  8. Food odors trigger an endocrine response that affects food ingestion and metabolism.

    PubMed

    Lushchak, Oleh V; Carlsson, Mikael A; Nässel, Dick R

    2015-08-01

    Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin-like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling. PMID:25782410

  9. Plasticity and epistasis strongly affect bacterial fitness after losing multiple metabolic genes.

    PubMed

    D'Souza, Glen; Waschina, Silvio; Kaleta, Christoph; Kost, Christian

    2015-05-01

    Many bacterial lineages lack seemingly essential metabolic genes. Previous work suggested selective benefits could drive the loss of biosynthetic functions from bacterial genomes when the corresponding metabolites are sufficiently available in the environment. However, the factors that govern this "genome streamlining" remain poorly understood. Here we determine the effect of plasticity and epistasis on the fitness of Escherichia coli genotypes from whose genome biosynthetic genes for one, two, or three different amino acids have been deleted. Competitive fitness experiments between auxotrophic mutants and prototrophic wild-type cells in one of two carbon environments revealed that plasticity and epistasis strongly affected the mutants' fitness individually and interactively. Positive and negative epistatic interactions were prevalent, yet on average cancelled each other out. Moreover, epistasis correlated negatively with the expected effects of combined auxotrophy-causing mutations, thus producing a pattern of diminishing returns. Moreover, computationally analyzing 1,432 eubacterial metabolic networks revealed that most pairs of auxotrophies co-occurred significantly more often than expected by chance, suggesting epistatic interactions and/or environmental factors favored these combinations. Our results demonstrate that both the genetic background and environmental conditions determine the adaptive value of a loss-of-biochemical-function mutation and that fitness gains decelerate, as more biochemical functions are lost. PMID:25765095

  10. Rice Debranching Enzyme Isoamylase3 Facilitates Starch Metabolism and Affects Plastid Morphogenesis

    PubMed Central

    Yun, Min-Soo; Umemoto, Takayuki; Kawagoe, Yasushi

    2011-01-01

    Debranching enzymes, which hydrolyze α-1 and 6-glucosidic linkages in α-polyglucans, play a dual role in the synthesis and degradation of starch in plants. A transposon-inserted rice mutant of isoamylase3 (isa3) contained an increased amount of starch in the leaf blade at the end of the night, indicating that ISA3 plays a role in the degradation of transitory starch during the night. An epitope-tagged ISA3 expressed in Escherichia coli exhibited hydrolytic activity on β-limit dextrin and amylopectin. We investigated whether ISA3 plays a role in amyloplast development and starch metabolism in the developing endosperm. ISA3–green fluorescent protein (GFP) fusion protein expressed under the control of the rice ISA3 promoter was targeted to the amyloplast stroma in the endosperm. Overexpression of ISA3 in the sugary1 mutant, which is deficient in ISA1 activity, did not convert water-soluble phytoglycogen to starch granules, indicating that ISA1 and ISA3 are not functionally redundant. Both overexpression and loss of function of ISA3 in the endosperm generated pleomorphic amyloplasts and starch granules. Furthermore, chloroplasts in the leaf blade of isa3 seedlings were large and pleomorphic. These results suggest that ISA3 facilitates starch metabolism and affects morphological characteristics of plastids in rice. PMID:21551159

  11. Campomanesia adamantium extract induces DNA damage, apoptosis, and affects cyclophosphamide metabolism.

    PubMed

    Martello, M D; David, N; Matuo, R; Carvalho, P C; Navarro, S D; Monreal, A C D; Cunha-Laura, A L; Cardoso, C A L; Kassuya, C A L; Oliveira, R J

    2016-01-01

    Campomanesia adamantium (Cambess.) O. Berg. is originally from Brazil. Its leaves and fruits have medicinal properties such as anti-inflammatory, antidiarrheal and antiseptic properties. However, the mutagenic potential of this species has been reported in few studies. This study describes the mutagenic/antimutagenic, splenic phagocytic, and apoptotic activities of C. adamantium hydroethanolic extract with or without cyclophosphamide in Swiss mice. The animals orally received the hydroethanolic extract at doses of 30, 100, or 300 mg/kg with or without 100 mg/kg cyclophosphamide. Mutagenesis was evaluated by performing the micronucleus assay after treatment for 24, 48, and 72 h, while splenic phagocytic and apoptotic effects were investigated after 72 h. Short-term exposure of 30 and 100 mg/kg extract induced mild clastogenic/aneugenic effects and increased splenic phagocytosis and apoptosis in the liver, spleen, and kidneys. When the extract was administered in combination with cyclophosphamide, micronucleus frequency and apoptosis reduced. Extract components might affect cyclophosphamide metabolism, which possibly leads to increased clearance of this chemotherapeutic agent. C. adamantium showed mutagenic activity and it may decrease the effectiveness of drugs with metabolic pathways similar to those associated with cyclophosphamide. Thus, caution should be exercised while consuming these extracts, especially when received in combination with other drugs. PMID:27173259

  12. Inhibition of mitochondrial complex II affects dopamine metabolism and decreases its uptake into striatal synaptosomes.

    PubMed

    Cakała, Magdalena; Drabik, Jacek; Kaźmierczak, Anna; Kopczuk, Dorota; Adamczyk, Agata

    2006-01-01

    The mitochondrial toxin, 3-nitropropionic acid (3-NP), is a specific inhibitor of succinate dehydrogenase, complex II in the mitochondrial respiratory chain. The aim of our study was to determine the relationship between inhibition of mitochondrial complex II and dopamine (DA) metabolism and its transport into rat striatal synaptosomes after exposure to 3-NP. The study was carried out using spectrophotometric, radiochemical and HPLC methods. Our data showed that inhibition of succinate dehydrogenase by intraperitoneal (i.p.) injection of 3-NP (cumulated dose 100 mg/kg in 4 days) significantly affected DA metabolism, leading to the accumulation of its metabolites, 3,4-dihydroxylphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the rat striatum. These experimental conditions had no effect on free radical dependent lipid peroxidation in the brain. In vitro experiments revealed that DA and DOPAC significantly decrease lipid peroxidation in the brain homogenate. Moreover, 3-NP significantly inhibited [3H]DA uptake into striatal synaptosomes by specific dopamine transporter (DAT). The scavengers of superoxide radical (O2-) Tempol and Trolox had no effect on DAT function, but the nitric oxide synthase (NOS) inhibitor N w-nitro-L-arginine (100 microM) prevented 3-NP-evoked DAT down-regulation. In summary, our results indicate that inhibition of mitochondrial complex II by 3-NP enhances DA degradation and decreases its uptake into synaptosomes. It is suggested that NO and energy failure are responsible for alteration of the dopaminergic system in the striatum. PMID:17183449

  13. Failure of caffeine to affect metabolism during 60 min submaximal exercise.

    PubMed

    Titlow, L W; Ishee, J H; Riggs, C E

    1991-01-01

    Caffeine consumption prior to athletic performance has become commonplace. The usual dosage is approximately 200 mg, a level of caffeine ingestion equivalent to two cups of brewed coffee. This study was designed to examine the effects of a common level of caffeine ingestion, specifically 200 mg, on metabolism during submaximal exercise performance in five males. The subjects performed two 60-min monitored treadmill workouts at 60% maximal heart rate during a 2-week period. The subjects were randomly assigned, double-blind to receive a caffeine or placebo capsule 60 min prior to exercise. Testing was performed in the afternoon following a midnight fast. Venous blood was withdrawn pre-exercise, every 15 min during the workout, and 10 min after recovery. Blood was analysed for free fatty acid, triglycerides, glucose, lactic acid, haemoglobin and haematocrit. The respiratory exchange ratio (R), perceived exertion (RPE) and oxygen uptake were measured every 4 min during exercise. An examination of the data with repeated-measures ANOVA revealed no significant differences between the two groups. Within the limitations of the study, it was concluded that 200 mg caffeine failed to affect metabolism during 60 min submaximal exercise. PMID:1856908

  14. Factors Affecting the Absorption, Metabolism, and Excretion of Cocoa Flavanols in Humans.

    PubMed

    Cifuentes-Gomez, Tania; Rodriguez-Mateos, Ana; Gonzalez-Salvador, Isidro; Alañon, María Elena; Spencer, Jeremy P E

    2015-09-01

    Cocoa is rich in a subclass of flavonoids known as flavanols, the cardiovascular health benefits of which have been extensively reported. The appearance of flavanol metabolites in the systemic circulation after flavanol-rich food consumption is likely to mediate the physiological effects on the vascular system, and these levels are influenced by numerous factors, including food matrix, processing, intake, age, gender, or genetic polymorphisms, among others. This review will focus on our current understanding of factors affecting the absorption, metabolism, and excretion of cocoa flavanols in humans. Second, it will identify gaps in these contributing factors that need to be addressed to conclusively translate our collective knowledge into the context of public health, dietary guidelines, and evidence-based dietary recommendations. PMID:25711140

  15. Escherichia coli carbon source metabolism