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Sample records for non-alcoholic steatohepatitis nash

  1. Therapies in non-alcoholic steatohepatitis (NASH).

    PubMed

    Oseini, Abdul M; Sanyal, Arun J

    2017-01-01

    The hallmark of non-alcoholic fatty liver disease (NAFLD) is excessive fatty accumulation in the hepatocytes, which may be an isolated event (non-alcoholic fatty liver, NAFL) or accompanied by evidence of inflammation and cell injury with or without fibrosis (non-alcoholic steatohepatitis, NASH). NASH, the more aggressive form of NAFLD, may progress to cirrhosis and hepatocellular carcinoma. Since NASH is estimated to overtake hepatitis C virus infection as the leading cause of liver transplantation in the US in the coming decade, and there are no current FDA-approved therapies for this disease, the need to find appropriate therapeutic targets is now more urgent than ever before. Diet and other lifestyle modifications have always been difficult to maintain and this approach alone has not slowed the rising tide of the disease. While the results of traditional therapies such as vitamin E and pioglitazone have been significant for steatosis and inflammation, they have had no effect on fibrosis, which is the strongest indicator of mortality in this condition. However, the understanding of the pathogenesis and progression of NASH has evolved and several promising novel therapies to target and possibly reverse fibrosis are being evaluated, making the future outlook of NASH therapy more optimistic.

  2. [Non-alcoholic fatty liver disease (NAFLD) /non-alcoholic steatohepatitis (NASH) and nutrition].

    PubMed

    Ishii, Kiyo-aki; Takamura, Toshinari

    2016-03-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the form of triglycerides in the hepatocytes. A more severe form of NAFLD with necrosis, inflammation, and fibrosis is called non-alcoholic steatohepatitis (NASH). The liver is located in the center of the body's organ network and acts as a coordinator of glucose and lipid metabolism. Therefore, it is important to perform nutritional therapy of patients with NAFLD/NASH while maintaining the energy balance in the entire body.

  3. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV.

    PubMed

    Rockstroh, Jürgen Kurt

    2017-04-01

    Abnormal liver enzymes (LE) are common in patients infected with the human immunodeficiency virus (HIV) even in the absence of viral hepatitis or alcohol abuse. With availability of antiretroviral combination therapy, life expectancy has improved dramatically and as a consequence the spectrum of liver disease is changing. Increased reports on the development of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) in HIV coinfected patients raise questions around prevalence, clinical manifestations, and clinical outcome of these liver diseases in HIV coinfection. Moreover, the potential impact of combination antiretroviral therapy as well as direct HIV effects on the emergence of non-alcoholic fatty liver disease needs to be explored. This review summarizes the recent literature on NAFLD and NASH in HIV.

  4. CEACAM1 loss links inflammation to Insulin Resistance in obesity and Non-alcoholic Steatohepatitis (NASH)

    PubMed Central

    Najjar, Sonia M.; Russo, Lucia

    2014-01-01

    Mounting epidemiological evidence points to an association between metabolic syndrome and non-alcoholic steatohepatitis (NASH), an increasingly recognized new epidemic. NASH pathologies include hepatocellular ballooning, lobular inflammation, hepatocellular injury, apoptosis and hepatic fibrosis. We will review the relationship between insulin resistance and inflammation in visceral obesity and NASH in an attempt to shed more light on the pathogenesis of these major metabolic diseases. Moreover, we will identify loss of the Carcinoembryonic antigen-related cell adhesion molecule 1 as a unifying mechanism linking the immunological and metabolic abnormalities in NASH. PMID:24258517

  5. Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course.

    PubMed

    Cortez-Pinto, Helena; Camilo, Maria Ermelinda

    2004-12-01

    Non-alcoholic fatty liver disease (NAFLD) is a frequent syndrome encompassing fatty liver alone and steatohepatitis (NASH). Often asymptomatic, the suspicion arises because of abnormal aminotransferases or a bright liver on abdominal ultrasound. It should be suspected during evaluation of associated conditions as obesity, diabetes or dyslipidaemia. The diagnostic evaluation must exclude other potential causes of liver disease and may include a liver biopsy, the only method able to confirm features of necroinflammation and fibrosis that define NASH and its prognostic implications. Indeed, the presence of necroinflammation has been associated with a significant risk of progression to cirrhosis and eventually hepatocellular carcinoma. Age >45 years, obesity and diabetes have also been associated with an increased risk of liver fibrosis and progression to cirrhosis. Given the high prevalence of NAFLD, general measures of life-style changes, focusing on exercise, diet, and total alcohol abstinence, should be implemented before a liver biopsy is considered.

  6. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

    PubMed Central

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M.; Coelho, A.M.M.; Xerfan, M.P.; Cogliati, B.; Barbeiro, D.F.; Mazo, D.F.C.; Kubrusly, M.S.; D'Albuquerque, L.A.C.; Souza, H.P.; Carrilho, F.J.; Oliveira, C.P.

    2015-01-01

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

  7. Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)

    PubMed Central

    Takaki, Akinobu; Kawai, Daisuke; Yamamoto, Kazuhide

    2013-01-01

    Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease. PMID:24132155

  8. Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis

    PubMed Central

    Coombes, Jason D.; Choi, Steve S.; Swiderska-Syn, Marzena; Manka, Paul P.; Reid, Danielle; Palma, Elena; Briones-Orta, Marco A.; Xie, Guanhua; Younis, Rasha; Kitamura, Naoto; Peruta, Marco della; Bitencourt, Shanna; Dollé, Laurent; Oo, Ye Htun; Mi, Zhiyong; Kuo, Paul C.; Williams, Roger; Chokshi, Shilpa; Canbay, Ali; Claridge, Lee C.; Eksteen, Bertus; Diehl, Anna Mae; Syn, Wing-Kin

    2016-01-01

    Introduction Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH. Methods Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and αSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis. Results MCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated αSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice. Conclusion OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH. PMID:26529285

  9. Non-Alcoholic Steatohepatitis (NASH): Risk Factors in Morbidly Obese Patients.

    PubMed

    Losekann, Alexandre; Weston, Antonio C; de Mattos, Angelo A; Tovo, Cristiane V; de Carli, Luis A; Espindola, Marilia B; Pioner, Sergio R; Coral, Gabriela P

    2015-10-23

    The aim was to investigate the prevalence of non-alcoholic steatohepatitis (NASH) and risk factors for hepatic fibrosis in morbidly obese patients submitted to bariatric surgery. This retrospective study recruited all patients submitted to bariatric surgery from January 2007 to December 2012 at a reference attendance center of Southern Brazil. Clinical and biochemical data were studied as a function of the histological findings of liver biopsies done during the surgery. Steatosis was present in 226 (90.4%) and NASH in 176 (70.4%) cases. The diagnosis of cirrhosis was established in four cases (1.6%) and fibrosis in 108 (43.2%). Risk factors associated with NASH at multivariate analysis were alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN); glucose ≥ 126 mg/dL and triglycerides ≥ 150 mg/dL. All patients with ALT ≥1.5 times the ULN had NASH. When the presence of fibrosis was analyzed, ALT > 1.5 times the ULN and triglycerides ≥ 150 mg/dL were risk factors, furthermore, there was an increase of 1% in the prevalence of fibrosis for each year of age increase. Not only steatosis, but NASH is a frequent finding in MO patients. In the present study, ALT ≥ 1.5 times the ULN identifies all patients with NASH, this finding needs to be further validated in other studies. Moreover, the presence of fibrosis was associated with ALT, triglycerides and age, identifying a subset of patients with more severe disease.

  10. Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH).

    PubMed

    Agarwal, Naresh; Sharma, Barjesh Chander

    2005-10-01

    Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin

  11. Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)?

    PubMed

    Tariq, Zoon; Green, Charlotte J; Hodson, Leanne

    2014-08-01

    Non-alcoholic fatty liver disease (NAFLD) is not a single disease entity, rather it describes a spectrum of liver conditions that range from fatty liver (steatosis) to more severe steatosis coupled with marked inflammation and fibrosis [non-alcoholic steatohepatitis (NASH)] to severe liver disease such as cirrhosis and possibly hepatocellular carcinoma. Obesity, notably abdominal obesity, is a common risk factor for NAFLD. The pathogenesis from steatosis to NASH is poorly understood, and the 'two hit' model, as suggested nearly two decades ago, provides a feasible starting point for characterization of underlying mechanisms. This review will examine the oxidative stress factors ('triggers') which have been implicated as a 'second hit' in the development of primary NASH. It would be reasonable to assume that multiple, rather than single, pro-oxidative intracellular and extracellular triggers act in conjunction promoting oxidative stress that drives the development of NASH. It is likely that the common denominator of these pro-oxidative triggers is mitochondrial dysfunction. Understanding the contribution of each of these 'triggers' is an essential step in starting to understand and elucidate the mechanisms responsible for progression from steatosis to NASH, thus enabling the development of therapeutic targeting to prevent NASH development and progression.

  12. Mallory-Denk Body (MDB) formation modulates Ufmylation expression epigenetically in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH).

    PubMed

    Liu, Hui; Gong, Ming; French, Barbara A; Li, Jun; Tillman, Brittany; French, Samuel W

    2014-12-01

    Promoter CpG island hypermethylation is an important mechanism for inactivating key cellular enzymes that mediate epigenetic processes in hepatitis-related hepatocellular carcinoma (HCC). The ubiquitin-fold modifier 1 (Ufm1) conjugation pathway (Ufmylation) plays an essential role in protein degradation, protein quality control and signal transduction. Previous studies showed that the Ufmylation pathway was downregulated in alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH) and in mice fed DDC, resulting in the formation of Mallory-Denk Bodies (MDBs). In this study, we further discovered that betaine, a methyl donor, fed together with DDC significantly prevents the increased expression of Ufmylation in drug-primed mice fed DDC. Betaine significantly prevented transcript silencing of Ufm1, Uba5 and UfSP1 where MDBs developed and also prevented the increased expression of FAT10 and LMP7 caused by DDC re-fed mice. Similar downregulation of Ufmylation was observed in multiple AH and NASH biopsies which had formed MDBs. The DNA methylation levels of Ufm1, Ufc1 and UfSP1 in the promoter CpG region were significantly increased both in AH and NASH patients compared to normal subjects. DNA (cytosine-5-)-methyltransferase 1 (DNMT1) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) mRNA levels were markedly upregulated in AH and NASH patients, implying that the maintenance of Ufmylation methylation might be mediated by DNMT1 and DNMT3B together. These data show that MDB formation results from Ufmylation expression epigenetically in AH and NASH patients. Promoter CpG methylation may be a major mechanism silencing Ufmylation expression. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Role of adipose tissue in methionine–choline-deficient model of non-alcoholic steatohepatitis (NASH)☆

    PubMed Central

    Jha, Pooja; Knopf, Astrid; Koefeler, Harald; Mueller, Michaela; Lackner, Carolin; Hoefler, Gerald; Claudel, Thierry; Trauner, Michael

    2014-01-01

    Methionine–choline-deficient (MCD) diet is a widely used dietary model of non-alcoholic steatohepatitis (NASH) in rodents. However, the contribution of adipose tissue to MCD-induced steatosis, and inflammation as features of NASH are not fully understood. The goal of this study was to elucidate the role of adipose tissue fatty acid (FA) metabolism, adipogenesis, lipolysis, inflammation and subsequent changes in FA profiles in serum and liver in the pathogenesis of steatohepatitis. We therefore fed ob/ob mice with control or MCD diet for 5 weeks. MCD-feeding increased adipose triglyceride lipase and hormone sensitive lipase activities in all adipose depots which may be attributed to increased systemic FGF21 levels. The highest lipase enzyme activity was exhibited by visceral WAT. Non-esterified fatty acid (NEFA)-18:2n6 was the predominantly elevated FA species in serum and liver of MCD-fed ob/ob mice, while overall serum total fatty acid (TFA) composition was reduced. In contrast, an overall increase of all FA species from TFA pool was found in liver, reflecting the combined effects of increased FA flux to liver, decreased FA oxidation and decrease in lipase activity in liver. NAFLD activity score was increased in liver, while WAT showed no changes and BAT showed even reduced inflammation. Conclusion: This study demonstrates a key role for adipose tissue lipases in the pathogenesis of NASH and provides a comprehensive lipidomic profiling of NEFA and TFA homeostasis in serum and liver. Our findings provide novel mechanistic insights for the role of WAT in progression of MCD-induced liver injury. PMID:24594481

  14. Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats.

    PubMed

    Saleh, Dalia O; Ahmed, Rania F; Amin, Mohamed M

    2017-03-01

    The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day)(-1)) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.

  15. Quantitative imaging of fibrotic and morphological changes in liver of non-alcoholic steatohepatitis (NASH) model mice by second harmonic generation (SHG) and auto-fluorescence (AF) imaging using two-photon excitation microscopy (TPEM).

    PubMed

    Yamamoto, Shin; Oshima, Yusuke; Saitou, Takashi; Watanabe, Takao; Miyake, Teruki; Yoshida, Osamu; Tokumoto, Yoshio; Abe, Masanori; Matsuura, Bunzo; Hiasa, Yoichi; Imamura, Takeshi

    2016-12-01

    Non-alcoholic steatohepatitis (NASH) is a common liver disorder caused by fatty liver. Because NASH is associated with fibrotic and morphological changes in liver tissue, a direct imaging technique is required for accurate staging of liver tissue. For this purpose, in this study we took advantage of two label-free optical imaging techniques, second harmonic generation (SHG) and auto-fluorescence (AF), using two-photon excitation microscopy (TPEM). Three-dimensional ex vivo imaging of tissues from NASH model mice, followed by image processing, revealed that SHG and AF are sufficient to quantitatively characterize the hepatic capsule at an early stage and parenchymal morphologies associated with liver disease progression, respectively.

  16. Oral Nitrate Reductase Activity Is Not Associated with Development of Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH): A Pilot Study.

    PubMed

    Barzin, Gilda; Merat, Shahin; Nokhbeh-Zaeem, Habibeh; Saniee, Parastoo; Pedramnia, Shahrzad; Mostashfi Habibabadi, Ali; Nasseri-Moghaddam, Siavosh

    2014-01-01

    BACKGROUND NAFLD/NASH is a manifestation of metabolic syndrome and is associated with obesity/overweight. Not all obese/overweight individuals develop NASH. Gastro-esophageal reflux disease (GERD) is considered a gastrointestinal manifestation of the metabolic syndrome and is associated with obesity/overweight. Again not all obese/overweight individuals develop GERD. Recent data show association of dietary nitrate content and oral nitrate reductase activity (NRA) with GERD. Nitrates need to be converted to nitrite (done in human beings by nitrate reductase of oral bacteria exclusively) to be active in metabolic pathways. OBJECTIVE To assess the relation between NASH/NAFLD and oral NRA. METHODS Oral NRA was measured in individuals with NASH (compatible abdominal ultrasound and two elevated ALT/AST levels over six months) and was compared with that of those without NASH. Oral NRA was measured according to a previously reported protocol. RESULTS Eleven NASH patients and twelve controls were enrolled. Mean oral NRA activity were 2.82 vs. 3.51 μg nitrite-N formed per person per minute for cases and controls respectively (p=0.46). CONCLUSION According to our data, oral nitrite production is not different between individual swith and without NASH.

  17. Non alcoholic steatohepatitis a precursor for hepatocellular carcinoma development

    PubMed Central

    Jiang, Chun-Meng; Pu, Chun-Wen; Hou, Ya-Hui; Chen, Zhe; Alanazy, Mohammed; Hebbard, Lionel

    2014-01-01

    Hepatocellular carcinoma (HCC) is increasing in prevalence and is one of the most common cancers in the world. Chief amongst the risks of attaining HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The later has been shown to promote non alcoholic fatty liver disease, which can lead to the inflammatory form non alcoholic steatohepatitis (NASH). NASH is a complex metabolic disorder that can impact greatly on hepatic function. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give an overview of the recent novel mechanisms published that have been associated with NASH and subsequent HCC progression. We will focus our discussion on inflammation and gut derived inflammation and how they contribute to NASH driven HCC. PMID:25469014

  18. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis

    PubMed Central

    Le, Thuy-Anh; Loomba, Rohit

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations. PMID:25755424

  19. Management of Non-alcoholic Fatty Liver Disease and Steatohepatitis.

    PubMed

    Le, Thuy-Anh; Loomba, Rohit

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver enzymes and chronic liver disease in the US with expected rise in incidence paralleling the epidemic of obesity. A subset of patients with NAFLD have the progressive form of NAFLD that is termed non-alcoholic steatohepatitis (NASH), which is characterized by specific features on liver histology including hepatocellular ballooning degeneration, lobular inflammation, and zone-3 steatosis with or without peri-sinusoidal fibrosis. Non-alcoholic steatohepatitis can progress to cirrhosis and result in liver-related death. Insulin resistance is commonly seen in patients with NASH and often co-exists with other features of the metabolic syndrome including hypertension, hyperlipidemia, and obesity. Although weight loss through lifestyle modifications including dietary changes and increased physical exercise remains the backbone of management of NASH, it has proved challenging for patients to achieve and maintain weight loss goals. Thus, it is often necessary to couple lifestyle changes with another pharmacologic treatment for NASH. Insulin sensitizers including the biguanides (metformin), thiazolidinediones (pioglitazone and rosiglitazone), and glucagon-like peptide-1 receptor agonists (exenatide) are large groups of medications that have been studied for the treatment of NASH. Other agents with anti-inflammatory, anti-apoptotic, or anti-fibrotic properties which have been studied in NASH include vitamin E, pentoxifylline, betaine, and ursodeoxycholic acid. This review will provide a detailed summary on the clinical data behind the full spectrum of treatments that exist for NASH and suggest management recommendations.

  20. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

    PubMed Central

    Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

    2017-01-01

    Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

  1. The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α.

    PubMed

    Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

    2017-02-27

    Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

  2. Alcoholic and non-alcoholic steatohepatitis.

    PubMed

    Neuman, Manuela G; French, Samuel W; French, Barbara A; Seitz, Helmut K; Cohen, Lawrence B; Mueller, Sebastian; Osna, Natalia A; Kharbanda, Kusum K; Seth, Devanshi; Bautista, Abraham; Thompson, Kyle J; McKillop, Iain H; Kirpich, Irina A; McClain, Craig J; Bataller, Ramon; Nanau, Radu M; Voiculescu, Mihai; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomes, Paul G; Ganesan, Murali; Malnick, Steve

    2014-12-01

    This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible

  3. Alcoholic and non-alcoholic steatohepatitis

    PubMed Central

    Neuman, Manuela G.; French, Samuel W.; French, Barbara A.; Seitz, Helmut K.; Cohen, Lawrence B.; Mueller, Sebastian; Osna, Natalia A.; Kharbanda, Kusum K.; Seth, Devanshi; Bautista, Abraham; Thompson, Kyle J.; McKillop, Iain H.; Kirpich, Irina A.; McClain, Craig J.; Bataller, Ramon; Nanau, Radu M.; Voiculescu, Mihai; Opris, Mihai; Shen, Hong; Tillman, Brittany; Li, Jun; Liu, Hui; Thomas, Paul G.; Ganesan, Murali; Malnick, Steve

    2015-01-01

    This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible

  4. Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis

    PubMed Central

    Baker, Susan S.; Baker, Robert D.; Liu, Wensheng; Nowak, Norma J.; Zhu, Lixin

    2010-01-01

    Background Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals. Methodology/Principal Findings To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4). Conclusions/Significance The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD. PMID:20221393

  5. Non-alcoholic steatohepatitis in morbidly obese patients.

    PubMed

    Tran, Albert; Gual, Philippe

    2013-02-01

    The hepatic complications of morbid obesity range from steatosis to steatohepatitis (Non-alcoholic steatohepatitis [NASH]), fibrosis, cirrhosis and finally hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to a liver showing steatosis and then steatohepatitis are complex, including, per se, insulin-resistance, iron accumulation, oxidative stress and hepatocyte death. An imbalance in anti- and pro-inflammatory factors may be the trigger. These factors can originate from intra- or extrahepatic sites, particularly the adipose tissue and the gut. This review will provide insight into the current diagnosis and understanding of hepatic inflammation including non-invasive markers of NASH (markers of hepatocyte death), intrahepatic mechanisms (regulation of the immune and inflammatory response, hepatocellular iron deposition, hepatocyte death) and extrahepatic factors (from adipose tissue and gut) in morbidly obese patients. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  6. Non-alcoholic steatohepatitis in type 2 diabetes mellitus.

    PubMed

    Gupte, Parijat; Amarapurkar, Deepak; Agal, Subhash; Baijal, Rajiv; Kulshrestha, Pramod; Pramanik, Snehansu; Patel, Nikhil; Madan, Aruna; Amarapurkar, Anjali; Hafeezunnisa

    2004-08-01

    Non-alcoholic steatohepatitis (NASH) is commonly associated with type 2 diabetes mellitus (DM). Prevalence of NASH in type 2 DM has not been well studied and there is an epidemic rise in type 2 DM in Asian and Western populations. Its association with chronic liver disease in the form of NASH makes it an important health problem. Hence we have studied its prevalence and correlation of biochemical parameters with histological grades of non-alcoholic fatty liver disease (NAFLD) in otherwise asymptomatic type 2 DM patients. One hundred and forty-eight individuals were screened. Forty-eight individuals were excluded due to history of alcohol intake or liver disease as a result of other causes. One hundred non-alcoholic individuals with type 2 DM underwent abdominal ultrasonography (US abdomen). Forty-nine patients had evidence of fatty liver on US abdomen, and 32 of these 49 patients underwent liver biopsy. Four of 32 (12.5%) individuals had steatosis alone. Mild, moderate and severe NASH was present in 21/32 (65.5%), 4/32 (12.5%) and 3/32 (9.35%), respectively. Fibrosis was present in 7/32 (21.8%) patients (four grade 1 and three grade 3). There was no significant difference in body mass index (BMI), transaminase levels, serum cholesterol and triglyceride levels among patients with non-alcoholic fatty liver disease. We conclude that the prevalence of NASH is high in type 2 DM patients and liver biopsy is the only investigation to differentiate between non-alcoholic fatty liver and steatohepatitis.

  7. Immunological Mechanisms in the Pathophysiology of Non-Alcoholic Steatohepatitis

    PubMed Central

    Vonghia, Luisa; Michielsen, Peter; Francque, Sven

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by the presence of steatosis, inflammation and hepatocyte injury and constitutes hepatic manifestation of the metabolic syndrome. The pathogenesis of NASH is complex and implicates cross-talk between different metabolically active sites, such as liver and adipose tissue. Obesity is considered a chronic low-grade inflammatory state and the liver has been recognized as being an “immunological organ”. The complex role of the immune system in the pathogenesis of NASH is currently raising great interest, also in view of the possible therapeutic potential of immunotherapy in NASH. This review focuses on the disturbances of the cells constituting the innate and adaptive immune system in the liver and in adipose tissue. PMID:24084730

  8. [Non-alcoholic fatty liver disease and steatohepatitis].

    PubMed

    Pár, Gabriella; Horváth, Gábor; Pár, Alajos

    2013-07-21

    Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, the hepatic manifestations of metabolic syndrome with close association with inzulin resistance and obesity, are the most common liver diseases, affecting up to a third of the population worldwide. They confer increased risk for hepatocellular carcinoma as well as cardiovascular diseases. The review aims to summarize advances in epidemiology, pathogenesis and clinical management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Besides liver biopsy and biomarkers, a novel non-invasive diagnostic tool the called "controlled attenuation parameter" measuring the attenuation of ultrasound generated by the transient elastography transducer, can quantitatively assess the hepatic fat content and differentiate between steatosis grades. At the same time, liver stiffness (fibrosis) can also be evaluated. The authors present their own results obtained with the latter procedure. In non-alcoholic fatty liver disease, the lifestyle intervention, weight loss, diet and exercise supported by cognitive behavioural therapy represent the basis of management. Components of metabolic syndrome (obesity, dyslipidaemia, diabetes and arterial hypertension) have to be treated. Although there is no approved pharmacological therapy for NASH, it seems that long lasting administration of vitamin E in association with high dose ursodeoxycholic acid may be beneficial. In addition, omega-3 polyunsaturated fatty acid substitution can also decrease liver fat, however, the optimal dose is not known yet. Further controlled clinical studies are warranted to establish the real value of any suggested treatment modalities for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, although these are in experimental phase yet.

  9. Non-alcoholic steatohepatitis with normal aminotransferase values.

    PubMed

    Uslusoy, Hüseyin Saadettin; Nak, Selim Giray; Gülten, Macit; Biyikli, Zeynep

    2009-04-21

    To investigate the aspects of liver histology in patients with non-alcoholic steatohepatitis (NASH) who had normal aminotransferase levels. Thirty-four patients diagnosed with liver steatosis by ultrasonographic examination participated in the study. We compared all non-alcoholic fatty liver disease and NASH cases, according to aminotransferase level, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and presence of metabolic syndrome. Sixteen of 25 patients with high aminotransferase levels were diagnosed with NASH and nine with simple fatty liver according to liver histology. Among the nine patients with normal aminotransferase levels, seven had NASH and two had simple fatty liver. The patients with normal and high liver enzyme levels had almost the same prevalence of NASH and metabolic syndrome. Liver histology did not reveal any difference according to aminotransferase levels and AST/ALT ratio. Aminotransferase levels and AST/ALT ratio do not seem to be reliable predictors for NASH. Despite numerous non-invasive biomarkers, all patients with fatty liver should undergo liver biopsy.

  10. Non-alcoholic steatohepatitis with normal aminotransferase values

    PubMed Central

    Uslusoy, Hüseyin Saadettin; Nak, Selim Giray; Gülten, Macit; Bıyıklı, Zeynep

    2009-01-01

    AIM: To investigate the aspects of liver histology in patients with non-alcoholic steatohepatitis (NASH) who had normal aminotransferase levels. METHODS: Thirty-four patients diagnosed with liver steatosis by ultrasonographic examination participated in the study. We compared all non-alcoholic fatty liver disease and NASH cases, according to aminotransferase level, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and presence of metabolic syndrome. RESULTS: Sixteen of 25 patients with high aminotransferase levels were diagnosed with NASH and nine with simple fatty liver according to liver histology. Among the nine patients with normal aminotransferase levels, seven had NASH and two had simple fatty liver. The patients with normal and high liver enzyme levels had almost the same prevalence of NASH and metabolic syndrome. Liver histology did not reveal any difference according to aminotransferase levels and AST/ALT ratio. CONCLUSION: Aminotransferase levels and AST/ALT ratio do not seem to be reliable predictors for NASH. Despite numerous non-invasive biomarkers, all patients with fatty liver should undergo liver biopsy. PMID:19370784

  11. Molecular mechanisms of hepatic fibrosis in non-alcoholic steatohepatitis.

    PubMed

    Rombouts, Krista; Marra, Fabio

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in Western countries. The more severe form of this condition, non-alcoholic steatohepatitis (NASH), may progress to cirrhosis and its complications. Fibrosis and cirrhosis are the final outcomes of all chronic liver diseases; however, some morphological and biological differences distinguish fibrosis due to NASH from the forms secondary to other causes of liver damage. Fibrosis due to NASH develops primarily in the pericentral areas, surrounding groups of hepatocytes and thickening the space of Disse. This pericellular fibrosis eventually forms septa isolating regenerating nodules. The main cell type responsible for extracellular matrix deposition is represented by hepatic stellate cells that undergo activation in conditions of liver injury enabling them to participate in the liver wound healing process. Although the profibrogenic mechanisms operating in NASH are partly in common with those observed in other chronic liver diseases, the altered pattern of circulating adipokines, oxidative stress generation and the hormonal profile associated with the metabolic syndrome might have a specific role for the induction of fibrogenesis in this condition. In this paper, we review recent developments regarding the basic mechanisms of NASH and the involvement of hepatic stellate cells in this disease.

  12. Hyperlipidemic chicken as a model of non-alcoholic steatohepatitis.

    PubMed

    Ayala, Ignacio; Castillo, Antonia Martín; Adánez, Gracia; Fernández-Rufete, Ana; Pérez, Bartolomé García; Castells, Maria T

    2009-01-01

    Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD), currently the most common cause of abnormal liver tests. Given the difficulty of studying all the factors involved in it in human populations, studies in animal models might provide crucial insights in the pathogenesis of steatohepatitis. Several physiological features predispose birds to fat deposition in the liver. The present study was conceived to explore the possibilities of the chicken fed a cholesterol and fat enriched diet as a model for steatohepatitis. We used two different diets: a standard growing mash (control group) and a standard growing mash enriched with 2% cholesterol and 20% palm oil (hyperlipidemic group). We investigated the effect of feeding a cholesterol and fat enriched diet, on plasma lipid levels, liver enzymes and hepatic histopathology. Semiquantitative and quantitative assessment by image analysis was performed to determine changes in lipid deposits and inflammatory infiltration. Statistically significant increases were observed in all plasma lipid parameters, liver macroscopic features, fat deposits and cell-ballooning of hepatocytes between control and hyperlipidemic animals. Significant differences were also observed in the inflammatory infiltration parameters (number of foci, density, area and maximal diameter). Results show that diet-induced hypercholesterolemia and hypertriglyceridemia are associated with severe impairment of liver histology (fat accumulation, inflammation and cell-ballooning), reproducing histological features of human NAFLD. This model, which is easy and reproducible, offers economic and technical advantages. Furthermore, the reversibility of the pathologic changes makes it suitable for drug intervention studies of steatohepatitis.

  13. Translational approaches: from fatty liver to non-alcoholic steatohepatitis.

    PubMed

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-07-21

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis.

  14. Translational approaches: From fatty liver to non-alcoholic steatohepatitis

    PubMed Central

    Rosso, Natalia; Chavez-Tapia, Norberto C; Tiribelli, Claudio; Bellentani, Stefano

    2014-01-01

    Over the past few decades, non-alcoholic fatty liver disease (NAFLD) has become one, if not the most common, cause of chronic liver disease affecting both adults and children. The increasing number of cases at an early age is the most worrying aspect of this pathology, since it provides more time for its evolution. The spectrum of this disease ranges from liver steatosis to steatohepatitis, fibrosis and in some cases, hepatocellular carcinoma. NAFLD may not always be considered a benign disease and hepatologists must be cautious in the presence of fatty liver. This should prompt the use of the available experimental models to understand better the pathogenesis and to develop a rational treatment of a disease that is dangerously increasing. In spite of the growing efforts, the pathogenesis of NAFLD is still poorly understood. In the present article we review the most relevant hypotheses and evidence that account for the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis. The available in vitro and in vivo experimental models of NASH are discussed and revised in terms of their validity in translational studies. These studies must be aimed at the discovery of the still unknown triggers or mediators that induce the progression of hepatic inflammation, apoptosis and fibrosis. PMID:25083077

  15. Beneficial Effects of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis.

    PubMed

    Nakamoto, Kazuo; Takayama, Fusako; Mankura, Mitsumasa; Hidaka, Yuki; Egashira, Toru; Ogino, Tetsuya; Kawasaki, Hiromu; Mori, Akitane

    2009-05-01

    Oxidative stress is frequently considered as a central mechanism of hepatocellular injury in non-alcoholic steatohepatitis (NASH). The aim of this study was to investigate the effects of fermented green tea extracts (FGTE) on NASH. Rats were fed a choline-deficient high-fat diet for 4 weeks to nutritionally generate fatty livers. NASH was induced chemically by oxidative stress using repeated intraperitoneal injections of nitrite. Rats with NASH developed steatohepatitis and liver fibrosis after 6-week of such treatment. At 10 weeks, blood and liver samples were collected from anesthetized animals and assessed for extent of OS injury and effects of FGTE, by biochemical, histological and histochemical analyses. FGTE reduced serum levels of liver enzymes, lipid peroxidation and production of mitochondrial reactive oxygen species. In addition, FGTE showed inhibition of progressions of cirrhosis. Our findings suggest that our FGTE have strong radical scavenging activity and may be beneficial in the prevention of NASH progression.

  16. Beneficial Effects of Fermented Green Tea Extract in a Rat Model of Non-alcoholic Steatohepatitis

    PubMed Central

    Nakamoto, Kazuo; Takayama, Fusako; Mankura, Mitsumasa; Hidaka, Yuki; Egashira, Toru; Ogino, Tetsuya; Kawasaki, Hiromu; Mori, Akitane

    2009-01-01

    Oxidative stress is frequently considered as a central mechanism of hepatocellular injury in non-alcoholic steatohepatitis (NASH). The aim of this study was to investigate the effects of fermented green tea extracts (FGTE) on NASH. Rats were fed a choline-deficient high-fat diet for 4 weeks to nutritionally generate fatty livers. NASH was induced chemically by oxidative stress using repeated intraperitoneal injections of nitrite. Rats with NASH developed steatohepatitis and liver fibrosis after 6-week of such treatment. At 10 weeks, blood and liver samples were collected from anesthetized animals and assessed for extent of OS injury and effects of FGTE, by biochemical, histological and histochemical analyses. FGTE reduced serum levels of liver enzymes, lipid peroxidation and production of mitochondrial reactive oxygen species. In addition, FGTE showed inhibition of progressions of cirrhosis. Our findings suggest that our FGTE have strong radical scavenging activity and may be beneficial in the prevention of NASH progression. PMID:19430612

  17. Hepatocellular carcinoma and non-alcoholic steatohepatitis: The state of play

    PubMed Central

    Charrez, Bérénice; Qiao, Liang; Hebbard, Lionel

    2016-01-01

    Hepatocellular carcinoma (HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease (NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis (NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation. PMID:26937137

  18. Centrizonal Arteries and Microvessels in Non-Alcoholic Steatohepatitis

    PubMed Central

    Gill, Ryan M.; Belt, Patricia; Wilson, Laura; Bass, Nathan M.; Ferrell, Linda D.

    2011-01-01

    Correct classification of non-alcoholic steatohepatitis (NASH) liver biopsies is of critical importance and relies on correct orientation to microscopic liver architecture. Centrizonal arteries can cause central zones to be mistaken for portal tracts, especially in the setting of centrizonal ductular reaction, and result in either missed diagnosis or inaccurate staging of NASH. 100 randomly selected biopsies from NASH Clinical Research Network participants (2/05-8/06, fibrosis stage >1a,) were evaluated for arteries and CD34 positive microvessels in the centrizonal region. Prevalence of both centrizonal arteries and CD34 positive microvessels was graded as 0 (none in central zones), 1 (1-2 central zones with vessels), 2 (< 50% of central zones with vessels), or 3 (≥ 50% of central zones with vessels). Centrizonal arteries and CD34 positive microvessels were present in 40 and 100 cases (40% and 100%), respectively. Arteries and CD34 positive microvessels were more commonly found in central zones in biopsies with greater degrees of fibrosis; 62% with arteries in stage 3-4 vs. 21% in stage 1-2 and 70% with microvessels in stage 3-4 vs. 25% in stage 1-2, with increased prevalence of both centrizonal arteries and CD34 positive microvessels correlating directly with fibrosis stage (p<0.001). Ductular reaction was a common finding (55%) in patients with central zone arteries. The presence of an aberrant centrizonal artery must be recognized to allow for correct orientation to liver architecture in NASH and, together with the finding of increased CD34 positive microvessel formation in higher stage fibrosis, suggests a possible association between neoangiogenesis and NASH progression to cirrhosis. PMID:21836480

  19. Conophylline inhibits non-alcoholic steatohepatitis in mice.

    PubMed

    Nakade, Yukiomi; Sakamoto, Kazumasa; Yamauchi, Taeko; Inoue, Tadahisa; Kobayashi, Yuji; Yamamoto, Takaya; Ishii, Norimitsu; Ohashi, Tomohiko; Sumida, Yoshio; Ito, Kiyoaki; Nakao, Haruhisa; Fukuzawa, Yoshitaka; Umezawa, Kazuo; Yoneda, Masashi

    2017-01-01

    Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 μg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation-, and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-β (TGF-β) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in β-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-β mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) α and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-β mRNA levels, and induces an increase in PPARα mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH.

  20. Recent advances in understanding/management of non-alcoholic steatohepatitis

    PubMed Central

    Pacana, Tommy

    2015-01-01

    Non-alcoholic steatohepatitis (NASH) can lead to advanced fibrosis, hepatocellular carcinoma, and end-stage liver disease requiring liver transplantation. A myriad of pathways and genetic influence contribute to NASH pathogenesis and liver disease progression. Diagnosing patients with NASH and advanced fibrosis is critical prior to treatment and prognostication. There has been ongoing interest in developing non-invasive biomarkers and tools for identifying NASH and advanced fibrosis. To date, there has been no approved therapy for NASH. Recently, the FLINT (Farnesoid X Receptor [FXR] Ligand Obeticholic Acid in NASH Treatment) trial provided promising results of the efficacy of obeticholic acid, a farnesoid X receptor agonist, in improving histological features of NASH and fibrosis. Long-term studies are needed to assess the safety of obeticholic acid and its effects on liver- and cardiovascular-related outcomes. PMID:25926979

  1. NASH (Nonalcoholic steatohepatitis): A case of multiorganelle failure.

    PubMed

    Caldwell, Stephen

    2014-10-01

    The clinical term 'multiorgan failure' lends itself, modified to 'multiorganelle failure', to the cascading events in cellular systems leading to hepatocyte injury, cell death, inflammation and fibrosis and ultimately to cirrhosis in NASH (non-alcoholic steatohepatitis). NASH is one of the most common forms of liver disease and constitutes the severe form of NAFLD (non-alcoholic fatty liver disease). The key features that distinguish potentially progressive NASH from relatively stable non-NASH fatty liver (NNFL, often referred to as simple steatosis) are cellular ballooning, inflammation and fibrosis. These findings, together with steatosis or accumulation of greater than normal hepatic lipid, usually constitute histological NASH seen on liver biopsy or in laboratory samples. Cellular ballooning is not specific to NASH but it is perhaps the most emblematic finding on histological samples. The ballooned hepatocyte has evidence of cytoskeletal injury (depletion and condensation as Mallory-Denk bodies), accumulation of partially oxidized small fat droplets, mitochondrial morphological changes presumably related to organelle dysfunction, dilated endoplasmic reticulum and autophagosomes - an attempt at cellular repair. Ballooning itself likely results from a combination of cytoskeletal injury resulting in loss of normal cell shape and from accumulation of injured and somewhat derelict small fat droplets and dilated endoplasmic reticulum. Cellular injury in NASH and especially cellular ballooning can be viewed as a process of 'multi-organelle failure' beginning with generation of super oxide and failure to contain the subsequent oxidative injury and by-products in an environment rich in lipid fuel. These events lead to activation of imunologic pathways. Dysfunction of the small fat droplet appears to be a central mechanism and the oxidative injury can be viewed as the process of rancidification - the chemical decomposition of oils, lipids and fats.

  2. CD44 is a key player in non-alcoholic steatohepatitis.

    PubMed

    Patouraux, Stéphanie; Rousseau, Déborah; Bonnafous, Stéphanie; Lebeaupin, Cynthia; Luci, Carmelo; Canivet, Clémence M; Schneck, Anne-Sophie; Bertola, Adeline; Saint-Paul, Marie-Christine; Iannelli, Antonio; Gugenheim, Jean; Anty, Rodolphe; Tran, Albert; Bailly-Maitre, Béatrice; Gual, Philippe

    2017-08-01

    Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. The role of CD44 was evaluated in CD44(-/-) mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated. Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44(-/-) mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44(+) cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007). Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation

  3. Endoplasmic Reticulum Stress Response in Non-alcoholic Steatohepatitis: The Possible Role of Physical Exercise.

    PubMed

    Passos, Emanuel; Ascensão, António; Martins, Maria João; Magalhães, José

    2015-07-01

    Sedentary lifestyle coupled with excessive consumption of high caloric food has been related to the epidemic increase of non-alcoholic fatty liver disease, which can progress from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and, eventually, may culminate in hepatocellular carcinoma. Although the precise mechanisms underlying the progression of NASH are not completely understood, endoplasmic reticulum (ER) dysfunction seems to play a key role in the process. Hepatic ER stress has been associated to hepatic steatosis, insulin resistance, inflammation, oxidative stress and hepatocyte death, contributing to liver dysfunction. Physical exercise seems to be the most effective preventive and therapeutic non-pharmacological strategy to mitigate several features related to NASH, possibly targeting most of the referred mechanisms associated with the pathophysiology of ER-related NASH. Nevertheless, little is known about the impact of physical exercise on NASH-related ER stress. In this review, we will discuss the ER stress associated to NASH conditions and highlight the possible benefits of physical exercise in the attenuation and/or reversion of NASH-related ER stress. Copyright © 2015. Published by Elsevier Inc.

  4. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis.

    PubMed

    Griffett, Kristine; Welch, Ryan D; Flaveny, Colin A; Kolar, Grant R; Neuschwander-Tetri, Brent A; Burris, Thomas P

    2015-04-01

    Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation and fibrosis. There are currently no targeted therapies for NASH. We developed a liver-specific LXR inverse agonist, SR9238, which effectively reduces hepatic lipogenesis in models of obesity and hepatic steatosis. We hypothesized that suppression of lipogenesis, which is pathologically elevated in NASH may suppress progression of hepatic steatosis to NASH. NASH was induced in B6 V-lep (ob)/J (ob/ob) mice using a custom complete rodent diet (HTF) containing high amounts of trans-fat, fructose, and cholesterol. Once NASH was induced, mice were treated with SR9238 for one month by i.p. injection. Plasma lipid levels and liver health were analyzed by clinical chemistry. QPCR, western blot, and immunohistochemistry were used to assess disease severity. Ob/ob mice are obese and diabetic thus they are commonly used as models for the study of metabolic diseases. These mice quickly developed the NASH phenotype when provided the HTF diet. The mice develop hepatic steatosis, severe hepatic inflammation and fibrosis on the HTF diet. Treatment with SR9238 significantly reduced the severity of hepatic steatosis and most importantly reduced hepatic inflammation and ameliorated hepatic fibrosis. Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans.

  5. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis

    PubMed Central

    McKee, Chad; Sigala, Barbara; Soeda, Junpei; Mouralidarane, Angelina; Morgan, Maelle; Mazzoccoli, Gianluigi; Rappa, Francesca; Cappello, Francesco; Cabibi, Daniela; Pazienza, Valerio; Selden, Claire; Roskams, Tania; Vinciguerra, Manlio; Oben, Jude A.

    2015-01-01

    Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF-α converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD. PMID:25744849

  6. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Albanian overweight children.

    PubMed

    Kodhelaj, K; Resuli, B; Petrela, E; Malaj, V; Jaze, H

    2014-02-01

    Overweight and obesity has emerged as a significant global health problem in the pediatric population. Childhood non-alcoholic fatty liver disease (NAFLD) has become a common and important liver disease. Although mostly benign, some children with NAFLD develop fibrosis and in some case cirrhosis. The aims of this study were to determine the prevalence of NAFLD/non-alcoholic steatohepatitis (NASH) in overweight Albanian children, to evaluate the demographic and biochemical details and to assess the association between the severity of fatty liver changes and demographic and biochemical abnormalities. A total of 80 school aged children, 24 overweight (85th≤BMI≤94th percentile) and 55 obese (BMI≥94th percentile), aged 10.43±2.2 years (M±SD) were included in the current study, in January-December 2010. Their age was in the range of 7-15 years. Their sex distribution was 36 female and 44 male. The children were enrolled to the Tirana schools and none of them were part of any weight or diet programmer. Children who were found to have TBC, evidence of HBV or HCV, infections, drug toxicity, autoimmune hepatitis, inborn error of metabolism or concomitant cortisteroid therapy were excluded. Laboratory parameters were measured at the time of bioclinical examinations. Fatty liver was diagnosed by ultrasonography detection of the most characteristic features of fatty infiltration. The scoring system was used in order to graduate the severity of the disease. The child was considered to have mild, moderate and severe fatty liver changes if the overall score was 1-3, 4-6 and 7-9, respectively. Multivariate regression analysis was used to assess the association between the different variables and the severity of NAFLD. NAFLD was present in 55/80 (68.7%) of the overweight children, 34 (61.8%) boys and 21 (38.2%) girls. Mild, moderate and severe degree of fatty liver were found in 35 (43.7%), 19 (23.7%) and 1 (1.3%), respectively. Nash was seen in 13 (23.7%) of the children

  7. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis.

    PubMed

    Armstrong, M J; Hazlehurst, J M; Hull, D; Guo, K; Borrows, S; Yu, J; Gough, S C; Newsome, P N; Tomlinson, J W

    2014-07-01

    Systemic insulin resistance (IR) is a primary feature in non-alcoholic steatohepatitis (NASH), however, there remain limited data on tissue-specific insulin sensitivity in vivo. We examined tissue-specific (adipose, muscle and liver) insulin sensitivity and inflammation in 16 European Caucasian patients with biopsy-confirmed NASH and in 15 healthy controls. All underwent a two-step hyperinsulinaemic euglycaemic clamp incorporating stable isotope measurements of carbohydrate and lipid metabolism with concomitant subcutaneous adipose tissue (SAT) microdialysis. Hepatic and muscle insulin sensitivity were decreased in patients with NASH compared with controls, as demonstrated by reduced suppression of hepatic glucose production and glucose disposal (Gd) rates following insulin infusion. In addition, rates of lipolysis were higher in NASH patients with impaired insulin-mediated suppression of free fatty acid levels. At a tissue specific level, abdominal SAT in patients with NASH was severely insulin resistant, requiring >sixfold more insulin to cause ½-maximal suppression of glycerol release when compared with healthy controls. Furthermore, patients with NASH had significantly higher circulating levels of pro-inflammatory adipocytokines than controls. NASH patients have profound IR in the liver, muscle and in particular adipose tissues. This study represents the first in vivo description of dysfunctional SAT in patients with NASH. © 2014 The Authors. Diabetes, Obesity and Metabolism published by JohnWiley & Sons Ltd.

  8. Non-alcoholic Steatohepatitis in a Sample of Iranian Adult Population: Age is a Risk Factor.

    PubMed

    Rogha, Mehran; Najafi, Nazila; Azari, Azadeh; Kaji, Mahboubeh; Pourmoghaddas, Zahra; Rajabi, Fereshteh; Rezaee, Mina

    2011-01-01

    Non-alcoholic Steatohepatitis (NASH) is a cause of cirrhosis. Detecting its preventable causes could be useful in decreasing the disease and its complications. This study aimed to assess the prevalence of NASH in adult population living in Isfahan city as a sample of Iranian population. Blood samples of 2030 individuals referring to Dr. Shariati Hospital for routine health checkup were collected. All individuals with high liver enzymes [aspartate aminotransferase (AST) and/or Alanine aminotransferease (ALT)] were included in the study. Known causes of altered liver enzymes were excluded. Second blood samples were obtained 6 months later and those cases with persistent enzyme elevation were surveyed with ultrasonography. In the first survey, 234 individuals (11.5 %) had ALT levels of more than 40 U/L. By rechecking samples after 6 months, 50% of all high serum ALT individuals remained at high level. After conducting complementary biochemical tests, 3.3% of the population was considered to have NASH; 20% of NASH cases did not have any abnormal findings in ultrasonography. Hypercholesterolemia was the most coexisting risk factor in NASH cases. We found a reverse correlation between ALT level and age (P = 0.02). The prevalence of NASH was comparable with other countries. According to the significantl correlation between ALT level and age, preventive interactions in younger individuals would decrease the incidence of NASH.

  9. An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis.

    PubMed

    Marin, Veronica; Rosso, Natalia; Dal Ben, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvia

    2016-01-01

    Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches.

  10. An Animal Model for the Juvenile Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

    PubMed Central

    Marin, Veronica; Rosso, Natalia; Dal Ben, Matteo; Raseni, Alan; Boschelle, Manuela; Degrassi, Cristina; Nemeckova, Ivana; Nachtigal, Petr; Avellini, Claudio; Tiribelli, Claudio; Gazzin, Silvia

    2016-01-01

    Non Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) are the hepatic manifestations of the metabolic syndrome; worrisome is the booming increase in pediatric age. To recreate the full spectrum of juvenile liver pathology and investigate the gender impact, male and female C57Bl/6 mice were fed with high fat diet plus fructose in the drinking water (HFHC) immediately after weaning (equal to 3-years old human), and disease progression followed for 16 weeks, until adults (equal to 30-years old human). 100% of subjects of both genders on HFHC diet developed steatosis in 4weeks, and some degree of fibrosis in 8weeks, with the 86% of males and 15% of females presenting a stage 2 fibrosis at 16weeks. Despite a similar final liver damage both groups, a sex difference in the pathology progression was observed. Alterations in glucose homeostasis, dyslipidemia, hepatomegaly and obese phenotype were evident from the very beginning in males with an increased hepatic inflammatory activity. Conversely, such alterations were present in females only at the end of the HFHC diet (with the exception of insulin resistance and the hepatic inflammatory state). Interestingly, only females showed an altered hepatic redox state. This juvenile model appears a good platform to unravel the underlying gender dependent mechanisms in the progression from NAFLD to NASH, and to characterize novel therapeutic approaches. PMID:27391242

  11. Effect of pioglitazone, quercetin and hydroxy citric acid on extracellular matrix components in experimentally induced non-alcoholic steatohepatitis

    PubMed Central

    Mohan, Surapaneni Krishna; Veeraraghavan, Vishnu Priya; Jainu, Mallika

    2015-01-01

    Objective(s): Non-alcoholic steatohepatitis (NASH), is an important component of Non-alcoholic fatty liver disease (NAFLD) spectrum, which progresses to the end stage liver disease, if not diagnosed and treated properly. The disproportionate production of pro- and anti-inflammatory adipokines secreted from fat contributes to the pathogenesis of NASH. In this study, the comparative effect of pioglitazone, quercetin and hydroxy citric acid on extracellular matrix (ECM) component levels were studied in experimentally induced NASH. Materials and Methods: The experimental protocol consists of using 48 male Wister rats, which were divided into 8 groups. The levels of hyaluronic acid, leptin and adiponectin were monitored in experimental NASH. Results: The experimental NASH rats treated with pioglitazone showed significant decrease in the levels of hyaluronic acid and significant increase in adiponectin levels when compared to experimentally induced NASH group, but did not show any effect on the levels of leptin. Contrary to these two drugs, viz. pioglitazone and hydroxy citric acid, the group treated with quercetin showed significant decrease in the levels of hyaluronic acid and leptin and significant decrease in adiponectin levels compared with that of experimentally induced NASH NASH group, offering maximum protection against NASH. Conclusion: Considering our findings, it could be concluded that quercetin may offer maximum protection against NASH by significantly increasing the levels of adiponectin, when compared to pioglitazone and hydroxy citric acid. PMID:26557974

  12. Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis.

    PubMed

    Niebergall, Lorissa J; Jacobs, René L; Chaba, Todd; Vance, Dennis E

    2011-12-01

    Several studies suggest that low levels of hepatic phosphatidylcholine (PC) play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). CTP: phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for PC biosynthesis. Liver-specific elimination of CTα (LCTα(-/-)) in mice fed a chow diet decreases very-low-density lipoprotein secretion, reduces lipid efflux from liver, and causes mild steatosis. We fed LCTα(-/-) mice a high fat diet to determine if impaired PC biosynthesis played a role in development of NASH. LCTα(-/-) mice developed NASH within one week of high fat feeding. Hepatic CTα deficiency caused hepatic steatosis, a 2-fold increase in ceramide mass, and a 20% reduction in PC content. In an attempt to prevent NASH, LCTα(-/-) mice were either injected daily with CDP-choline or fed the high fat diet supplemented with betaine. In addition, LCTα(-/-) mice were injected with adenoviruses expressing CTα. CDP-choline injections and adenoviral expression of CTα increased hepatic PC, while dietary betaine supplementation normalized hepatic triacylglycerol but did not alter hepatic PC mass in LCTα(-/-) mice. Interestingly, none of the treatments normalized hepatic ceramide mass or fully prevented the development of NASH in LCTα(-/-) mice. These results show that normalizing the amount of hepatic PC is not sufficient to prevent NASH in LCTα(-/-) mice. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Hepatoprotective effects of pycnogenol in a rat model of non-alcoholic steatohepatitis.

    PubMed

    Mei, Lin; Mochizuki, Miyako; Hasegawa, Noboru

    2012-10-01

    Oxidative stress is considered as a mechanism of hepatocellular injury in non-alcoholic steatohepatitis (NASH). Pycnogenol (PYC) is the natural plant extract from the bark of Pinus pinaster Aiton. and has potent antioxidant activities. We studied the protective effect of PYC on excessive fat accumulation in the liver fed a methionine-choline deficient (MCD) high-fat diet for 6 weeks. Pycnogenol (10 mg/kg body weight) was orally administered for 5 weeks. At the end of the experiment, blood and liver samples were collected and assessed for effects of PYC by histopathological and biochemical analyses. Histopathological analyses of liver tissues stained with Azan-Mallory showed hepatic macrovesicular steatosis and fibrosis in MCD-fed rats. Supplementation of PYC prevented this effect. Pycnogenol treatment significantly decreased the liver triglyceride and serum alanine amino transferase levels. Our results indicated that orally administered PYC may serve to prevent NASH-induced liver damage.

  14. Prevalence and risk factors for biopsy-proven non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in a prospective cohort of adult patients with gallstones.

    PubMed

    García-Monzón, Carmelo; Vargas-Castrillón, Javier; Porrero, José Luís; Alonso, María Teresa; Bonachía, Oscar; Castillo, María José; Marcos, Alberto; Quirós, Esther; Ramos, Beatriz; Sánchez-Cabezudo, Carlos; Villar, Sol; Sáez, Alicia; Rodríguez de Cía, Javier; del Pozo, Elvira; Vega-Piris, Lorena; Soto-Fernández, Susana; Lo Iacono, Oreste; Miquilena-Colina, María Eugenia

    2015-08-01

    Relationship between gallstones and non-alcoholic fatty liver disease (NAFLD), and largely non-alcoholic steatohepatitis (NASH), is uncertain. To determine the prevalence, non-invasive fibrosis markers profile and risk factors for biopsy-proven NAFLD and NASH among patients with gallstones. Anthropometric and laboratory evaluation, an abdominal ultrasound and a liver biopsy were performed to 215 consecutive patients with gallstones referred for cholecystectomy. Prevalence of NASH was 10.2% whereas that of simple steatosis (SS) was 41.4%. In the cohort of NAFLD patients, negative predictive values for advanced fibrosis of FIB-4 and NAFLD fibrosis score were 96 and 95% respectively. Gallstone patients with NASH had a higher mean homeostatic model assessment (HOMA) score than those with SS (P = 0.015). Noteworthy, NASH was 2.5-fold more frequent in patients with gallstones who had metabolic syndrome than in those who did not (P < 0.001). Fatty liver on ultrasound was observed in 90.9% of gallstone patients with NASH compared with 61.8% of those with SS (P = 0.044). Using multivariate logistic regression, increased HOMA score (OR, 3.47; 95% CI, 1.41-8.52; P = 0.007) and fatty liver on ultrasound (OR, 23.27; 95% CI, 4.15-130.55; P < 0.001) were the only factors independently associated with NASH. Prevalence of NASH among patients with gallstones is lower than estimated previously, but NASH is frequent particularly in those patients with concurrent metabolic syndrome. The combination of an increased HOMA score with fatty liver on ultrasound has a good accuracy for predicting NASH in patients with gallstones. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model.

    PubMed

    Winkler, Sandra; Borkham-Kamphorst, Erawan; Stock, Peggy; Brückner, Sandra; Dollinger, Matthias; Weiskirchen, Ralf; Christ, Bruno

    2014-08-15

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver.

  16. New therapeutic perspectives in non-alcoholic steatohepatitis.

    PubMed

    Ampuero, Javier; Sánchez-Torrijos, Yolanda; Aguilera, Virginia; Bellido, Francisco; Romero-Gómez, Manuel

    2017-09-02

    Management of non-alcoholic steatohepatitis is focused on restitution of metabolic derangement, weight loss and drugs able to improve steatosis, ballooning and fibrosis. Life-style interventions based on Mediterranean diet and increasing physical activity are the first line therapy. In patients with unsuccessful life-style intervention several drugs are under development: agonist PPAR, agonist GLP-1R and agonist FXR together with drugs focussing on inflammation, ballooning, apoptosis and fibrosis. Bariatric surgery or advanced endoscopy are reserved for morbid obese without response to life-style intervention and weighting loss drugs. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

  17. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

    SciTech Connect

    Winkler, Sandra; Borkham-Kamphorst, Erawan; Stock, Peggy; Brückner, Sandra; Dollinger, Matthias; Weiskirchen, Ralf; Christ, Bruno

    2014-08-15

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.

  18. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action.

    PubMed

    de Mello, Vanessa D; Matte, Ashok; Perfilyev, Alexander; Männistö, Ville; Rönn, Tina; Nilsson, Emma; Käkelä, Pirjo; Ling, Charlotte; Pihlajamäki, Jussi

    2017-04-03

    Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m(2), type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q = 0.0036) and cancer (q = 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r = -0.45, P = 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

  19. Effects of Oral Administration of Silymarin in a Juvenile Murine Model of Non-alcoholic Steatohepatitis.

    PubMed

    Marin, Veronica; Gazzin, Silvia; Gambaro, Sabrina E; Dal Ben, Matteo; Calligaris, Sonia; Anese, Monica; Raseni, Alan; Avellini, Claudio; Giraudi, Pablo J; Tiribelli, Claudio; Rosso, Natalia

    2017-09-12

    The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.

  20. Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

    PubMed Central

    Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

    2014-01-01

    Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

  1. Non-alcoholic steatohepatitis: a non-invasive diagnosis by analysis of exhaled breath.

    PubMed

    Verdam, Froukje J; Dallinga, Jan W; Driessen, Ann; de Jonge, Charlotte; Moonen, Edwin J C; van Berkel, Joep B N; Luijk, Jakobus; Bouvy, Nicole D; Buurman, Wim A; Rensen, Sander S; Greve, Jan Willem M; van Schooten, Frederik Jan

    2013-03-01

    Histological evaluation of a liver biopsy is the current gold standard to diagnose non-alcoholic steatohepatitis (NASH), but the procedure to obtain biopsies is associated with morbidity and high costs. Hence, only subjects at high risk are biopsied, leading to underestimation of NASH prevalence, and undertreatment. Since analysis of volatile organic compounds in breath has been shown to accurately identify subjects with other chronic inflammatory diseases, we investigated its potential as a non-invasive tool to diagnose NASH. Wedge-shaped liver biopsies from 65 subjects (BMI 24.8-64.3 kg/m(2)) were obtained during surgery and histologically evaluated. The profile of volatile organic compounds in pre-operative breath samples was analyzed by gas chromatography-mass spectrometry and related to liver histology scores and plasma parameters of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Three exhaled compounds were sufficient to distinguish subjects with (n=39) and without NASH (n=26), with an area under the ROC curve of 0.77. The negative and positive predictive values were 82% and 81%. In contrast, elevated ALT levels or increased AST/ALT ratios both showed negative predictive values of 43%, and positive predictive values of 88% and 70%, respectively. The breath test reduced the hypothetical percentage of undiagnosed NASH patients from 67-79% to 10%, and of misdiagnosed subjects from 49-51% to 18%. Analysis of volatile organic compounds in exhaled air is a promising method to indicate NASH presence and absence. In comparison to plasma transaminase levels, the breath test significantly reduced the percentage of missed NASH patients and the number of unnecessarily biopsied subjects. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  2. Plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor levels in non-alcoholic steatohepatitis.

    PubMed

    Yener, S; Akarsu, M; Demir, T; Akinci, B; Sagol, O; Bayraktar, F; Ozcan, M A; Tankurt, E; Yesil, S

    2007-11-01

    This study was conducted to demonstrate the plasminogen activator inhibitor- 1 (PAI-1) and thrombin activatable fibrinolysis inhibitor antigen (TAFI-Ag) levels in non-alcoholic steatohepatitis (NASH). Twenty-seven patients with biopsy-proven NASH and 18 healthy controls (HC) were recruited for the study. Anthropometric data, liver histology (no.=20) and laboratory parameters including PAI-1 and TAFI-Ag assessments were recorded. When compared with HC, patients with NASH had higher body weight, higher waist circumference, elevated blood pressure, higher fasting plasma glucose (FPG) levels and higher homeostasis model assessment (HOMA) scores. The mean plasma PAI-1 levels of patients was found to be higher than HC (87.60 ng/ml vs 30.84 ng/ml p=0.000) and mean plasma TAFI-Ag levels of patients was found to be significantly lower (8.69 microg/ml vs 12.19 microg/ml p=0.000). PAI-1 levels were correlated with systolic blood pressure, age, body weight, transaminases, waist circumference, FPG, body mass index, and HOMA score. TAFI-Ag levels were found to be negatively correlated with transaminases, waist circumference, and body weight. In multiple regression analysis, BMI was the independent variable effecting PAI-1 levels. We did not show any association between PAI-1, TAFI-Ag, disease activity score and fibrosis score. HOMA was the independent variable effecting liver fibrosis in our patients. In this study we demonstrated that patients with biopsy-proven NASH had higher PAI-1 and lower TAFI-Ag expression than HC. Elevated levels of PAI-1 in NASH is the consequence of insulin resistance state. Lower TAFI-Ag levels may be related to the overactivation of TAFI pathway resulting in TAFI-Ag depletion. Furthermore, liver function disturbances may impair TAFI production in NASH. We also showed that NASH patients even with slight elevations of transaminases feature marked insulin resistance and components of metabolic syndrome.

  3. Lycium barbarum polysaccharides protect rat liver from non-alcoholic steatohepatitis-induced injury

    PubMed Central

    Xiao, J; Liong, E C; Ching, Y P; Chang, R C C; Fung, M L; Xu, A M; So, K F; Tipoe, G L

    2013-01-01

    Background: Lycium barbarum polysaccharides (LBPs) are antioxidant and neuroprotective derivative from Wolfberry. However, whether LBP has a protective effect in non-alcoholic steatohepatitis (NASH)-induced hepatic injury is still unknown. Objective: We aimed to study the possible hepatoprotective effects and mechanisms of LBP on a diet-induced NASH rat model. Methods and Design: In this study, female rats were fed a high-fat diet to induce NASH with or without an oral 1 mg kg−1 LBP feeding daily for 8 weeks. After 8 weeks, blood serum and liver samples from each rat were subjected to histological analysis, biochemical and molecular measurements. Results: Compared with control rats, NASH rats showed typical NASH features including an increase in liver injury, lipid content, fibrosis, oxidative stress, inflammation and apoptosis. In contrast, NASH+LBP-co-treated rats showed (1) improved histology and free fatty acid levels; (2) re-balance of lipid metabolism; (3) reduction in profibrogenic factors through the TGF-β/SMAD pathway; (4) improved oxidative stress through cytochrome P450 2E1-dependent pathway; (5) reduction in hepatic pro-inflammatory mediators and chemokines production; and (6) amelioration of hepatic apoptosis through the p53-dependent intrinsic and extrinsic pathways. The preventive effects of LBP were partly modulated through the PI3K/Akt/FoxO1, LKB1/AMPK, JNK/c-Jun and MEK/ERK pathways and the downregulation of transcription factors in the liver, such as nuclear factor-κB and activator protein-1. Conclusion: LBP is a novel hepatoprotective agent against NASH caused by abnormal liver metabolic functions. PMID:23877747

  4. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis

    PubMed Central

    Farhadi, Ashkan; Gundlapalli, Sushama; Shaikh, Maliha; Frantzides, Constantine; Harrell, Laura; Kwasny, Mary M.; Keshavarzian, Ali

    2014-01-01

    Introduction One of the proposed second hit mechanisms in the pathophysiology of non-alcoholic steatohepatitis (NASH) is hepatic oxidative stress triggered by elevated levels of endotoxin. We investigated one possible mechanism for the endotoxaemia – disruption of intestinal barrier integrity. Methods We enrolled 16 subjects with fatty liver (10 NASH; 6 steatosis) and 12 healthy subjects. Steatosis and NASH were diagnosed by liver biopsy using the Brunt criteria. Gastrointestinal permeability was measured using urinary excretion of 5-h lactulose/mannitol (L/M) ratio and 24-h sucralose. Permeability testing was repeated after aspirin challenge. Results Groups had similar baseline urinary 0–5 h L/M ratio (small bowel permeability) and 0–24 h sucralose (whole-gut permeability). Aspirin increased 0–5 h urinary L/M in most subjects. In contrast, aspirin significantly increased whole-gut permeability only in NASH subjects. In fact, the major increase in the urinary sucralose occurred in the 6–24 h samples, which points towards the colon as the major site responsible for aspirin-induced leakiness in NASH patients. Serum endotoxin levels were significantly higher in NASH subjects. Discussion Our findings suggest that aspirin acts on the colon to unmask a susceptibility to gut leakiness in patients with NASH. This effect may be the underlying mechanism for increased serum endotoxin, which is the second hit (after altered lipid metabolism) that is required to initiate a necroinflammatory cascade in hepatocytes which are already primed with obesity-induced abnormal lipid homoeostasis. PMID:18397235

  5. β7-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis.

    PubMed

    Drescher, Hannah K; Schippers, Angela; Clahsen, Thomas; Sahin, Hacer; Noels, Heidi; Hornef, Mathias; Wagner, Norbert; Trautwein, Christian; Streetz, Konrad L; Kroy, Daniela C

    2017-06-01

    Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β7-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. Constitutive β7-Integrin deficient (β7(-/-)) and MAdCAM-1 deficient (MAdCAM-1(-/-)) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. β7(-/-) mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1(-/-) mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β7(-/-) mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β7(-/-) animals. In contrast, MAdCAM-1(-/-) mice showed an upregulation of the anti-oxidative stress response. β7(-/-) animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (TReg) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1(-/-) mice. Those changes finally resulted in earlier and stronger collagen accumulation in β7(-/-) mice, whereas MAdCAM-1(-/-) mice were protected from fibrosis initiation. Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β7-Integrin unexpectedly exerts protective effects. β7(-/-) mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of

  6. A New Model For Non-Alcoholic Steatohepatitis in the Rat Utilizing Total Enteral Nutrition to Overfeed a High Polyunsaturated Fat Diet

    USDA-ARS?s Scientific Manuscript database

    We have used total enteral nutrition (TEN) to moderately overfeed rats high polyunsaturated fat diets to develop a model for non-alcoholic steatohepatitis (NASH). Male Sprague-Dawley rats were fed by TEN a 187 kcal/kg 3/4 /d diet containing 5% (total calories) corn oil or a 220 kcal/kg 3/4 /d diet i...

  7. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model

    PubMed Central

    Fan, Jian-Gao; Xu, Zheng-Jie; Wang, Guo-Liang

    2005-01-01

    AIM: To explore the relationship between changes of intestinal environment and pathogenesis of non-alcoholic steatohepatitis (NASH). METHODS: Forty-two Sprague-Dawley rats were randomly divided into model group (n = 24), treatment group (n = 12), and control group (n = 6). The rats of model and treatment groups were given high-fat diet, and those of the control group were given normal diet. Furthermore, the rats of treatment group were given lactulose after 8 wk of high-fat diet. Twelve rats of the model group were killed at 8 wk of high-fat diet. At the 16 wk the rats of treatment group, control group, and the rest of the model group were killed. The serum levels of aminotransferase were measured and the histology of livers was observed by H&E staining. RESULTS: The livers of rats presented the pathological features of steatohepatitis with higher serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the model group after 16 wk. Compared to the model group, the serum levels of ALT and AST in treatment group decreased significantly and were close to the normal group, and the hepatic inflammation scores also decreased markedly than those in the model group after 16 wk (5.83±2.02 vs 3.63±0.64, P<0.05), but were still higher than those in the model group after 8 wk (3.63±0.64 vs 1.98±0.90, P<0.05). However, the degree of hepatic steatosis had no changes in treatment group compared to the model group after 16 wk. CONCLUSION: Lactulose could ameliorate the hepatic inflammation of rats with steatohepatitis induced by fat-rich diet, but could not completely prevent the development of steatohepatitis. It is suggested that intestinal environmental changes such as intestinal bacteria overgrowth, are one of the important factors in the pathogenesis of NASH. PMID:16124065

  8. Two cinnamoyloctopamine antioxidants from garlic skin attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis.

    PubMed

    Wu, Zheng-Rong; Peng-Chen; Yang-Li; Li, Jian-Ying; Xin-Wang; Yong-Wang; Guo, Ding-Ding; Lei-Cui; Guan, Qian-Guo; Li, Hong-Yu

    2015-01-15

    Hepatic oxidative stress plays a key role in the development of non-alcoholic steatohepatitis (NASH), therefore, treatment approaches that address the antioxidant is helpful in the therapy of patients with NASH. N-trans-coumaroyloctopamine (1) and N-trans-feruloyloctopamine (2) were identified as the primary antioxidant constituents of garlic skin with high antioxidant activities. The aim of this study was to elucidate the protective effect and mechanism of the antioxidants on NASH in rats. The results provide morphological and molecular biological evidences for the protective role of the antioxidant 2 in ameliorating oxidative stress and hepatic apoptosis in experimental NASH for the first time. Mechanism study indicated that the antioxidant 2 significantly reduced the expression of COX-2 mRNA and protein by western blot, RT-PCR and immunohistochemical techniques.

  9. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets

    PubMed Central

    Higuera-de la Tijera, Fátima; Servín-Caamaño, Alfredo I

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-α, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of

  10. Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

    PubMed Central

    Takeuchi, Masayoshi; Takino, Jun-ichi; Sakasai-Sakai, Akiko; Takata, Takanobu; Ueda, Tadashi; Tsutsumi, Mikihiro; Hyogo, Hideyuki; Yamagishi, Sho-ichi

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease around the world. It includes a spectrum of conditions from simple steatosis to non-alcoholic steatohepatitis (NASH) and can lead to fibrosis, cirrhosis, liver failure, and/or hepatocellular carcinoma. NAFLD is also associated with other medical conditions such as obesity, diabetes mellitus (DM), metabolic syndrome, hypertension, insulin resistance, hyperlipidemia, and cardiovascular disease (CVD). In diabetes, chronic hyperglycemia contributes to the development of both macro- and microvascular conditions through a variety of metabolic pathways. Thus, it can cause a variety of metabolic and hemodynamic conditions, including upregulated advanced glycation end-products (AGEs) synthesis. In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs, were found to make a significant contribution to the pathogenesis of DM-induced angiopathy. Furthermore, accumulating evidence suggests that the binding of TAGE with their receptor (RAGE) induces oxidative damage, promotes inflammation, and causes changes in intracellular signaling and the expression levels of certain genes in various cell populations including hepatocytes and hepatic stellate cells. All of these effects could facilitate the pathogenesis of hypertension, cancer, diabetic vascular complications, CVD, dementia, and NASH. Thus, inhibiting TAGE synthesis, preventing TAGE from binding to RAGE, and downregulating RAGE expression and/or the expression of associated effector molecules all have potential as therapeutic strategies against NASH. Here, we examine the contributions of RAGE and TAGE to various conditions and novel treatments that target them in order to prevent the development and/or progression of NASH. PMID:25544875

  11. BENEFICIAL EFFECTS OF MINERALOCORTICOID RECEPTOR BLOCKADE IN EXPERIMENTAL NON-ALCOHOLIC STEATOHEPATITIS

    PubMed Central

    Pizarro, Margarita; Solís, Nancy; Quintero, Pablo; Barrera, Francisco; Cabrera, Daniel; Santiago, Pamela Rojasde; Arab, Juan Pablo; Padilla, Oslando; Roa, Juan Carlos; Moshage, Han; Wree, Alexander; Inzaugarat, Eugenia; Feldstein, Ariel E.; Fardella, Carlos E.; Baudrand, Rene; Riquelme, Arnoldo; Arrese, Marco

    2015-01-01

    Background Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient-amino-acid–defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation, and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. Results CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted PMID:25646700

  12. Physical activity and nutrition attitudes in obese Hispanic children with non-alcoholic steatohepatitis

    PubMed Central

    Hattar, Lana N; Wilson, Theresa A; Tabotabo, Leanel A; Smith, E O’Brian; Abrams, Stephanie H

    2011-01-01

    AIM: To assess nutrition, physical activity and healthful knowledge in obese children with biopsy-proven non-alcoholic steatohepatitis (NASH or NA) compared to children without liver disease. METHODS: Children with biopsy-proven NASH comprised the NASH group. Age, sex and ethnicity matched control groups consisted of obese (OB) and lean (CO) children with no liver disease. Subjects were administered the School Physical Activity and Nutrition Survey and one blood draw was obtained. RESULTS: Fifty-seven patients were enrolled with a mean age of 12.1 ± 2.1 years, and all were Hispanic. Even though the OB and NA had a similar increased body mass index (%), 35% of the NA group always read nutrition labels compared to none in the OB (P < 0.05), and more NA children felt their diet is “less healthy”. NA consumed the least amount of fruits with only 25% having ≥ 1 fruit/d vs 45% in OB and 64.7% in CO (P < 0.05 NA vs CO). Only 15% of NA subjects performed light exercise vs 35% and 59% of OB and CO groups, respectively (P = 0.02). The mean physical activity score was lowest in the NA group (P < 0.05). Amongst the subjects with NASH, we found that 100% of patients with grade 2 or 3 fibrosis had a sedentary score > 2 compared to only 63.6% of those with grade 1 or no fibrosis (P < 0.05). CONCLUSION: Children with NASH had increased se-dentary behavior, decreased activity, and fruit intake. Larger studies may determine the benefit of changing these behaviors as treatment for NASH. PMID:22110265

  13. Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes.

    PubMed

    Liang, Wen; Verschuren, Lars; Mulder, Petra; van der Hoorn, José W A; Verheij, Joanne; van Dam, Andrea D; Boon, Mariette R; Princen, Hans M G; Havekes, Louis M; Kleemann, Robert; van den Hoek, Anita M

    2015-11-01

    Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH. Transgenic APOE*3Leiden.CETP mice were fed a high-fat and high-cholesterol diet with or without salsalate for 12 and 20 weeks. The effects on body weight, plasma biochemical variables, liver histology and hepatic gene expression were assessed. Salsalate prevented weight gain, improved dyslipidemia and insulin resistance and ameliorated diet-induced NASH, as shown by decreased hepatic microvesicular and macrovesicular steatosis, reduced hepatic inflammation and reduced development of fibrosis. Salsalate affected lipid metabolism by increasing β-oxidation and decreasing lipogenesis, as shown by the activation of PPAR-α, PPAR-γ co-activator 1β, RXR-α and inhibition of genes controlled by the transcription factor MLXIPL/ChREBP. Inflammation was reduced by down-regulation of the NF-κB pathway, and fibrosis development was prevented by down-regulation of TGF-β signalling. Salsalate exerted a preventive effect on the development of NASH and progression to fibrosis. These data suggest a clinical application of salsalate in preventing NASH. © 2015 The British Pharmacological Society.

  14. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report.

    PubMed

    Kargiotis, Konstantinos; Katsiki, Niki; Athyros, Vasilios G; Giouleme, Olga; Patsiaoura, Kalliopi; Katsiki, Evangelia; Mikhailidis, Dimitri P; Karagiannis, Asterios

    2014-05-01

    There is no widely accepted treatment for non-alcoholic fatty liver disease (NAFLD) or its advanced form, non-alcoholic steatohepatitis (NASH). We administered rosuvastatin (10 mg/day) for 1 year in patients with metabolic syndrome (MetS), NASH on liver biopsy and dyslipidaemia (but without diabetes or arterial hypertension). Patients also received lifestyle advice. We report preliminary results for 6 patients. The second biopsy (at the end of the study) showed complete resolution of NASH in 5 patients, while the 6(th), which had no improvement, developed arterial hypertension and substantial rise in triglyceride levels during the study. We suspect alcohol abuse despite advice to abstain. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were reduced by 76 and 61%, respectively (p < 0.001 for both), during treatment, while γ-glutamyl transpeptidase (γ-GT), and alkaline phosphatase (AP) showed smaller non significant reductions. Fasting plasma glucose and glycated haemoglobin (HbA1c) were significantly reduced (p<0.05). Lipid values were totally normalised and liver ultrasonography showed a complete resolution of NASH in 5 patients. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed to treatment with rosuvastatin. A substantial limitation of the study is the small number of patients. These preliminary findings suggest that rosuvastatin could ameliorate NASH within a year of treatment in MetS patients with dyslipidaemia.

  15. Pediatric non-alcoholic steatohepatitis: the first report on the ultrastructure of hepatocyte mitochondria.

    PubMed

    Lotowska, Joanna M; Sobaniec-Lotowska, Maria E; Bockowska, Sylwia B; Lebensztejn, Dariusz M

    2014-04-21

    To investigate the ultrastructure of abnormal hepatocyte mitochondria, including their cellular and hepatic zonal distribution, in bioptates in pediatric non-alcoholic steatohepatitis (NASH). Ultrastructural investigations were conducted on biopsy liver specimens obtained from 10 children (6 boys and 4 girls) aged 2-14 years with previously clinicopathologically diagnosed NASH. The disease was diagnosed if liver biopsy revealed steatosis, inflammation, ballooned hepatocytes, Mallory hyaline, or focal necrosis, varying degrees of fibrosis in the absence of clinical, serological, or histological findings of infectious liver diseases, autoimmune hepatitis, metabolic liver diseases, or celiac disease. For ultrastructural analysis, fresh small liver blocks (1 mm(3) volume) were fixed in a solution containing 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer. The specimens were postfixed in osmium tetroxide, subsequently dehydrated through a graded series of ethanols and propylene oxide, and embedded in Epon 812. The material was sectioned on a Reichert ultramicrotome to obtain semithin sections, which were stained with methylene blue in sodium borate. Ultrathin sections were contrasted with uranyl acetate and lead citrate, and examined using an Opton EM 900 transmission electron microscope. Ultrastructural analysis of bioptates obtained from children with non-alcoholic steatohepatitis revealed characteristic repetitive mitochondrial abnormalities within hepatocytes; mainly mitochondrial polymorphisms such as megamitochondria, loss of mitochondrial cristae, and the presence of linear crystalline inclusions within the mitochondrial matrix of an increased electron density. The crystalline inclusions were particularly evident within megamitochondria (MMC), which seemed to be distributed randomly both within the hepatic parenchymal cell and the zones of hepatic lobule, without special variations in abundance. The inclusions appeared as bundles viewed

  16. Pediatric non-alcoholic steatohepatitis: The first report on the ultrastructure of hepatocyte mitochondria

    PubMed Central

    Lotowska, Joanna M; Sobaniec-Lotowska, Maria E; Bockowska, Sylwia B; Lebensztejn, Dariusz M

    2014-01-01

    AIM: To investigate the ultrastructure of abnormal hepatocyte mitochondria, including their cellular and hepatic zonal distribution, in bioptates in pediatric non-alcoholic steatohepatitis (NASH). METHODS: Ultrastructural investigations were conducted on biopsy liver specimens obtained from 10 children (6 boys and 4 girls) aged 2-14 years with previously clinicopathologically diagnosed NASH. The disease was diagnosed if liver biopsy revealed steatosis, inflammation, ballooned hepatocytes, Mallory hyaline, or focal necrosis, varying degrees of fibrosis in the absence of clinical, serological, or histological findings of infectious liver diseases, autoimmune hepatitis, metabolic liver diseases, or celiac disease. For ultrastructural analysis, fresh small liver blocks (1 mm3 volume) were fixed in a solution containing 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer. The specimens were postfixed in osmium tetroxide, subsequently dehydrated through a graded series of ethanols and propylene oxide, and embedded in Epon 812. The material was sectioned on a Reichert ultramicrotome to obtain semithin sections, which were stained with methylene blue in sodium borate. Ultrathin sections were contrasted with uranyl acetate and lead citrate, and examined using an Opton EM 900 transmission electron microscope. RESULTS: Ultrastructural analysis of bioptates obtained from children with non-alcoholic steatohepatitis revealed characteristic repetitive mitochondrial abnormalities within hepatocytes; mainly mitochondrial polymorphisms such as megamitochondria, loss of mitochondrial cristae, and the presence of linear crystalline inclusions within the mitochondrial matrix of an increased electron density. The crystalline inclusions were particularly evident within megamitochondria (MMC), which seemed to be distributed randomly both within the hepatic parenchymal cell and the zones of hepatic lobule, without special variations in abundance. The inclusions

  17. Lysosomal cholesterol accumulation: driver on the road to inflammation during atherosclerosis and non-alcoholic steatohepatitis.

    PubMed

    Hendrikx, T; Walenbergh, S M A; Hofker, M H; Shiri-Sverdlov, R

    2014-05-01

    Many studies show an association between the accumulation of cholesterol inside lysosomes and the progression towards inflammatory disease states that are closely related to obesity. While in the past, the knowledge regarding lysosomal cholesterol accumulation was limited to its association with plaque severity during atherosclerosis, recently, a growing body of evidence indicates a causal link between lysosomal cholesterol accumulation and inflammation. These findings make lysosomal cholesterol accumulation an important target for intervention in metabolic diseases that are characterized by the presence of an inflammatory response. In this review, we aim to show the importance of cholesterol trapping inside lysosomes to the development of inflammation by focusing upon cardiovascular disease and non-alcoholic steatohepatitis (NASH) in particular. We summarize current data supporting the hypothesis that lysosomal cholesterol accumulation plays a key role in the development of inflammation during atherosclerosis and NASH. In addition, potential mechanisms by which disturbed lysosomal function can trigger the inflammatory response, the challenges in improving cholesterol trafficking in macrophages and recent successful research directions will be discussed.

  18. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis

    PubMed Central

    Chackelevicius, Carla Melisa; Gambaro, Sabrina Eliana; Tiribelli, Claudio; Rosso, Natalia

    2016-01-01

    The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies. PMID:27895397

  19. Antioxidant and hepatoprotective effects of extract of ginkgo biloba in rats of non-alcoholic steatohepatitis.

    PubMed

    Zhou, Zhong-Yin; Tang, Shi-Qi; Zhou, Yong-Ming; Luo, He-Sheng; Liu, Xing

    2010-10-01

    To evaluate the therapeutic effect and mechanism of extract of ginkgo biloba (EGB) in treatment of diet-induced non-alcoholic steatohepatitis (NASH) in rats. The experiment was conducted in the Laboratory, Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China from June 2009 to December 2009. In this study, the rat model of NASH was produced by feeding high-fat diet. Sixty rats were randomly divided into 3 groups: Normal group: normal diet, drinking water; Model group: high-fat diet, single-distilled water 10 ml/kg gavage once a day for 12 weeks; and Treated group: high-fat diet, EGB 6 mg/kg gavage once a day for 12 weeks. At the end of 12 weeks, all rats were killed. The serum biochemical, fibrosis markers, superoxide dismutase (SOD), malondialdehyde (MDA), the pathological changes, and the expression levels of nuclear factor KB (NF-κB)p65 protein in the liver were observed. The contents of serum alanine transaminase aspartate aminotransferase, fibrosis markers, and pathological grading of liver fibrosis and the staining intensity of NF-κBp65 protein in the liver of rats in treated group were significantly lower than those in the model group. Activities of superoxide dismutase were elevated, but levels of malondialdehyde were decreased in the treated group as compared with the model group. Extract of ginkgo biloba has antioxidant and hepatoprotective effects and can inhibit liver fibrosis in rat of NAHS.

  20. Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma: Implications for Lycopene Intervention

    PubMed Central

    Ip, Blanche C.; Wang, Xiang-Dong

    2013-01-01

    Increased prevalence of non-alcoholic fatty liver disease (NAFLD) is one of the consequences of the current obesity epidemic. NAFLD is a major form of chronic liver disease that is highly prevalent in obese and overweight adults and children. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD, and uncontrolled inflammation as displayed in NASH has been identified as one of the key events in enhancing hepatic carcinogenesis. Lycopene is a non-provitamin A carotenoid and the pigment principally responsible for the characteristic deep-red color of ripe tomato and tomato products, as well as some fruits and vegetables. Lycopene’s innate antioxidant and anti-inflammatory properties have generated research interests on its capacity to protect against human diseases that are associated with oxidative stress and inflammation. In addition, differential mechanisms of lycopene metabolism including endogenous cleavage by carotenoid cleavage oxygenases (BCOs), generate lycopene metabolites that may also have significant impact on human disease development. However, it remains to be elucidated as to whether lycopene or its metabolites apolycopenoids have protective effects against obesity-related complications including inflammation and tumorigenesis. This article summarizes the in vivo experiments that elucidated molecular mechanisms associated with obesity-related hepatic inflammation and carcinogenesis. This review also provides an overview of lycopene metabolism, and the molecular pathways involved in the potential beneficial properties of lycopene and apolycopenoids. More research is clearly needed to fully unravel the importance of BCOs in tomato carotenoid metabolism and the consequence on human health and diseases. PMID:24379011

  1. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis.

    PubMed

    Chackelevicius, Carla Melisa; Gambaro, Sabrina Eliana; Tiribelli, Claudio; Rosso, Natalia

    2016-11-07

    The nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a wide histological spectrum ranging from benign simple steatosis to non-alcoholic steatohepatitis (NASH). Sustained inflammation in the liver is critical in this process. Hepatic macrophages, including liver resident macropaghes (Kupffer cells), monocytes infiltrating the injured liver, as well as specific lymphocytes subsets play a pivotal role in the initiation and perpetuation of the inflammatory response, with a major deleterious impact on the progression of fatty liver to fibrosis. During the last years, Th17 cells have been involved in the development of inflammation not only in liver but also in other organs, such as adipose tissue or lung. Differentiation of a naïve T cell into a Th17 cell leads to pro-inflammatory cytokine and chemokine production with subsequent myeloid cell recruitment to the inflamed tissue. Th17 response can be mitigated by T regulatory cells that secrete anti-inflammatory cytokines. Both T cell subsets need TGF-β for their differentiation and a characteristic plasticity in their phenotype may render them new therapeutic targets. In this review, we discuss the role of the Th17 pathway in NAFLD progression to NASH and to liver fibrosis analyzing different animal models of liver injury and human studies.

  2. Connexin 32 and luteolin play protective roles in non-alcoholic steatohepatitis development and its related hepatocarcinogenesis in rats.

    PubMed

    Sagawa, Hiroyuki; Naiki-Ito, Aya; Kato, Hiroyuki; Naiki, Taku; Yamashita, Yoriko; Suzuki, Shugo; Sato, Shinya; Shiomi, Kosuke; Kato, Akihisa; Kuno, Toshiya; Matsuo, Yoichi; Kimura, Masahiro; Takeyama, Hiromitsu; Takahashi, Satoru

    2015-12-01

    Non-alcoholic steatohepatitis (NASH) has the potential to lead to the development of cirrhosis and hepatocellular carcinoma (HCC). Connexin (Cx) 32, a hepatocyte gap-junction protein, plays a preventive role in hepatocarcinogenesis. However, the precise contribution of Cx32 in the development of NASH has not been established. In this study, we aimed to clarify the role of Cx32 and the chemopreventive effect of luteolin, an antioxidant flavonoid, on the progression of NASH and NASH-related hepatocarcinogenesis. Cx32 dominant negative transgenic (Cx32ΔTg) and wild-type (Wt) rats at 10 weeks of age were given diethylnitrosamine and fed methionine-choline-deficient diet (MCDD) or MCDD with luteolin for 12 weeks. MCDD induced steatohepatitis and fibrosis along with increased inflammatory cytokine expression and reactive oxygen species in the liver. These effects were more severe in Cx32ΔTg rats as compared with Wt rats, and significantly suppressed by luteolin in both genotypes. Concerning NASH-related hepatocarcinogenesis, the number of glutathione S-transferase placental form (GST-P)-positive foci was greater in Cx32ΔTg versus Wt rats, and significantly reduced by luteolin in Cx32ΔTg rats. Microarray analysis identified brain expressed, X-linked 1 (Bex1) as an upregulated gene in Cx32ΔTg rat liver. Quantitative RT-PCR and in situ hybridization revealed that increased Bex1 mRNA was localized in GST-P-positive foci in Cx32ΔTg rats, and the expression level was significantly decreased by luteolin. Moreover, Bex1 knockdown resulted in significant growth inhibition of the rat HCC cell lines. These results show that Cx32 and luteolin have suppressive roles in inflammation, fibrosis and hepatocarcinogenesis during NASH progression, suggesting a potential therapeutic application for NASH.

  3. Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice

    PubMed Central

    Park, Han-Sol; Jang, Jung Eun; Ko, Myoung Seok; Woo, Sung Hoon; Kim, Bum Joong; Kim, Hyun Sik; Park, Hye Sun; Park, In-Sun; Koh, Eun Hee

    2016-01-01

    Background Non-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO) and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH), but underlying mechanisms of this prevention are largely unknown. Methods Seven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD) with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day), for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver. Results Statin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα) were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels. Conclusion Statins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH. PMID:27098507

  4. Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.

    PubMed

    Jeurissen, Mike L J; Walenbergh, Sofie M A; Houben, Tom; Hendrikx, Tim; Li, Jieyi; Oligschlaeger, Yvonne; van Gorp, Patrick J; Gijbels, Marion J J; Bitorina, Albert; Nessel, Isabell; Radtke, Freddy; Vooijs, Marc; Theys, Jan; Shiri-Sverdlov, Ronit

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.

  5. Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice

    PubMed Central

    Jeurissen, Mike L. J.; Walenbergh, Sofie M. A.; Houben, Tom; Hendrikx, Tim; Li, Jieyi; Oligschlaeger, Yvonne; van Gorp, Patrick J.; Gijbels, Marion J. J.; Bitorina, Albert; Nessel, Isabell; Radtke, Freddy; Vooijs, Marc; Theys, Jan; Shiri-Sverdlov, Ronit

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH) and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4) attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/-) mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp) with bone marrow from wild type (Wt) or DLL4f/fLysMCre+/0 (DLL4del) mice and fed either chow or high fat, high cholesterol (HFC) diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM) of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can’t be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis. PMID:27898698

  6. Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis.

    PubMed

    Klein, Thomas; Fujii, Masato; Sandel, Jan; Shibazaki, Yuichiro; Wakamatsu, Kyoko; Mark, Michael; Yoneyama, Hiroyuki

    2014-09-01

    Non-alcoholic steatohepatitis (NASH) is a primary cause of cirrhosis and hepatocellular carcinoma. Dipeptidyl peptidase (DPP)-4 inhibitors are established therapies for type 2 diabetes and although DPP-4 inhibitors can reduce hepatic steatosis, their impact on local inflammation and fibrosis in NASH remains unknown. Using two different experimental treatment regimens (4- and 2-week treatments) in streptozotocin-treated neonatal mice on a high-fat diet, we show that the DPP-4 inhibitor linagliptin (10 and 30 mg/kg) significantly attenuated the NAS score from 4.9 ± 0.6 to 3.7 ± 0.4 and 3.6 ± 0.3, respectively, in the 4-week study. In the 2-week study, linagliptin 10 mg/kg significantly reduced NAS score from 4.1 ± 0.4 to 2.4 ± 0.4. Telmisartan was used as a positive control in both studies and lowered NAS score to 1.9 ± 0.7 and 1.4 ± 0.3, respectively. Due to streptozotocin treatment, elevated glucose levels were unchanged by either drug treatment. Further, linagliptin 10 mg/kg significantly reduced mRNA levels of SOCS-3 (from 1.68 ± 0.2 to 0.83 ± 0.08), IFN-γ (from 4.0 ± 0.5 to 2.3 ± 0.3), and TNF-α (from 5.7 ± 0.5 to 2.13 ± 0.3). The latter observation was confirmed by immunohistochemistry of TNF-α in liver specimens. In addition, using microautoradiography, we showed that the distribution of radiolabeled linagliptin was heterogeneous with the highest density associated with interlobular bile ducts and portal tracts (acini). In conclusion, these studies confirm that linagliptin has high exposure in hepatic tissue and has both anti-inflammatory and anti-steatotic activity in NASH.

  7. [Role of metabolic lipases and lipotoxicity in the development of non-alcoholic steatosis and non-alcoholic steatohepatitis].

    PubMed

    Berlanga, Alba; Guiu-Jurado, Esther; Porras, José Antonio; Aragonès, Gemma; Auguet, Teresa

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in developed countries, covering a spectrum of pathological conditions ranging from single steatosis to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. Its pathogenesis has been often interpreted by the "double-hit" hypothesis, where the lipid accumulation in the liver is followed by proinflammatory mediators inducing inflammation, hepatocellular injury and fibrosis. Nowadays, a more complex model suggests that free fatty acids and their metabolites could be the true lipotoxic agents that contribute to the development of NAFLD and hepatic insulin resistance, suggesting a central role for metabolic lipases in that process.

  8. Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis.

    PubMed

    Zhao, Lei; Westerhoff, Maria; Pai, Rish K; Choi, Won-Tak; Gao, Zu-Hua; Hart, John

    2017-09-01

    There is increasing interest in the role of ductular reaction as part of the pathogenesis and characteristic histology of non-alcoholic steatohepatitis. However, earlier studies did not separately assess the contribution of periportal and centrilobular zone ductular reaction over the spectrum of non-alcoholic steatohepatitis, and their clinical significance remains unclear. We herein analyzed the character of ductular reaction in each hepatic zone in non-alcoholic steatohepatitis biopsies and for the first time evaluated the prognostic value of ductular reaction in baseline biopsies as a predictor of progression of fibrosis in subsequent biopsies. A total of 90 non-alcoholic steatohepatitis liver biopsies were included in the cohort. The relationships among ductular reaction, grade, stage, and other common histopathologic findings in non-alcoholic steatohepatitis were analyzed in a cross-sectional manner. Among these patients, a total of 47 patients underwent sequential liver biopsies in the absence of effective treatment. The frequency of ductular reaction and the other histopathologic parameters in the initial biopsies were analyzed as predictors of progression of fibrosis in the second biopsies in a longitudinal analysis. Centrilobular ductular reaction was identified in 90% of patients and 38% of centrilobular zones. The prevalence of centrilobular ductular reaction increased as non-alcoholic steatohepatitis grade increased (P=0.0002) and also as stage of fibrosis increased (P<0.0001) in the cross-sectional study. In the longitudinal study, the frequency of centrilobular ductular reaction in the initial biopsies was significantly higher in the group of progressors and correlated with the rate of fibrosis progression (P=0.02). Centrilobular ductular reaction is common in non-alcoholic steatohepatitis and its presence correlates significantly with increasing necroinflammatory activity and fibrosis stage. Development of centrilobular ductular reaction appears to

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

    PubMed

    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

    2016-04-01

    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. To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mt(FVB/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). At baseline conditions, C57BL/6J-mt(FVB/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-mt(FVB/N) mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial dysfunction. However, a second hit, such as dietary stress

  10. A genetic risk score is associated with hepatic triglyceride content and non-alcoholic steatohepatitis in Mexicans with morbid obesity.

    PubMed

    León-Mimila, Paola; Vega-Badillo, Joel; Gutiérrez-Vidal, Roxana; Villamil-Ramírez, Hugo; Villareal-Molina, Teresa; Larrieta-Carrasco, Elena; López-Contreras, Blanca E; Kauffer, Luis R Macías; Maldonado-Pintado, Diana G; Méndez-Sánchez, Nahúm; Tovar, Armando R; Hernández-Pando, Rogelio; Velázquez-Cruz, Rafael; Campos-Pérez, Francisco; Aguilar-Salinas, Carlos A; Canizales-Quinteros, Samuel

    2015-04-01

    Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near/in PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes associated with non-alcoholic fatty liver disease (NAFLD) mainly in individuals of European ancestry. The aim of the study was to test whether these genetic variants and a genetic risk score (GRS) are associated with elevated liver fat content and non-alcoholic steatohepatitis (NASH) in Mexicans with morbid obesity. 130 morbidly obese Mexican individuals were genotyped for six SNPs in/near PNPLA3, NCAN, LYPLAL1, PPP1R3B, and GCKR genes. Hepatic fat content [triglyceride (HTG) and total cholesterol (HTC)] was quantified directly in liver biopsies and NASH was diagnosed by histology. A GRS was tested for association with liver fat content and NASH using logistic regression models. In addition, 95 ancestry-informative markers were genotyped to estimate population admixture proportions. After adjusting for age, sex and admixture, PNPLA3, LYPLAL1, GCKR and PPP1R3B polymorphisms were associated with higher HTG content (P < 0.05 for PNPLA3, LYPLAL1, GCKR polymorphisms and P = 0.086 for PPP1R3B). The GRS was significantly associated with higher HTG and HTC content (P = 1.0 × 10(-4) and 0.048, respectively), steatosis stage (P = 0.029), and higher ALT levels (P = 0.002). Subjects with GRS ≥ 6 showed a significantly increased risk of NASH (OR = 2.55, P = 0.045) compared to those with GRS ≤ 5. However, the GRS did not predict NASH status, as AUC of ROC curves was 0.56 (P = 0.219). NAFLD associated loci in Europeans and a GRS based on these loci contribute to the accumulation of hepatic lipids and NASH in morbidly obese Mexican individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. (-)-Epigallocatechin-3-gallate suppresses hepatic preneoplastic lesions developed in a novel rat model of non-alcoholic steatohepatitis.

    PubMed

    Sumi, Takafumi; Shirakami, Yohei; Shimizu, Masahito; Kochi, Takahiro; Ohno, Tomohiko; Kubota, Masaya; Shiraki, Makoto; Tsurumi, Hisashi; Tanaka, Takuji; Moriwaki, Hisataka

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH, which is accompanied by increased oxidative stress and inflammation in the liver, is associated with hepatic carcinogenesis. Green tea catechins (GTCs) possess anti-oxidant, anti-inflammatory, and cancer-preventive properties. In this study, we investigated whether (-)-epigallocatechin-3-gallate (EGCG), a major component of GTCs, inhibits NAFLD/NASH-related liver tumorigenesis. Male 8-week-old Sprague-Dawley (SD) rats were administered a single intraperitoneal injection of a hepatic carcinogen diethylnitrosamine (DEN, 30 mg/kg body weight) and then fed a high-fat diet (HFD) for 7 weeks. The rats were also provided tap water containing 0.01% or 0.1% EGCG during the experiment. At sacrifice, the livers of SD rats treated with DEN and HFD exhibited marked development of glutathione S-transferase placental form (GST-P)-positive foci, a hepatic preneoplastic lesion, and this was associated with hepatic steatosis, oxidative stress and inflammation, and hepatocyte proliferation. EGCG administration, however, inhibited the development of GST-P-positive foci by decreasing hepatic triglyceride content, reducing hepatic fibrosis, lowering oxidative stress, attenuating inflammation, and inhibiting excessive hepatocyte proliferation in DEN- and HFD-treated SD rats. These findings suggest that the experimental model of SD rats treated with HFD and DEN, in which histopathological and pathophysiological characteristics of NASH and the development of hepatic premalignant lesions were observed, might facilitate the evaluation of liver tumorigenesis associated with NAFLD/NASH. Administering EGCG, a GTC, might serve as an effective chemoprevention modality for NAFLD/NASH-related liver tumorigenesis.

  12. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.

    PubMed

    Koliaki, Chrysi; Szendroedi, Julia; Kaul, Kirti; Jelenik, Tomas; Nowotny, Peter; Jankowiak, Frank; Herder, Christian; Carstensen, Maren; Krausch, Markus; Knoefel, Wolfram Trudo; Schlensak, Matthias; Roden, Michael

    2015-05-05

    The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.

  13. Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

    PubMed

    Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

    2016-02-01

    Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis.

  14. Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis

    PubMed Central

    Wahlang, Banrida; Prough, Russell A.; Falkner, K. Cameron; Hardesty, Josiah E.; Song, Ming; Clair, Heather B.; Clark, Barbara J.; States, J. Christopher; Arteel, Gavin E.; Cave, Matthew C.

    2016-01-01

    Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr−/− and Car−/− mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr−/− mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr−/− mice. Both Pxr−/− and Car−/− mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car−/− mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr−/− mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr−/− mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the ‘off-target’ effects of PCBs in steatohepatitis. PMID:26612838

  15. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis

    PubMed Central

    Armstrong, Matthew J.; Hull, Diana; Guo, Kathy; Barton, Darren; Hazlehurst, Jonathan M.; Gathercole, Laura L.; Nasiri, Maryam; Yu, Jinglei; Gough, Stephen C.; Newsome, Philip N.; Tomlinson, Jeremy W.

    2016-01-01

    Background & Aims Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH. Methods Fourteen patients were randomised to 1.8 mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomised, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes. Results Liraglutide reduced BMI (−1.9 vs. +0.04 kg/m2; p <0.001), HbA1c (−0.3 vs. +0.3%; p <0.01), cholesterol-LDL (−0.7 vs. +0.05 mmol/L; p <0.01), ALT (−54 vs. −4.0 IU/L; p <0.01) and serum leptin, adiponectin, and CCL-2 (all p <0.05). Liraglutide increased hepatic insulin sensitivity (−9.36 vs. −2.54% suppression of hepatic endogenous glucose production with low-dose insulin; p <0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (−24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum non-esterified fatty acids; p <0.05), and specifically within subcutaneous adipose tissue (p <0.05). In addition, liraglutide decreased hepatic de novo lipogenesis in vivo (−1.26 vs. +1.30%; p <0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p <0.01). Conclusions Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of

  16. Systems Level Metabolic Phenotype of Methotrexate Administration in the Context of Non-alcoholic Steatohepatitis in the Rat

    PubMed Central

    Kyriakides, Michael; Hardwick, Rhiannon N.; Jin, Zhaosheng; Goedken, Michael J.; Holmes, Elaine; Cherrington, Nathan J.; Coen, Muireann

    2014-01-01

    Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs. PMID:25145655

  17. Advanced non-alcoholic steatohepatitis cirrhosis: A high-risk population for pre-liver transplant portal vein thrombosis

    PubMed Central

    Stine, Jonathan G; Argo, Curtis K; Pelletier, Shawn J; Maluf, Daniel G; Caldwell, Stephen H; Northup, Patrick G

    2017-01-01

    AIM To examine if liver transplant recipients with high-risk non-alcoholic steatohepatitis (NASH) are at increased risk for pre-transplant portal venous thrombosis. METHODS Data on all liver transplants in the United States from February 2002 through September 2014 were analyzed. Recipients were sorted into three distinct groups: High-risk (age > 60, body mass index > 30 kg/m2, hypertension and diabetes), low-risk and non-NASH cirrhosis. Multivariable logistic regression models were constructed. RESULTS Thirty-five thousand and seventy-two candidates underwent liver transplantation and of those organ recipients, 465 were transplanted for high-risk and 2775 for low-risk NASH. Two thousand six hundred and twenty-six (7.5%) recipients had pre-transplant portal vein thrombosis; 66 (14.2%) of the high-risk NASH group had portal vein thrombosis vs 328 (11.8%) of the low-risk NASH group. In general, all NASH recipients were less likely to be male or African American and more likely to be obese. In adjusted multivariable regression analyses, high-risk recipients had the greatest risk of pre-transplant portal vein thrombosis with OR = 2.11 (95%CI: 1.60-2.76, P < 0.001) when referenced to the non-NASH group. CONCLUSION Liver transplant candidates with high-risk NASH are at the greatest risk for portal vein thrombosis development prior to transplantation. These candidates may benefit from interventions to decrease their likelihood of clot formation and resultant downstream hepatic decompensating events. Prospective study is needed. PMID:28217250

  18. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

    PubMed

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies.

  19. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases

    PubMed Central

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies. PMID:27458508

  20. An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function

    PubMed Central

    Lee, Ju Hee; Kang, Yea Eun; Chang, Joon Young; Park, Ki Cheol; Kim, Hyeon-Woo; Kim, Jung Tae; Kim, Hyun Jin; Yi, Hyon-Seung; Shong, Minho; Chung, Hyo Kyun; Kim, Koon Soon

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a prevalent obesity-related disease that affects large populations throughout the world due to excessive calorie intake and an increasingly sedentary lifestyle. Fibroblast growth factor 21 (FGF21) has recently emerged as a promising therapeutic candidate for the treatment of obesity and diabetes. FGF21 is a starvation-induced pleiotropic hormone with various beneficial metabolic effects, and pharmacological treatment in rodents has been shown to improve insulin sensitivity and decrease simple fatty liver disease. However, its effects on reversing the symptoms of advanced liver disease have yet to be validated. Here, we investigated the protective effects of the LY2405319 compound, an engineered FGF21 variant, in a non-alcoholic steatohepatitis (NASH) model using leptin-deficient ob/ob mice and a methionine- and choline-deficient (MCD) diet to induce steatohepatitis. LY2405319 treatment in ob/ob mice corroborated previous results showing that improvements in the metabolic parameters were due to increased mitochondrial oxygen consumption rate and fatty acid oxidation. LY2405319 treatment in ob/ob mice on an MCD diet significantly reduced the symptoms of steatohepatitis, as confirmed by Masson’s trichrome staining intensity. Serum levels of AST and ALT were also reduced, suggesting an attenuation of liver injury, while detection of inflammatory markers showed decreased mRNA expression of TGF-β1 and type-I collagen, and decreased phosphorylation of NF-kB p65, JNK1/2, and p38. Collectively, these data show that LY2405319 treatment attenuated MCD diet-induced NASH progression. We propose that the LY2405319 compound is a potential therapeutic candidate for the treatment of advanced liver disease. PMID:27904677

  1. Disease-specific miR-34a as diagnostic marker of non-alcoholic steatohepatitis in a Chinese population

    PubMed Central

    Liu, Xiao-Lin; Pan, Qin; Zhang, Rui-Nan; Shen, Feng; Yan, Shi-Yan; Sun, Chao; Xu, Zheng-Jie; Chen, Yuan-Wen; Fan, Jian-Gao

    2016-01-01

    AIM To assess disease-specific circulating microRNAs (miRNAs) in non-alcoholic steatohepatitis (NASH) patients. METHODS A total of 111 biopsy-proven non-alcoholic fatty liver disease (NAFLD) or chronic hepatitis B (CHB) patients and healthy controls from mainland China were enrolled to measure their serum levels of miR-122, -125b, -146b, -16, -21, -192, -27b and -34a. The correlations between serum miRNAs and histological features of NAFLD were determined. The diagnostic value of miRNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI), respectively. RESULTS Circulating miR-122, -16, -192 and -34a showed differential expression levels between NAFLD and CHB patients, and miR-34a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples (P < 0.01). Serum miR-122, -192 and -34a levels were correlated with steatosis (R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity (R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum miR-16 levels were associated with fibrosis (R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of miR-34a for NASH (area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but miR-16 showed a limited performance in the diagnosis of significant fibrosis in NASH. CONCLUSION Circulating miR-34a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH. PMID:27956809

  2. Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study.

    PubMed

    Cobbold, Jeremy F L; Atkinson, Stephen; Marchesi, Julian R; Smith, Ann; Wai, Sann N; Stove, Julie; Shojaee-Moradie, Fariba; Jackson, Nicola; Umpleby, A Margot; Fitzpatrick, Julie; Thomas, E Louise; Bell, Jimmy D; Holmes, Elaine; Taylor-Robinson, Simon D; Goldin, Robert D; Yee, Michael S; Anstee, Quentin M; Thursz, Mark R

    2017-04-20

    Gut microbial dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy. Patients with biopsy-proven NASH and elevated aminotransferase values were included in this open-label pilot study, all receiving 6 weeks rifaximin 400 mg twice daily, followed by a 6-week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6 weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic-euglycemic clamp. Fifteen patients (13 men and 2 women) with a median (range) age of 46 (32-63) years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6 weeks of therapy, no differences were seen in ALT (55 [33-191] vs. 63 [41-218] IU/L, P = 0.41), peripheral glucose uptake (28.9 [19.4-48.3] to 25.5 [17.7-47.9] μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 [15.3-51.7]% vs. 30.0 [10.8-50.5]%, P = 0.47), or hepatic lipid content (21.6 [2.2-46.2]% vs. 24.8 [1.7-59.3]%, P = 0.59) before and after rifaximin treatment. After 12 weeks from baseline, serum ALT increased to 83 (30-217) IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment-estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment. These data do not indicate a beneficial effect of rifaximin in patients with NASH. © 2017 The Japan Society of Hepatology.

  3. Hepatocellular carcinoma development in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Is it going to be the "Plague" of the 21st century? A literature review focusing on pathogenesis, prevention and treatment.

    PubMed

    Argyrou, Chrysoula; Moris, Demetrios; Vernadakis, Spiridon

    2017-01-01

    Liver carcinogenesis in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is a subject of intense research nowadays, since NAFLD is the most common chronic liver disease, affecting a great percentage of the population worldwide, while hepatocellular carcinoma (HCC), which represents the most common primary liver malignancy, is the third leading cause of cancer-related mortality. The underlying pathogenic pathways of both NAFLD and HCC are not completely understood, but there is growing evidence that they share many common pathophysiologic mechanisms and risk factors. Due to lack of solid evidence, though, the ultimate goal of designing effective diagnostic tools, treatment options and screening policies remain unmet for the time being. This review article aims to present recent data available regarding pathogenesis, diagnosis and management of HCC and NAFLD, as well as to highlight the importance of the development of HCC in the setting of NAFLD and NASH.

  4. Contributions of Streptococcus mutans Cnm and PA antigens to aggravation of non-alcoholic steatohepatitis in mice

    PubMed Central

    Naka, Shuhei; Hatakeyama, Rina; Takashima, Yukiko; Matsumoto-Nakano, Michiyo; Nomura, Ryota; Nakano, Kazuhiko

    2016-01-01

    Streptococcus mutans, a major pathogen of dental caries, can cause infective endocarditis after invading the bloodstream. Recently, intravenous administration of specific S. mutans strains was shown to aggravate non-alcoholic steatohepatitis (NASH) in a mouse model fed a high-fat diet. Here, we investigated the mechanism of this aggravation in a NASH mouse model by focusing on the S. mutans cell surface collagen-binding protein (Cnm) and the 190-kDa protein antigen (PA). Mice that were intravenously administered a S. mutans strain with a defect in Cnm (TW871CND) or PA (TW871PD) did not show clinical or histopathological signs of NASH aggravation, in contrast to those administered the parent strain TW871. The immunochemical analyses demonstrated higher levels of interferon-γ and metallothionein expression in the TW871 group than in the TW871CND and TW871PD groups. Analysis of bacterial affinity to cultured hepatic cells in the presence of unsaturated fatty acids revealed that the incorporation rate of TW871 was significantly higher than those of TW871CND and TW871PD. Together, our results suggest that Cnm and PA are important cell surface proteins for the NASH aggravation caused by S. mutans adhesion and affinity for hepatic cells. PMID:27833139

  5. Neonatal exposure to genistein ameliorates high-fat diet-induced non-alcoholic steatohepatitis in rats.

    PubMed

    Huang, Chengfei; Qiao, Xubai; Dong, Bing

    2011-07-01

    Non-alcoholic steatohepatitis (NASH) is becoming a prevalent disease in developing countries with no effective therapy. Isoflavones such as genistein have been shown to prevent NASH in a rat model, but the effects of neonatal exposure to genistein on lipid metabolism have been rarely studied. In the present study, three doses of genistein (30, 300 or 1200 μg/rat per d) were injected (subcutaneously) into neonatal male Sprague-Dawley rats at postnatal days 1-5. After weaning, these rats were allowed free access to a high-fat diet for 6 weeks. The results demonstrate that NASH was induced by high fat feeding in the control rats, whereas genistein-treated rats displayed smaller body weight, and lower hepatic inflammation and steatosis. The mid dose of genistein was most effective. Neonatal exposure to genistein also resulted in a lower incidence of apoptotic cells in the liver. Additionally, neonatal genistein-treated rats showed lower hepatic expression of fatty acid synthase and sterol regulatory element-binding protein-1, but higher expression of PPARα, indicative of lower rates of lipid synthesis and higher rates of β-oxidation. These results indicate that neonatal treatment with genistein has a prolonged effect on hepatic lipid metabolism that is maintained post-weaning, offering a potential approach for the prevention of hepatic steatosis and NASH.

  6. Non-invasive diagnosis for differentiating non-alcoholic steatohepatitis from simple steatosis: a meta-analysis and systematic review.

    PubMed

    Verhaegh, Pauline; Bavalia, Roisin; Winkens, Bjorn; Masclee, Ad; Jonkers, Daisy; Koek, Ger

    2017-08-21

    Non-alcoholic fatty liver disease (NAFLD) is a rapidly increasing health problem. Liver biopsy is the most sensitive test to differentiate between non-alcoholic steatohepatitis (NASH) and simple steatosis (SS), but non-invasive diagnostics are warranted. We performed a systematic review on non-invasive tests for differentiating NASH from SS, focusing on blood markers. A systematic search in PubMed, Medline and Embase (1990-2016) using defined keywords, limited to full-text papers in English and human adults, resulted in 2608 hits. After screening by two independent reviewers, 122 eligible articles using liver biopsy as gold standard were identified. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) were determined using metafor in R. In total, 122 studies were identified, in which 219 different blood markers, either as single marker (n=107) or as part of scoring systems (n=112), and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. Most extensively studied were alanine aminotransferase (sensp 63.5%, specp 74.4%) within routine biochemical tests, adiponectin (sensp 72.0%, specp 75.7%) within inflammatory markers, CK18-M30 (sensp 68.4%, specp 74.2%) within markers of cell death/proliferation and HOMA-IR (sensp 69.0%, specp 72.7%) within the metabolic markers. Two scoring systems could also be pooled, NASH test (NASH vs borderline NASH+SS sensp 22.9%, specp 95.3%) and the GlycoNASH test (sensp 67.1%, specp 63.8%). None of the pooled results revealed good sensitivity and specificity (≥80%), however, blood markers as part of scoring systems in single studies, showed promising results as non-invasive diagnostics for NASH. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from SS. Copyright © 2017 AGA Institute. Published by Elsevier Inc

  7. Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis (NASH) mouse model.

    PubMed

    Kawakami, Sakura; Han, Kyu-Ho; Nakamura, Yumi; Shimada, Ken-ichiro; Kitano, Tomoko; Aritsuka, Tsutomu; Nagura, Taizo; Ohba, Kiyoshi; Nakamura, Kimihide; Fukushima, Michihiro

    2012-01-01

    The effects of betaine supplementation on non-alcoholic steatohepatitis (NASH) model mice were examined by measuring the accumulation of fat in the livers of NASH model mice compared to a control. Betaine from sugar beets was provided to the model mice as a dietary supplement. After 3 wk of dietary supplementation, there were no significant differences in body weight or liver weight between the groups. However, the liver to body weight ratio in the high-fat diet with betaine (HFB) group was significantly (p<0.05) higher than that in the high-fat diet (HF) group. There were no differences in serum triglyceride (TG) concentrations, AST and ALT activities, or hepatic glutathione concentrations between the groups. Hepatic TG level in the HFB group was significantly (p<0.05) lower than that in the HF group. Hepatic cells obtained from the HF group showed increased occurrence of explosive puff and necrosis as compared with those in the HFB group. Betaine supplementation had an inhibitory effect on fat accumulation in the liver: the Oil red-positive area in the HFB group (0.82 ± 0.85%) was significantly (p<0.001) smaller than that in the HF group (9.06 ± 2.24%). These results indicate the potential of betaine to serve as an agent for amelioration of hepatic steatosis in NASH model mice.

  8. Shear Wave Elastography for Assessment of Steatohepatitis and Hepatic Fibrosis in Rat Models of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Kang, Bo-Kyeong; Lee, Seung Soo; Cheong, Hyunhee; Hong, Seung Mo; Jang, Kiseok; Lee, Moon-Gyu

    2015-12-01

    The purpose of this study was to evaluate shear wave elastography (SWE) as a method for determining the severity of non-alcoholic fatty liver disease (NAFLD) and the stage of hepatic fibrosis, as well as the major determinants of liver elasticity among the various histologic and biomolecular changes associated with NAFLD. Rat NAFLD models with various degrees of NAFLD severity were created and imaged using SWE. The explanted livers were subjected to histopathologic evaluation and RNA expression analysis. Among the histologic and biomolecular findings, the fibrosis stage and the collagen RNA level were significant independent factors associated with liver elasticity (p < 0.001). Liver elasticity was effective in detecting non-alcoholic steatohepatitis (NASH) and in determining fibrosis stage, and the corresponding areas under the receiver operating characteristic curves were 0.963 and 0.927-0.997, respectively. In conclusion, SWE is a potential non-invasive method for the detection of NASH and staging of hepatic fibrosis in patients with NAFLD.

  9. Effects of Eriobotrya japonica seed extract on oxidative stress in rats with non-alcoholic steatohepatitis.

    PubMed

    Yoshioka, Saburo; Hamada, Atsuhide; Jobu, Kohei; Yokota, Junko; Onogawa, Masahide; Kyotani, Shojiro; Miyamura, Mitsuhiko; Saibara, Toshiji; Onishi, Saburo; Nishioka, Yutaka

    2010-02-01

    Non-alcoholic steatohepatitis is associated with the deposition of lipid droplets in the liver, and is characterised histologically by the infiltration of inflammatory cells, hepatocellular degeneration and liver fibrosis. Oxidative stress may play an important role in the onset and deterioration of non-alcoholic steatohepatitis. We previously reported that an Eriobotrya japonica seed extract, extracted in 70% ethanol, exhibited antioxidant actions in vitro and in vivo. In this study, we examined the effect of this extract in a rat model of non-alcoholic steatohepatitis. The seed extract was given in the drinking water to fats being fed a methionine-choline-deficient diet for 15 weeks. Increases in alanine aminotransferase and aspartate aminotransferase levels were significantly inhibited in rats fed the seed extract compared with the group on the diet alone. Formation of fatty droplets in the liver was also inhibited. Antioxidant enzyme activity in liver tissue was higher than in the diet-only group and lipid peroxidation was reduced compared with rats that also received the extract. Expression of 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal was lower in the rats given the seed extract than in the diet-only group. In the former, liver tissue levels of transforming growth factor-beta and collagen were also decreased. Thus, the E. japonica seed extract inhibited fatty liver, inflammation and fibrosis, suggesting its usefulness in the treatment of non-alcoholic steatohepatitis.

  10. Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.

    PubMed

    Loffredo, L; Del Ben, M; Perri, L; Carnevale, R; Nocella, C; Catasca, E; Baratta, F; Ceci, F; Polimeni, L; Gozzo, P; Violi, F; Angelico, F

    2016-08-01

    Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (<35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake. Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes. Cocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients. © 2016 John Wiley & Sons Ltd.

  11. Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

    PubMed

    Konuma, Kuniha; Itoh, Michiko; Suganami, Takayoshi; Kanai, Sayaka; Nakagawa, Nobutaka; Sakai, Takeru; Kawano, Hiroyuki; Hara, Mitsuko; Kojima, Soichi; Izumi, Yuichi; Ogawa, Yoshihiro

    2015-01-01

    Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

  12. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis.

    PubMed

    Francque, Sven; Verrijken, An; Caron, Sandrine; Prawitt, Janne; Paumelle, Réjane; Derudas, Bruno; Lefebvre, Philippe; Taskinen, Marja-Riitta; Van Hul, Wim; Mertens, Ilse; Hubens, Guy; Van Marck, Eric; Michielsen, Peter; Van Gaal, Luc; Staels, Bart

    2015-07-01

    Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPARα, β/δ, and γ expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up. Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 year. 125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 year of follow-up. Liver PPARα expression negatively correlated with the presence of NASH (p=0.001) and with severity of steatosis (p=0.003), ballooning (p=0.001), NASH activity score (p=0.008) and fibrosis (p=0.003). PPARα expression was positively correlated to adiponectin (R(2)=0.345, p=0.010) and inversely correlated to visceral fat (R(2)=-0.343, p<0.001), HOMA IR (R(2)=-0.411, p<0.001) and CK18 (R(2)=-0.233, p=0.012). Liver PPARβ/δ and PPARγ expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPARα expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPARα and its target genes was significantly associated with histological improvement (p=0.008). Human liver PPARα gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPARα and its target genes. These data might suggest that PPARα is a potential therapeutic target in NASH. Copyright © 2015. Published by Elsevier B.V.

  13. Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis.

    PubMed

    Amarapurka, D N; Amarapurkar, A D; Patel, N D; Agal, S; Baigal, R; Gupte, P; Pramanik, S

    2006-01-01

    Nonalcoholic steatohepatitis (NASH) is common cause of chronic liver disease strongly associated with insulin resistance leading to fibrosis. No factors that determine increasing fibrosis have been well recognized. Liver biopsy is considered as gold standard for diagnosis and prognosis of this disease. To identify independent predictive factors of liver fibrosis in patients of NASH with diabetes. During the year 2001 and 2002 total 36 patients of NASH associated with diabetes were included in the study. The diagnosis of NASH was based on 1) presence of steatosis, inflammation and ballooning on liver biopsy 2) Intake of alcohol < 20 gm of ethanol per week 3) Exclusion of other liver diseases. Patients were labeled as diabetic if random glucose was > 200 mg/dL or fasting glucose more than 140 mg/dL on 2 occasion or having documented use of oral hypoglycemic medications or insulin. Clinical and biochemical variables such as age, sex, obesity, hypercholesterolemia, AST, ALT and AST: ALT were examined for predictors of fibrosis using univariate and multiple regression statistical analysis. Obesity was defined as BMI > 30 for both males and females. Hypercholesterolemia was considered when fasting cholesterol level was above 95th percentile of normal on at least 2 occasions. Fibrosis was noted as present or absent on histology. Of 36 patients 17 were females and 19 males with age range of 25 to 75 years, mean age 50.8 years. Fibrosis was present in 11 (30.5%) and absent in 25 (69.4%) patients. Univariate and multiple correlations co-efficient failed to detect significant association of fibrosis with above mentioned variables. However multiple regression and logistic regression analysis (MLR) detected statistical significance for AST, ALT levels and AST: ALT ratio between fibrosis and no fibrosis in 80.6% patients. There is no definite noninvasive test that helps to predict liver fibrosis however AST, ALT levels and AST: ALT ratio may help to determine the fibrosis in

  14. MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis.

    PubMed

    Katsura, Akiko; Morishita, Asahiro; Iwama, Hisakazu; Tani, Joji; Sakamoto, Teppei; Tatsuta, Miwa; Toyota, Yuka; Fujita, Koji; Kato, Kiyohito; Maeda, Emiko; Nomura, Takako; Miyoshi, Hisaaki; Yoneyama, Hirohito; Himoto, Takashi; Fujiwara, Shintaro; Kobara, Hideki; Mori, Hirohito; Niki, Toshiro; Ono, Masafumi; Hirashima, Mitsuomi; Masaki, Tsutomu

    2015-04-01

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. microRNAs (miRNAs) are small non-coding RNAs that negatively regulate messenger RNA (mRNA). Recently, it was demonstrated that the aberrant expression of certain miRNAs plays a pivotal role in liver disease. The aim of the present study was to evaluate changes in miRNA profiles associated with metformin treatment in a NASH model. Eight-week-old male mice were fed a methionine- and choline-deficient (MCD) diet alone or with 0.08% metformin for 15 weeks. Metformin significantly downregulated the level of plasma transaminases and attenuated hepatic steatosis and liver fibrosis. The expression of miRNA-376a, miRNA‑127, miRNA-34a, miRNA-300 and miRNA-342-3p was enhanced among the 71 upregulated miRNAs, and the expression of miRNA-122, miRNA-194, miRNA-101b and miRNA-705 was decreased among 60 downregulated miRNAs in the liver of MCD-fed mice when compared with control mice. Of note, miRNA profiles were altered following treatment with metformin in MCD-fed mice. miRNA-376a, miRNA‑127, miRNA-34a, miRNA-300 and miRNA-342-3p were downregulated, but miRNA-122, miRNA-194, miRNA‑101b and miRNA-705 were significantly upregulated in MCD-fed mice treated with metformin. miRNA profiles were altered in MCD-fed mice and metformin attenuated this effect on miRNA expression. Therefore, miRNA profiles are a potential tool that may be utilized to clarify the mechanism behind the metformin-induced improvement of hepatic steatosis and liver fibrosis. Furthermore, identification of targetable miRNAs may be used as a novel therapy in human NASH.

  15. The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma

    PubMed Central

    Shimomura, Yasuyuki; Takaki, Akinobu; Wada, Nozomu; Yasunaka, Tetsuya; Ikeda, Fusao; Maruyama, Takayuki; Tamaki, Naofumi; Uchida, Daisuke; Onishi, Hideki; Kuwaki, Kenji; Nakamura, Shinichiro; Nouso, Kazuhiro; Miyake, Yasuhiro; Koike, Kazuko; Tomofuji, Takaaki; Morita, Manabu; Yamamoto, Kazuhide; Okada, Hiroyuki

    2017-01-01

    Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function. PMID:28154266

  16. Similar Reduction of Cholesterol-Adjusted Vitamin E Serum Levels in Simple Steatosis and Non-Alcoholic Steatohepatitis

    PubMed Central

    Pastori, Daniele; Baratta, Francesco; Carnevale, Roberto; Cangemi, Roberto; Del Ben, Maria; Bucci, Tommaso; Polimeni, Licia; Labbadia, Giancarlo; Nocella, Cristina; Scardella, Laura; Pani, Arianna; Pignatelli, Pasquale; Violi, Francesco; Angelico, Francesco

    2015-01-01

    Objectives: Reduced vitamin E levels have been reported in patients with non-alcoholic steatohepatitis (NASH), but no conclusive data on patients with simple steatosis (SS) are available. Aim of this study was to investigate the association between serum vitamin E levels and SS. Methods: A cohort of 312 patients with cardio-metabolic risk factors was screened for liver steatosis by ultrasonography (US). We reasonably classified as SS patients with US-fatty liver, normal liver function tests (LFTs) and with Cytokeratin 18 <246 mIU/ml. Liver biopsy was performed in 41 patients with US-fatty liver and persistent elevation of LFTs (>6 months). Serum cholesterol-adjusted vitamin E (Vit E/chol) levels were measured. Results: Mean age was 53.9±12.5 years and 38.4% were women. Non-alcoholic fatty liver disease (NAFLD) was detected at US in 244 patients; of those 39 had biopsy-proven NASH and 2 borderline NASH. Vit E/chol was reduced in both SS (3.4±2.0, P<0.001), and NASH (3.5±2.1, P=0.006) compared with non-NAFLD patients (4.8±2.0 μmol/mmol chol). No difference was found between SS and NASH (P=0.785). After excluding patients with NASH, a multivariable logistic regression analysis found that Vit E/chol (odds ratio (OR): 0.716, 95% confidence interval (CI) 0.602–0.851, P<0.001), alanine aminotransferase (ALT, OR: 1.093, 95% CI 1.029–1.161, P=0.004), body mass index (OR: 1.162, 95% CI 1.055–1.279, P=0.002) and metabolic syndrome (OR: 5.725, 95% CI 2.247–14.591, P<0.001) were factors independently associated with the presence of SS. Conclusions: Reduced vitamin E serum levels are associated with SS, with a similar reduction between patients with SS and NASH, compared with non-NAFLD patients. Our findings suggest that the potential benefit of vitamin E supplementation should be investigated also in patients with SS. PMID:26426796

  17. Dual effect of silymarin on experimental non-alcoholic steatohepatitis induced by irinotecan.

    PubMed

    Marcolino Assis-Júnior, Eudmar; Melo, Anielle Torres; Pereira, Venúcia Bruna Magalhães; Wong, Deysi Viviana Tenazoa; Sousa, Nathalia Ribeiro Pinho; Oliveira, Christiane Mendes Gonçalves; Malveira, Lara Raissa Cavalcante; Moreira, Leonardo Silva; Souza, Marcellus Henrique Loiola Ponte; Almeida, Paulo Roberto Carvalho; Lima-Júnior, Roberto César Pereira

    2017-07-15

    Irinotecan-based regimens are commonly used for treatment of colorectal cancer, which is limited by mucositis and non-alcoholic steatohepatitis (NASH). Silymarin (SIL) prevents fatty liver disease in the clinical setting and in models of liver damage induced chemically. This study investigated the possible effect of SIL on irinotecan (IRI)-induced NASH. Swiss female mice were injected with saline (SAL 5ml/kg i.p.), IRI (50mg/kg i.p.), SIL (150mg/kg p.o.) or IRI (50mg/kg i.p.)+(SIL 1.5, 15 or 150mg/kg p.o.) thrice/week/7weeks. On the seventh week, blood samples were collected for transaminases assay and livers were collected for histopathology, measurement of the total lipids, malondyadehyde (MDA), non-protein sulfhydryl groups (NPSH), cytokines (IL-1β, IL 6 and IL-10), 3-nitrotyrosine (N-Tyr) and toll-like receptor 4 (TLR4) immunoexpression, quantification of NF-kB, α-smooth muscle actin (α-SMA), and Escherichia coli 16S rRNA gene (RRS) expression. IRI increased liver transaminases, neutrophil infiltration, lipid accumulation, MDA, IL-1β and IL-6 levels, N-Tyr and TLR4 immunostaining, NF-kB, α-SMA expression and RRS versus the SAL group (p<0.05). Additionally, SIL (1.5mg/kg) improved these parameters (p<0.05), except neutrophil infiltration and RSS versus the IRI group. Furthermore, the SIL (15mg/kg) only improved the inflammatory parameters, the expression of α-SMA and RRS versus the IRI group (p<0.05). The higher dose of SIL (150mg/kg) was even more deleterious than the intermediate dose. Therefore, silymarin showed a dual effect on liver damage induced by IRI. Hepatoprotection seems to involve the inhibition of oxidative stress and protein nitrosylation, preventing activation of hepatic fibrosis mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

    PubMed Central

    Kakehashi, Anna; Stefanov, Vasily E.; Ishii, Naomi; Okuno, Takahiro; Fujii, Hideki; Kawai, Kazuaki; Kawada, Norifumi; Wanibuchi, Hideki

    2017-01-01

    To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV+ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV+ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis. PMID:28218651

  19. MSP is a negative regulator of inflammation and lipogenesis in ex vivo models of non-alcoholic steatohepatitis

    PubMed Central

    Chanda, Dipanjan; Li, Jieyi; Oligschlaeger, Yvonne; Jeurissen, Mike L J; Houben, Tom; Walenbergh, Sofie M A; Shiri-Sverdlov, Ronit; Neumann, Dietbert

    2016-01-01

    Non-alcoholic steatohepatitis (NASH), a metabolic disorder consisting of steatosis and inflammation, is considered the hepatic equivalent of metabolic syndrome and can result in irreversible liver damage. Macrophage-stimulating protein (MSP) is a hepatokine that potentially has a beneficial role in hepatic lipid and glucose metabolism via the activation of AMP-activated protein kinase (AMPK). In the current study, we investigated the regulatory role of MSP in the development of inflammation and lipid metabolism in various NASH models, both in vitro and ex vivo. We observed that MSP treatment activated the AMPK signaling pathway and inhibited lipopolysaccharide (LPS)- and palmitic acid (PA)-induced gene expression of pro-inflammatory cytokines in primary mouse hepatocytes. In addition, MSP treatment resulted in a significant reduction in PA-induced lipid accumulation and inhibited the gene expression of key lipogenic enzymes in HepG2 cells. Upon short hairpin RNA-induced knockdown of RON (the membrane-bound receptor for MSP), the anti-inflammatory and anti-lipogenic effects of MSP were markedly ablated. Finally, to mimic NASH ex vivo, we challenged bone marrow-derived macrophages with oxidized low-density lipoprotein (oxLDL) in combination with LPS. OxLDL+LPS exposure led to a marked inhibition of AMPK activity and a robust increase in inflammation. MSP treatment significantly reversed these effects by restoring AMPK activity and by suppressing pro-inflammatory cytokine gene expression and secretion under this condition. Taken together, these data suggest that MSP is an effective inhibitor of inflammation and lipid accumulation in the stressed liver, thereby indicating that MSP has a key regulatory role in NASH. PMID:27609031

  20. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice

    PubMed Central

    Miyazaki, Tsuneyuki; Shirakami, Yohei; Kubota, Masaya; Ideta, Takayasu; Kochi, Takahiro; Sakai, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Shimizu, Masahito

    2016-01-01

    Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects. PMID:26871288

  1. Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice.

    PubMed

    Miyazaki, Tsuneyuki; Shirakami, Yohei; Kubota, Masaya; Ideta, Takayasu; Kochi, Takahiro; Sakai, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Shimizu, Masahito

    2016-03-01

    Obesity and related metabolic abnormalities play a key role in liver carcinogenesis. Non-alcoholic steatohepatitis (NASH), which is often complicated with obesity and diabetes mellitus, is associated with the development of hepatocellular carcinoma (HCC). Sodium alginate (SA), which is extracted from brown seaweeds, is marketed as a weight loss supplement because of its high viscosity and gelling properties. In the present study, we examined the effects of SA on the progression of NASH and related liver carcinogenesis in monosodium glutamate (MSG)-treated mice, which show obesity, diabetes mellitus, and NASH-like histopathological changes. Male MSG-mice were intraperitoneally injected with diethylnitrosamine at 2 weeks of age, and, thereafter, they received a basal diet containing high- or low-molecular-weight SA throughout the experiment (16 weeks). At sacrifice, control MSG-treated mice fed the basal-diet showed significant obesity, hyperinsulinemia, steatosis and hepatic tumor development. SA administration suppressed body weight gain; improved insulin sensitivity, hyperinsulinemia, and hyperleptinemia; attenuated inflammation in the liver and white adipose tissue; and inhibited hepatic lipogenesis and progression of NASH. SA also reduced oxidative stress and increased anti-oxidant enzyme levels in the liver. Development of hepatic tumors, including liver cell adenoma and HCC, and hepatic pre-neoplastic lesions was significantly inhibited by SA supplementation. In conclusion, oral SA supplementation improves liver steatosis, insulin resistance, chronic inflammation, and oxidative stress, preventing the development of liver tumorigenesis in obese and diabetic mice. SA may have ability to suppress steatosis-related liver carcinogenesis in obese and diabetic subjects.

  2. Physical exercise prevents and mitigates non-alcoholic steatohepatitis-induced liver mitochondrial structural and bioenergetics impairments.

    PubMed

    Gonçalves, Inês O; Passos, Emanuel; Rocha-Rodrigues, Silvia; Diogo, Cátia V; Torrella, Joan R; Rizo, David; Viscor, Ginés; Santos-Alves, Estela; Marques-Aleixo, Inês; Oliveira, Paulo J; Ascensão, António; Magalhães, José

    2014-03-01

    Exercise is considered a non-pharmacological tool against several lifestyle disorders in which mitochondrial dysfunction is involved. The present study aimed to analyze the preventive (voluntary physical activity-VPA) and therapeutic (endurance training-ET) role of exercise against non-alcoholic steatohepatitis (NASH)-induced liver mitochondrial dysfunction. Sixty male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n=20), standard-diet VPA (SVPA, n=10), high-fat diet sedentary (HS, n=20) and high-fat diet VPA (HVPA, n=10). After 9weeks of diet-treatment, half of SS and HS animals were engaged in an ET program (SET and HET) for 8weeks, 5days/week and 60min/day. Liver mitochondrial oxygen consumption and transmembrane-electric potential (ΔΨ) were evaluated in the presence of glutamate-malate (G/M), palmitoyl-malate (P/M) and succinate (S/R). Mitochondrial enzymes activity, lipid and protein oxidation, oxidative phosphorylation (OXPHOS) subunits, cytochrome c, adenine nucleotide translocator (ANT) and uncoupling protein-2 (UCP2) content were assessed. HS groups show the histological features of NASH in parallel with decreased ΔΨ and respiratory control (RCR) and ADP/O ratios (G/M and P/M). A state 3 decrease (G/M and S/R), FCCP-induced uncoupling respiration (S/R) and ANT content were also observed. Both exercise types counteracted oxygen consumption (RCR, ADP/O and FCCP-uncoupling state) impairments and improved ΔΨ (lag-phase). In conclusion, exercise prevented or reverted (VPA and ET, respectively) the bioenergetic impairment induced by NASH, but only ET positively remodeled NASH-induced liver structural damage and abnormal mitochondria. It is possible that alterations in inner membrane integrity and fatty acid oxidation may be related to the observed phenotypes induced by exercise.

  3. Aggressive non-alcoholic steatohepatitis following rapid weight loss and/or malnutrition.

    PubMed

    Tsai, Jia-Huei; Ferrell, Linda D; Tan, Vivian; Yeh, Matthew M; Sarkar, Monika; Gill, Ryan M

    2017-03-03

    While non-alcoholic steatohepatitis is a slowly progressive disease, patients may rarely present in acute liver failure. We describe six patients who developed severe hepatic dysfunction following rapid weight loss or malnutrition. Rapid weight loss (18 to 91 kg) occurred after Roux-en-Y gastric bypass in four patients and starvation-like dieting or hypoalbuminemia was noted in two patients. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including extensive/circumferential centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, abundant/prominent hepatocellular balloons, and numerous Mallory-Denk bodies, but there was no history of excess alcohol consumption. This study characterizes clinicopathologic features of aggressive non-alcoholic steatohepatitis following rapid weight loss or malnutrition, which should be included in the differential diagnosis with alcohol when a patient is considered for liver transplantation. The mechanism of liver injury in aggressive steatohepatitis is unknown, but rapid fat mobilization in obese patients may potentially cause oxidative stress to the liver and further study is needed to determine if there is a genetic predisposition to this form of injury and if antioxidants may protect the liver during rapid weight loss/malnutrition.Modern Pathology advance online publication, 3 March 2017; doi:10.1038/modpathol.2017.13.

  4. The CCR2 Inhibitor Propagermanium Attenuates Diet-Induced Insulin Resistance, Adipose Tissue Inflammation and Non-Alcoholic Steatohepatitis

    PubMed Central

    van den Hoek, Anita M.; Kleemann, Robert

    2017-01-01

    Background and aim Obese patients with chronic inflammation in white adipose tissue (WAT) have an increased risk of developing non-alcoholic steatohepatitis (NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment of immune cells to WAT and liver, thereby promoting the inflammatory component of the disease. Herein, we examined whether intervention with propagermanium, an inhibitor of CCR2, would attenuate tissue inflammation and NASH development. Methods Male C57BL/6J mice received a high-fat diet (HFD) for 0, 6, 12 and 24 weeks to characterize the development of early disease symptoms of NASH, i.e. insulin resistance and WAT inflammation (by hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal time point for intervention. In a separate study, mice were pretreated with HFD followed by propagermanium treatment (0.05% w/w) after 6 weeks (early intervention) or 12 weeks (late intervention). NASH was analyzed after 24 weeks of diet feeding. Results Insulin resistance in WAT developed after 6 weeks of HFD, which was paralleled by modest WAT inflammation. Insulin resistance and inflammation in WAT intensified after 12 weeks of HFD, and preceded NASH development. The subsequent CCR2 intervention experiment showed that early, but not late, propagermanium treatment attenuated insulin resistance. Only the early treatment significantly decreased Mcp-1 and CD11c gene expression in WAT, indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated that propagermanium treatment decreased macrovesicular steatosis and tended to reduce lobular inflammation, with more pronounced effects in the early intervention group. Propagermanium improved the ratio between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, quantified by CD11c and Arginase-1 gene expression in both intervention groups. Conclusions Overall, early propagermanium administration was more effective to improve insulin

  5. Evaluating the Influence of Side Stream Cigarette Smoke at an Early Stage of Non-Alcoholic Steatohepatitis Progression in Mice

    PubMed Central

    Kim, Jong Won; Yun, Hyejin; Choi, Seong-Jin; Lee, Sang-Hyub; Park, Surim; Lim, Chae Woong; Lee, Kyuhong; Kim, Bumseok

    2017-01-01

    Side stream cigarette smoke (SSCS) is known to be as harmful and hazardous to human health as is active smoking. In this study, we investigated the relationship between the exposure to SSCS and its stimulatory and subacute effects on the progression of non-alcoholic steatohepatitis (NASH). A methionine and choline-deficient plus high fat (MCDHF) diet was administered to C57BL/6 mice for 6 weeks. During the first three weeks of MCDHF diet feeding, each diet group was exposed to SSCS (0, 20, 40 μg/L) or fresh air for 2 hrs per day and 5 days per week. Additional experiments were performed by increasing the concentration (0, 30, 60 μg/L) and exposure time (6 hours per day) of SSCS. According to histopathologic analysis and serum levels of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST), there were no differences in hepatic fat deposition, fibrosis, apoptosis or liver damage in MCDHF-fed mice based on SSCS exposure. There were also no differences in the expression of inflammation-, oxidative stress- or fibrosis-related genes between MCDHF-fed mice with or without SSCS exposure. Therefore, it is concluded that SSCS with current exposure amounts does not have additive detrimental effects on the early stage of NASH. PMID:28133511

  6. Salidroside alleviates oxidative stress in the liver with non- alcoholic steatohepatitis in rats.

    PubMed

    Yang, Ze-ran; Wang, Hui-fang; Zuo, Tie-cheng; Guan, Li-li; Dai, Ning

    2016-04-14

    Nonalcoholic steatohepatitis (NASH) is characterized by fat accumulation in the hepatocyte, inflammation, liver cell injury, and varying degrees of fibrosis, and can lead to oxidative stress in liver. Here, we investigated whether Salidroside, a natural phenolic antioxidant product, can protect rat from liver injury during NASH. NASH model was established by feeding the male SD rats with high-fat and high-cholesterol diet for 14 weeks. Four groups of male SD rats including, normal diet control group, NASH model group, and Salidroside treatment group with150mg/kg and 300 mg/kg respectively, were studied. Salidroside was given by oral administration to NASH in rats from 9 weeks to 14 weeks. At the end of 14 weeks, liver and serum were harvested, and the liver injury, oxidative stress and histological features were evaluated. NASH rats exhibited significant increases in the following parameters as compared to normal diet control rats: fat droplets with foci of inflammatory cell infiltration in the liver. ALT, AST in serum and TG, TC in hepatocyte elevated. Oxidative responsive genes including CYP2E1 and Nox2 increased. Additionally, NASH model decreased antioxidant enzymes SOD, GSH, GPX, and CAT in the liver due to their rapid depletion after battling against oxidative stress. Compared to NASH model group, treatment rats with Salidroside effectively reduced lipid accumulation, inhibited liver injury in a does-dependent manner. Salidroside treatment restored antioxidant enzyme levels, inhibited expression of CYP2E1 and Nox2 mRNA in liver, which prevented the initial step of generating free radicals from NASH. The data presented here show that oral administration of Salidroside prevented liver injury in the NASH model, likely through exerting antioxidant actions to suppress oxidative stress and the free radical-generating CYP2E1 enzyme, Nox2 in liver.

  7. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression

    PubMed Central

    Loyer, Xavier; Paradis, Valérie; Hénique, Carole; Vion, Anne-Clémence; Colnot, Nathalie; Guerin, Coralie L; Devue, Cécile; On, Sissi; Scetbun, Jérémy; Romain, Mélissa; Paul, Jean-Louis; Rothenberg, Marc E; Marcellin, Patrick; Durand, François; Bedossa, Pierre; Prip-Buus, Carina; Baugé, Eric; Staels, Bart; Boulanger, Chantal M; Tedgui, Alain; Rautou, Pierre-Emmanuel

    2016-01-01

    Objective Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH. Design We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient (Ldlr−/−) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined. Results Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr−/− fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice. Conclusions MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH. PMID:26338827

  8. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial

    PubMed Central

    Joy, Tisha R; McKenzie, Charles A; Tirona, Rommel G; Summers, Kelly; Seney, Shannon; Chakrabarti, Subrata; Malhotra, Neel; Beaton, Melanie D

    2017-01-01

    AIM To evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH). METHODS Twelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy. RESULTS Sitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mmol

  9. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: Analysis of isolated hepatic stellate cells

    PubMed Central

    KIM, MINA; YANG, SU-GEUN; KIM, JOON MI; LEE, JIN-WOO; KIM, YOUNG SOO; LEE, JUNG IL

    2012-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting α-smooth muscle actin (SMA)-positive cells and measuring α-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased α1-procollagen mRNA expression in isolated HSCs, the anti-fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-α mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-α. PMID:22710359

  10. A Comparison of Brunt Criteria, the Non Alcoholic Fatty Liver Disease Activity Score (NAS) & a Proposed NAS-including fibrosis as Valid Diagnostic Scores for NASH

    PubMed Central

    Santiago-Rolón, Amarilys; Purcell, Dagmary; Rosado, Kathia; Toro, Doris H.

    2016-01-01

    Objective Non-alcoholic steatohepatitis (NASH) can result in cirrhosis and end stage liver disease. It is of utmost importance to differentiate NASH from simple steatosis. The aim of this study is to determine the prevalence of NASH in Latino veterans with metabolic syndrome and compare histologic grading using Brunt Criteria, the NAFLD activity score (NAS), and a proposed NAS score including fibrosis. Methods Veterans with metabolic syndrome, hepatic steatosis and elevation of ALT/AST who underwent a liver biopsy from 2004-2010 were included in this study. Biopsies were evaluated by a single blinded Hepatopathologist. Steatosis, lobular inflammation, ballooning and fibrosis were graded per specimen. Each biopsy was evaluated using Brunt criteria, NAS and NAS plus fibrosis. Results Sixty patients were included in this study, 88.3% men with a mean age of 50.4 (± 12.8). 50.0% met criteria for NASH according to the Brunt system. When classifying biopsies using NAS, only 30.0% (18/60) had a score ≥5, while when adding fibrosis, the number of patients with a score ≥5 increased to 33 (55.0%). When evaluating the predictive ability of the two scoring systems, we found that NAS including fibrosis had a higher sensitivity than NAS (86.7% vs. 40.0%) and a lower specificity (76.7% vs. 80.0%). Conclusion In our population with metabolic syndrome and altered liver function tests, about 50-55% had steatohepatitis. There were significant differences between the scoring systems. When using NAS-plus-fibrosis more patients were recognized and the sensitivity increased. Further validation studies are required to evaluate this proposed NAS scoring System. PMID:26602577

  11. Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease

    PubMed Central

    Gallego-Durán, Rocío; Cerro-Salido, Pablo; Gomez-Gonzalez, Emilio; Pareja, María Jesús; Ampuero, Javier; Rico, María Carmen; Aznar, Rafael; Vilar-Gomez, Eduardo; Bugianesi, Elisabetta; Crespo, Javier; González-Sánchez, Francisco José; Aparcero, Reyes; Moreno, Inmaculada; Soto, Susana; Arias-Loste, María Teresa; Abad, Javier; Ranchal, Isidora; Andrade, Raúl Jesús; Calleja, Jose Luis; Pastrana, Miguel; Iacono, Oreste Lo; Romero-Gómez, Manuel

    2016-01-01

    There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy-proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73–0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77–0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients. PMID:27514671

  12. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis

    PubMed Central

    Schneck, Anne-Sophie; Anty, Rodolphe; Patouraux, Stéphanie; Bonnafous, Stéphanie; Rousseau, Déborah; Lebeaupin, Cynthia; Bailly-Maitre, Beatrice; Sans, Arnaud; Tran, Albert; Gugenheim, Jean; Iannelli, Antonio; Gual, Philippe

    2016-01-01

    The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m2) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss −13.7 [−16.4; −9.5] kg/m2), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death. PMID:27594839

  13. Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis.

    PubMed

    Schneck, Anne-Sophie; Anty, Rodolphe; Patouraux, Stéphanie; Bonnafous, Stéphanie; Rousseau, Déborah; Lebeaupin, Cynthia; Bailly-Maitre, Beatrice; Sans, Arnaud; Tran, Albert; Gugenheim, Jean; Iannelli, Antonio; Gual, Philippe

    2016-01-01

    The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m(2)) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss -13.7 [-16.4; -9.5] kg/m(2)), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death.

  14. Novel findings for the development of drug therapy for various liver diseases: Liver microsomal triglyceride transfer protein activator may be a possible therapeutic agent in non-alcoholic steatohepatitis.

    PubMed

    Fujita, Koji; Imajo, Kento; Shinohara, Yoshiyasu; Nozaki, Yuichi; Wada, Koichiro; Yoneda, Masato; Endo, Hiroki; Takahashi, Hirokazu; Abe, Yasunobu; Inamori, Masahiko; Shimamura, Takeshi; Kobayashi, Noritoshi; Kirikoshi, Hiroyuki; Kubota, Kensuke; Saito, Satoru; Nakajima, Atsushi

    2011-01-01

    The factors involved in the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

  15. Epigallocatechin gallate attenuated non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet.

    PubMed

    Ding, Yi; Sun, Xin; Chen, Yuning; Deng, Yue; Qian, Ke

    2015-08-15

    Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease. In this study, we evaluated the effects of Epigallocatechin gallate (EGCG) on methionine- and choline-deficient (MCD) diet-induced NASH. Our data showed that EGCG significantly prevented MCD diet-induced liver and body weight loss. Histological analysis showed that EGCG inhibited MCD diet-induced steatohepatitis including fat accumulation and inflammatory cells infiltration. Biochemical analysis data showed that EGCG significantly reduced the elevation of plasma ALT and AST levels but increased plasma triglyceride and cholesterol contents. However, EGCG significantly inhibited hepatic triglyceride and cholesterol content in MCD diet fed mice. Consistent with histology results, EGCG treatment significantly inhibited MCD diet-induced IL-1β, IL-6, TNF-α and MCP-1 mRNA expression. As an antioxidant, EGCG treatment significant inhibited hepatic MDA contents and increased hepatic SOD contents. In addition, transforming growth factor (TGF)-β, collagen I-α1, tissue inhibitor of metalloproteinase 1 (TIMP-1) and α-smooth muscle actin (SMA) mRNA expression, which are markers of hepatic fibrosis, were markedly inhibited by EGCG treatment. Western blot data showed that EGCG inhibited Smad2 and Smad3 phosphorylation in the liver and LX-2 cells which were involved in TGF-β-induced pathway. Taken together, EGCG attenuated NASH induced by MCD diet associated with ameliorating fibrosis, oxidative stress, and hepatic inflammation. Our results indicate that EGCG has beneficial roles in the development of MCD diet-induced NASH. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis.

    PubMed

    Cabrera, Daniel; Wree, Alexander; Povero, Davide; Solís, Nancy; Hernandez, Alejandra; Pizarro, Margarita; Moshage, Han; Torres, Javiera; Feldstein, Ariel E; Cabello-Verrugio, Claudio; Brandan, Enrique; Barrera, Francisco; Arab, Juan Pablo; Arrese, Marco

    2017-06-14

    Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1β expression through NF-κB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-κB-dependent mechanism may be involved in the therapeutic effects of ANDRO.

  17. Calycosin attenuates triglyceride accumulation and hepatic fibrosis in murine model of non-alcoholic steatohepatitis via activating farnesoid X receptor.

    PubMed

    Duan, Xingping; Meng, Qiang; Wang, Changyuan; Liu, Zhihao; Liu, Qi; Sun, Huijun; Sun, Pengyuan; Yang, Xiaobo; Huo, Xiaokui; Peng, Jinyong; Liu, Kexin

    2017-02-15

    Non-alcoholic steatohepatitis (NASH) represents the more severe end of hepatic steatosis and is associated with progressive liver disease. Calycosin, derived from the root of Radix Astragali, has been demonstrated to have favorable efficacy on acute liver injury. The present study was to investigate the hepatoprotective effect of calycosin on attenuating triglyceride accumulation and hepatic fibrosis, as well as explore the potential mechanism in murine model of NASH. The C57BL/6 male mice were fed with methionine choline deficient (MCD) diet for 4 weeks to induce NASH and treated with or without calycosin by oral gavage for 4 weeks. The body weight, liver weight and the liver to body weight ratios were measured. Serum ALT, AST, TG, TC, FFA, MCP-1 and mKC levels were accessed by biochemical methods. H&E staining and Oil red O staining were used to identify the amelioration of liver histopathology. Immunohistochemistry of a-SMA, Masson trichrome staining and Sirius red staining were used to identify the amelioration of hepatic fibrosis. The quantitative real-time-PCR and Western blot were applied to observe the expression changes of key factors involved in triglyceride synthesis, free fatty acid β-oxidation and hepatic fibrosis. Calycosin significantly inhibited body weight loss induced by MCD diet, decreased the ALT and AST activities, MCP-1 and mKC in a dose-dependent manner. The H&E and Oil red O staining indicated calycosin effectively improved hepatic steatosis, improved the degree of triglyceride accumulation. Masson trichrome and Sirius red staining indicated that calycosin treatment remarkably attenuated the degree of hepatic fibrosis. Immunohistochemistry of a-SMA demonstrated that calycosin attenuated hepatic fibrosis by inhibiting hepatic stellate cell activation. Further, calycosin inhibited the expression of SREBP-1c, FASN, ACC and SCD1 involved in triglyceride synthesis, promoted the expression of PPARa, CPT1, Syndecan-1 and LPL involved in free fatty

  18. [Non-alcoholic steatohepatitis induced by fast weight loss during the use of intragastric balloon--a case report].

    PubMed

    Benchimol, Alexander Koglin; Cardoso, Isabella Silva; Fandiño, Julia; Bittar, Thalita; Freitas, Sílvia; Coutinho, Walmir Ferreira

    2007-06-01

    Obesity is a chronic disease that has been considered an epidemic nowadays. It is associated to much co-morbidity, such as non-alcoholic fatty liver disease (NAFLD) and its complication, steatohepatitis. We report a case of a 58-year-old obese patient refractory to clinical treatment who was submitted to the use of intragastric balloon (BIB), developing steatohepatitis induced by fast weight loss.

  19. Evaluation of Methionine Content in a High-Fat and Choline-Deficient Diet on Body Weight Gain and the Development of Non-Alcoholic Steatohepatitis in Mice

    PubMed Central

    Chiba, Tsuyoshi; Suzuki, Sachina; Sato, Yoko; Itoh, Tatsuki; Umegaki, Keizo

    2016-01-01

    Aim Non-alcoholic steatohepatitis (NASH) is a globally recognized liver disease. A methionine- and choline-deficient diet is used to induce NASH in mice; however, this diet also causes severe body weight loss. To resolve this issue, we examined the effects of methionine content in a high-fat and choline-deficient (HFCD) diet on body weight and the development of NASH in mice. Methods C57BL/6J mice (male, 10 weeks of age) were fed an L-amino acid rodent (control) diet, high-fat (HF) diet, or HFCD diet containing various amounts of methionine (0.1–0.6% (w/w)) for 12 weeks. Plasma lipid levels, hepatic lipid content and inflammatory marker gene expression were measured, and a pathological analysis was conducted to evaluate NASH. Results The 0.1% methionine in HFCD diet suppressed body weight gain, which was lower than that with control diet. On the other hand, the 0.2% methionine in HFCD diet yielded similar body weight gains as the control diet, while more than 0.4% methionine showed the same body weight gains as the HF diet. Liver weights and hepatic lipid contents were the greatest with 0.1% methionine and decreased in a methionine dose-dependent manner. Pathological analysis, NAFLD activity scores and gene expression levels in the liver revealed that 0.1% and 0.2% methionine for 12 weeks induced NASH, whereas 0.4% and 0.6% methionine attenuated the induction of NASH by HFCD diet. However, the 0.2% methionine in HFCD diet did not induce insulin resistance, despite the body weight gain. Conclusions The 0.2% methionine in HFCD diet for 12 weeks was able to induce NASH without weight loss. PMID:27723801

  20. Evaluation of Methionine Content in a High-Fat and Choline-Deficient Diet on Body Weight Gain and the Development of Non-Alcoholic Steatohepatitis in Mice.

    PubMed

    Chiba, Tsuyoshi; Suzuki, Sachina; Sato, Yoko; Itoh, Tatsuki; Umegaki, Keizo

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is a globally recognized liver disease. A methionine- and choline-deficient diet is used to induce NASH in mice; however, this diet also causes severe body weight loss. To resolve this issue, we examined the effects of methionine content in a high-fat and choline-deficient (HFCD) diet on body weight and the development of NASH in mice. C57BL/6J mice (male, 10 weeks of age) were fed an L-amino acid rodent (control) diet, high-fat (HF) diet, or HFCD diet containing various amounts of methionine (0.1-0.6% (w/w)) for 12 weeks. Plasma lipid levels, hepatic lipid content and inflammatory marker gene expression were measured, and a pathological analysis was conducted to evaluate NASH. The 0.1% methionine in HFCD diet suppressed body weight gain, which was lower than that with control diet. On the other hand, the 0.2% methionine in HFCD diet yielded similar body weight gains as the control diet, while more than 0.4% methionine showed the same body weight gains as the HF diet. Liver weights and hepatic lipid contents were the greatest with 0.1% methionine and decreased in a methionine dose-dependent manner. Pathological analysis, NAFLD activity scores and gene expression levels in the liver revealed that 0.1% and 0.2% methionine for 12 weeks induced NASH, whereas 0.4% and 0.6% methionine attenuated the induction of NASH by HFCD diet. However, the 0.2% methionine in HFCD diet did not induce insulin resistance, despite the body weight gain. The 0.2% methionine in HFCD diet for 12 weeks was able to induce NASH without weight loss.

  1. Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet.

    PubMed

    Nakagami, Hironori; Shimamura, Munehisa; Miyake, Takashi; Shimosato, Takashi; Minobe, Noriko; Moritani, Toshinori; Kiomy Osako, Mariana; Nakagami, Futoshi; Koriyama, Hiroshi; Kyutoku, Mariko; Shimizu, Hideo; Katsuya, Tomohiro; Morishita, Ryuichi

    2012-01-01

    Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.

  2. Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

    PubMed

    Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

    2016-06-01

    We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

  3. Influence of nicotine on choline-deficient, L-amino acid-defined diet-induced non-alcoholic steatohepatitis in rats.

    PubMed

    Kanamori, Hiroyuki; Nakade, Yukiomi; Yamauchi, Taeko; Sakamoto, Kazumasa; Inoue, Tadahisa; Yamamoto, Takaya; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sumida, Yoshio; Nakao, Haruhisa; Fukuzawa, Yoshitaka; Yoneda, Masashi

    2017-01-01

    Nicotine, a major compound in cigarette smoke, decreases food intake and body weight gain in mammals; however, the influence of nicotine on the progression of non-alcoholic steatohepatitis (NASH) remains controversial. This study aimed to investigate the effect of nicotine on NASH in rat models. Male Wistar rats were fed choline-deficient, l-amino acid-defined (CDAA) diet and treated with nicotine or saline. Food intake, body weight gain, presence of hepatic steatosis, inflammation, and fibrosis were assessed 6 weeks after the rats were fed CDAA diet. Hepatic branch vagotomy was performed to elucidate the mechanism through which nicotine affected steatohepatitis. CDAA diet induced hepatic steatosis, inflammation, and fibrosis, as well as increased the expression of inflammation-related genes. Conversely, nicotine significantly attenuated food intake, body weight gain, and inhibited the CDAA-diet-induced hepatic steatosis, inflammation, and fibrosis, together with increased expression of inflammation-related genes. Hepatic branch vagotomy by itself decreased food intake, body weight gain, and attenuated the CDAA-diet-induced hepatic steatosis, but not inflammation. However, nicotine did not change the food intake, body weight gain, and CDAA diet-induced hepatic steatosis and inflammation in vagotomized rats. These results suggest that nicotine attenuates the CDAA-diet-induced hepatic steatosis and inflammation through the hepatic branch of the vagus nerve in rats.

  4. Cellular cholesterol accumulation modulates high fat high sucrose (HFHS) diet-induced ER stress and hepatic inflammasome activation in the development of non-alcoholic steatohepatitis.

    PubMed

    Bashiri, Amir; Nesan, Dinushan; Tavallaee, Ghazaleh; Sue-Chue-Lam, Ian; Chien, Kevin; Maguire, Graham F; Naples, Mark; Zhang, Jing; Magomedova, Lilia; Adeli, Khosrow; Cummins, Carolyn L; Ng, Dominic S

    2016-07-01

    Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Connexin32 deficiency is associated with liver injury, inflammation and oxidative stress in experimental non-alcoholic steatohepatitis.

    PubMed

    Tiburcio, Taynã Cristina; Willebrords, Joost; da Silva, Tereza Cristina; Pereira, Isabel Veloso Alves; Nogueira, Marina Sayuri; Crespo Yanguas, Sara; Maes, Michaël; Silva, Elisangela Dos Anjos; Dagli, Maria Lucia Zaidan; de Castro, Inar Alves; Oliveira, Cláudia Pinto; Vinken, Mathieu; Cogliati, Bruno

    2017-02-01

    Non-alcoholic steatohepatitis is a highly prevalent liver pathology featured by hepatocellular fat deposition and inflammation. Connexin32, which is the major building block of hepatocellular gap junctions, has a protective role in hepatocarcinogenesis and is downregulated in chronic liver diseases. However, the role of connexin32 in non-alcoholic steatohepatitis remains unclear. Connexin32(-/-) mice and their wild-type littermates were fed a choline-deficient high-fat diet. The manifestation of non-alcoholic steatohepatitis was evaluated based on a battery of clinically relevant read-outs, including histopathological examination, diverse indicators of inflammation and liver damage, in-depth lipid analysis, assessment of oxidative stress, insulin and glucose tolerance, liver regeneration and lipid-related biomarkers. Overall, more pronounced liver damage, inflammation and oxidative stress were observed in connexin32(-/-) mice compared to wild-type animals. No differences were found in insulin and glucose tolerance measurements and liver regeneration. However, two lipid-related genes, srebf1 and fabp3, were upregulated in Cx32(-/-) mice in comparison with wild-type animals. These findings suggest that connexin32-based signalling is not directly involved in steatosis as such, but rather in the sequelae of this process, which underlie progression of non-alcoholic steatohepatitis.

  6. Review article: novel methods for the treatment of non-alcoholic steatohepatitis - targeting the gut immune system to decrease the systemic inflammatory response without immune suppression.

    PubMed

    Ilan, Y

    2016-12-01

    The systemic immune system plays a role in inflammation and fibrogenesis associated with non-alcoholic steatohepatitis (NASH) and has become a potential target for drug development. In particular, the gut immune system has been suggested as a means for generating signals that can target the systemic immune system. To describe seven novel methods being developed for the treatment of NASH that target the gut immune system for alleviation of the systemic inflammatory response, including oral administration of fatty-liver-derived proteins, anti-CD3 antibodies, tumour necrosis factor fusion protein, anti-lipopolysaccharide antibodies, glucosylceramide, delayed-release mercaptopurine, and soy-derived extracts. A search for these methods for oral immunotherapy for NASH was conducted. Oral administration of these compounds provides an opportunity for immune modulation without immune suppression, with the advantage of being independent of a single molecular/inflammatory pathway. These modes of oral immune therapy demonstrate superior safety profiles, such that the patient is not exposed to general immune suppression. Moreover, these approaches target the whole spectrum of the disease and may serve as adjuvants to other therapies, such that they provide a platform for treatment of concomitant disorders in patients with NASH, including diabetes and hyperlipidaemia. Most of the compounds reviewed are currently in phase II trials, and it is anticipated that the acquisition of more clinical data in the next few years will enable the use of this new class of drugs for the treatment of NASH. Oral immunotherapy may provide a novel platform for the treatment of NASH. © 2016 The Author. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

  7. Alisol B 23-acetate protects against non-alcoholic steatohepatitis in mice via farnesoid X receptor activation

    PubMed Central

    Meng, Qiang; Duan, Xing-ping; Wang, Chang-yuan; Liu, Zhi-hao; Sun, Peng-yuan; Huo, Xiao-kui; Sun, Hui-jun; Peng, Jin-yong; Liu, Ke-xin

    2017-01-01

    Alisol B 23-acetate (AB23A) is a natural triterpenoid isolated from the traditional Chinese medicine rhizoma alismatis, which exhibits a number of pharmacological activities, including anti-hepatitis virus, anti-cancer and antibacterial effects. In this study we examined whether AB23A protected against non-alcoholic steatohepatitis (NASH) in mice, and the mechanisms underlying the protective effects. NASH was induced in mice fed a methionine and choline-deficient (MCD) diet for 4 weeks. The mice were simultaneously treated with AB23A (15, 30, and 60 mg·kg−1·d−1, ig) for 4 weeks. On the last day, blood samples and livers were collected. Serum liver functional enzymes, inflammatoru markers were assessed. The livers were histologically examined using H&E, Oil Red O, Masson's trichrome and Sirius Red staining. Mouse primary hepatocytes were used for in vitro experiments. The mechanisms underlying AB23A protection were analyzed using siRNA, qRT-PCR, and Western blot assays. AB23A treatment significantly and dose-dependently decreased the elevated levels of serum ALT and AST in MCD diet-fed mice. Furthermore, AB23A treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration and hepatic fibrosis in the mice. AB23A-induced decreases in serum and hepatic lipids were related to decreased hepatic lipogenesis through decreasing hepatic levels of SREBP-1c, FAS, ACC1 and SCD1 and increased lipid metabolism via inducing PPARα, CPT1α, ACADS and LPL. The reduction in inflammatory cell infiltration corresponded to deceased serum levels of mKC and MCP-1 and decreased hepatic gene expression of MCP-1 and VCAM-1. The reduction in hepatic fibrosis was correlated with decreased hepatic gene expression of fibrosis markers. The protective effects of AB23A were FXR-dependent, because treatment with the FXR agonist CDCA mimicked AB23A-induced hepato-protection in the mice, whereas co-administration of FXR antagonist guggulsterone abrogated AB23A

  8. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.

    PubMed

    Athyros, Vasilios G; Alexandrides, Theodore K; Bilianou, Helen; Cholongitas, Evangelos; Doumas, Michael; Ganotakis, Emmanuel S; Goudevenos, John; Elisaf, Moses S; Germanidis, Georgios; Giouleme, Olga; Karagiannis, Asterios; Karvounis, Charalambos; Katsiki, Niki; Kotsis, Vasilios; Kountouras, Jannis; Liberopoulos, Evangelos; Pitsavos, Christos; Polyzos, Stergios; Rallidis, Loukianos S; Richter, Dimitrios; Tsapas, Apostolos G; Tselepis, Alexandros D; Tsioufis, Konstantinos; Tziomalos, Konstantinos; Tzotzas, Themistoklis; Vasiliadis, Themistoklis G; Vlachopoulos, Charalambos; Mikhailidis, Dimitri P; Mantzoros, Christos

    2017-06-01

    Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause

  9. Epigallocatechin gallate attenuates experimental non-alcoholic steatohepatitis induced by high fat diet.

    PubMed

    Kuzu, Nalan; Bahcecioglu, Ibrahim Halil; Dagli, Adile Ferda; Ozercan, Ibrahim Hanifi; Ustündag, Bilal; Sahin, Kazim

    2008-08-01

    In the present study, we examined the preventive role of epigallocatechin gallate (EGCG) in an experimental non-alcoholic steatohepatitis model induced by a high fat diet. The study included 21 male Sprague-Dawley rats, which were equally divided into three groups. The first group was fed on a standard rat diet, the second group on a high fat diet (HFD), and the third group on a HFD + EGCG. The study concluded after 6 weeks. Histopathological examination was performed. Plasma and tissue MDA levels, glucose, insulin, alanine aminotransferase (ALT), aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, triglyceride, and cholesterol levels were studied. Insulin resistance was calculated by the homeostasis model of insulin resistance method. Steatosis, inflammation, ballooning degeneration, and necrosis increased significantly in the HFD group, compared to the control group (P < 0.01). Steatosis and inflammation decreased in the HFD + EGCG group, in comparison to the HFD group (P < 0.05, for each). There was a significant decline in ALT (P < 0.01), triglyceride (P < 0.01), insulin (P < 0.05), and glucose (P < 0.05) levels in the HFD + EGCG group, when compared to the HFD group. Plasma and liver MDA levels in the HFD + EGCG group were lower than those of the HFD group; the difference was significant (P < 0.01 for each). Glutathione levels in the HFD + EGCG group was significantly higher those in the HFD group. CYP 2E1 and alpha-smooth muscle actin expression decreased in the HFD + EGCG group, in comparison to the HFD group (P < 0.01, P < 0.05, respectively). EGCG reduces the development of experimental non-alcoholic steatohepatitis induced by a high fat diet. It seems to exercise this effect through its effect on lipid metabolism and antioxidant characteristics.

  10. Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats

    PubMed Central

    Wang, Jian-qing; Zou, Yu-hong; Huang, Cheng; Lu, Chao; Zhang, Lei; Jin, Yong; Lü, Xiong-wen; Liu, Li-ping; Li, Jun

    2012-01-01

    Aim: To study the protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. Methods: Male Sprague-Dawley rats were given a high-fat diet for 10 weeks. The rats were administered tiopronin (20 mg/kg) or a positive control drug ursodeoxycholic acid (UDCA, 15 mg/kg) via gavage daily from week 5 to week 10. After the rats were sacrificed, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and liver homogenate FFA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial analysis kits. The expression levels of CYP2E1 mRNA and protein were determined using RT-PCR and immunoblot assays, respectively. Results: Tiopronin significantly lowered both the serum ALT and AST levels, while only the serum ALT level was lowered by UDCA. Tiopronin significantly decreased the serum and liver levels of TG, TC and FFA as well as the serum LDL-C level, and increased the serum HDL-C level, while UDCA decreased the serum and liver TC levels as well as the serum LDL-C level, but did not change the serum levels of TG, FFA and HDL-C. Tiopronin apparently ameliorated the hepatocyte degeneration and the infiltration of inflammatory cells in the livers, but UDCA did not affect the pathological features of the livers. Both tiopronin and UDCA ameliorated the mitochondrial abnormality in the livers. The benefits of tiopronin were associated with increased SOD and GSH-Px activities, and with decreased MDA activity and CYP2E1 expression in the livers. Conclusion: Tiopronin exerts protective effects against non-alcoholic steatohepatitis in rats, which may be associated with its antioxidant properties and regulation of lipid metabolism. PMID:22543705

  11. Use of Non-Invasive Parameters of Non-Alcoholic Steatohepatitis and Liver Fibrosis in Daily Practice - An Exploratory Case-Control Study

    PubMed Central

    Sroubkova, Renata; Lenicek, Martin; Smid, Vaclav; Haluzik, Martin; Bruha, Radan

    2014-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of a metabolic syndrome. To date, liver biopsy has been the gold standard used to differentiate between simple steatosis and steatohepatitis/fibrosis. Our aim was to compare the relevance of serum non-invasive parameters and scoring systems in the staging of liver fibrosis and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. Methods and Findings A total of 112 consecutive patients diagnosed with NAFLD were included. A liver biopsy was performed on 56 patients. The Kleiner score was used for the staging and grading of the histology. Non-invasive parameters for fibrosis (hyaluronic acid; AST/ALT; fibrosis scoring indexes OELF, ELF, BARD score, APRI, NAFLD fibrosis score); and inflammation (M30 and M65 cytokeratin-18 fragments) were measured and calculated. The same analyses were performed in 56 patients diagnosed with NAFLD, who were not indicated for liver biopsy. Based on the liver histology, NASH was diagnosed in 38 patients; simple steatosis in 18 patients. A cut-off value of 750 U/L of serum M65 discriminated patients with and without NASH with a 80% sensitivity and 82% specificity (95% CI:57–95). Fibrosis stage F0–F2 was present in 39 patients; F3–F4 in 17 patients. Serum concentrations of hyaluronic acid were higher in patients with advanced fibrosis (p<0.01); a cut-off value of 25 µg/l discriminated patients with F3–F4 with a 90% sensitivity and 84% specificity from those with F0–F2 (95% CI:59–99). When applying the non-invasive criteria to those patients without a liver biopsy, NASH could only be diagnosed in 16%; however, advanced fibrosis could be diagnosed in 35% of them. Conclusions In patients with NAFLD, non-invasive serum parameters with a high accuracy can differentiate those patients with NASH and/or advanced fibrosis from those with simple steatosis. A substantial portion of those patients not indicated for liver biopsy might have undiagnosed

  12. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

    PubMed Central

    Anstee, Quentin M; Goldin, Robert D

    2006-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis. PMID:16436109

  13. Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

    2012-03-01

    The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities.

  14. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis.

    PubMed

    Barreyro, Fernando J; Holod, Silvia; Finocchietto, Paola V; Camino, Alejandra M; Aquino, Jorge B; Avagnina, Alejandra; Carreras, María C; Poderoso, Juan J; Gores, Gregory J

    2015-03-01

    Hepatocyte apoptosis, the hallmark of non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan. Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-β, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Morbidly obese patient with non-alcoholic steatohepatitis-related cirrhosis who died from sepsis caused by dental infection of Porphyromonas gingivalis: A case report.

    PubMed

    Omura, Yuno; Kitamoto, Mikiya; Hyogo, Hideyuki; Yamanoue, Takao; Tada, Yoshihiro; Boku, Noriko; Nishisaka, Takashi; Miyauchi, Mutsumi; Takata, Takashi; Chayama, Kazuaki

    2016-03-01

    Non-alcoholic steatohepatitis (NASH) is associated with increased risks of developing lifestyle-related diseases including type 2 diabetes, cardiovascular disease and cerebral vessel disease. While the two-hit hypothesis and, recently, multiple parallel hits hypothesis of NASH pathogenesis were proposed, further details have not emerged. Recently, dental infection of Porphyromonas gingivalis (P. gingivalis) has been reported as a critical risk factor for NASH progression, which acts as multiple parallel hits to induce inflammation and fibrogenic responses in steatosis. We describe here a 54-year-old woman who died from sepsis and was diagnosed with NASH. Briefly, her body mass index (BMI) at the age of 35 years old had been 25.6 kg/m(2) , but she became obese after withdrawing into her home at the age of 45 years. Severe obesity continued over 19 years without diabetes mellitus. She was admitted to our hospital due to a sudden disturbance of consciousness. On admission, her BMI was 48.5 kg/m(2) . Computed tomography revealed cirrhotic liver with massive ascites, and laboratory data indicated increased inflammatory responses, renal failure and C grade Child-Pugh classification, suggesting the diagnosis of sepsis. Also, severe periodontal disease was present, because the patient's front teeth fell out easily during intubation. Although the focus of infection was not specified, the oral flora Parvimonas micra, a periodontal pathogen, was detected in venous blood. In spite of intensive care including artificial respiration management and continuous hemodiafiltration, she died on the 43rd day after admission. Surprisingly, P. gingivalis was detected in her hepatocytes. This case may represent the significance of P. gingivalis in the progress to cirrhosis in NASH patients.

  16. Nitrosamine exposure exacerbates high fat diet-mediated type 2 diabetes mellitus, non-alcoholic steatohepatitis, and neurodegeneration with cognitive impairment

    PubMed Central

    2009-01-01

    Background The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods. Results NDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone. Conclusions Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics. PMID:20034403

  17. Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms.

    PubMed

    Ji, Guiyuan; Yang, Qinhe; Hao, Jing; Guo, Lina; Chen, Xiang; Hu, Jianping; Leng, Liang; Jiang, Zhuoqin

    2011-06-01

    Genistein is a naturally occurring plant-derived phytoestrogen present in the human diet, and is known to possess anti-cancer, anti-oxidant and anti-osteoporosis effects. Anti-inflammatory activity of genistein has been revealed in animal studies. In this paper, we investigated the anti-inflammatory effect of genistein on non-alcoholic steatohepatitis (NASH) rats induced by high fat diet (HFD), and explored its potential mechanisms. Rats were fed with normal chow diet or HFD for 12 weeks with or without low (4 mg/kg/day body weight) or high (8 mg/kg/day body weight) dose of genistein. Serum levels of aminotransferases, thiobarbituric acid-reactive substances (TBARS), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor beta (TGF-β(1)) were measured, hepatic inflammation, liver TBARS, IL-6, TNF-α and TGF-β(1) levels were determined, and proteins involved in mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways were assayed. The results showed that the NASH model rats reproduced typical pathogenetic and histopathological features of NASH in human, and genistein administration improved liver function, slowed down NASH progression, decreased the levels of TBARS, TNF-α and IL-6 in serum and liver, as well as inhibited IκB-α phosphorylation, nuclear translocation of NF-κB p65 subunit, and activation of c-Jun N-terminal kinase (JNK). In conclusion, genistein may be a promising drug to inhibit the inflammatory process and prevent liver damage in patients with NASH. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Camel milk ameliorates steatohepatitis, insulin resistance and lipid peroxidation in experimental non-alcoholic fatty liver disease

    PubMed Central

    2013-01-01

    Background Camel milk (CM) is gaining increasing recognition due to its beneficial effects in the control and prevention of multiple health problems. The current study aimed to investigate the effects of CM on the hepatic biochemical and cellular alterations induced by a high-fat, cholesterol-rich diet (HCD), specifically, non-alcoholic fatty liver disease (NAFLD). Methods Seventy male Wistar rats were divided into four groups: the Control (C) Group fed a standard diet; the Control + camel milk (CCM) Group fed a standard diet and CM, the Cholesterol (Ch) Group fed a HCD with no CM, and the Cholesterol + camel milk (ChM) Group fed a HCD and CM. The following parameters were investigated in the studied groups; basal, weekly random and final fasting blood glucose levels, intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT), serum insulin, serum lipids, liver functions, lipid peroxidation products, the antioxidant activity of catalase (CAT) and the levels of reduced glutathione (GSH). In addition, HOMA-IR as an index of insulin resistance (IR) and the histopathology of the hepatic tissue were assessed. Results The Ch Group developed features similar to those of non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis; inflammatory cellular infiltration in liver tissue; altered liver functions; and increased total cholesterol, triglycerides, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, atherogenic index (AI), blood glucose, IR, and malondialdehyde (MDA) levels. Additionally, feeding the HCD to animals in the Ch Group decreased CAT activity and the GSH and high-density lipoprotein (HDL) cholesterol levels. Camel milk intake for eight weeks decreased hepatic fat accumulation and inflammatory cellular infiltration, preserved liver function, increased the GSH levels and CAT activity, decreased the MDA levels, and ameliorated the changes in the lipid profile, AI, and IR in animals from the Ch

  19. Elevation of liver endoplasmic reticulum stress in a modified choline-deficient l-amino acid-defined diet-fed non-alcoholic steatohepatitis mouse model.

    PubMed

    Muraki, Yo; Makita, Yukimasa; Yamasaki, Midori; Amano, Yuichiro; Matsuo, Takanori

    2017-05-06

    Endoplasmic reticulum (ER) stress caused by accumulation of misfolded proteins is observed in several kinds of diseases. Since ER stress is reported to be involved in the progression of non-alcoholic steatohepatitis (NASH), highly sensitive and simple measurement methods are required for research into developing novel therapy for NASH. To investigate the involvement of ER stress in NASH pathogenesis in a mouse model, an assay for liver ER stress was developed using ER stress activated indicator-luciferase (ERAI-Luc) mice. To establish the assay method for detection of ER stress in the liver, tunicamycin (TM) (0.3 mg/kg i. p.) was administered to ERAI-Luc mice, and the luciferase activity was measured in ex vivo and in vivo. To evaluate ER stress in the NASH model, ERAI-Luc mice were fed a modified choline-deficient l-amino acid-defined (mCDAA) diet for 14 weeks. After measurement of ER stress by luminescence imaging, levels of liver lipids and pro-fibrotic and pro-inflammatory gene expression were measured as NASH-related indexes. In non-invasive whole-body imaging, TM elevated luciferase activity in the liver, induced by activation of ER stress. The highest luminescence in the liver was confirmed by ex vivo imaging of isolated tissues. In parallel with progression of NASH, elevated luminescence induced by ER stress in liver was observed in mCDAA diet-fed ERAI-Luc mice. Luciferase activity was significantly and positively correlated to levels of triglyceride and free cholesterol in the liver, as well as to the mRNA expression of type 1 collagen α1 chain and tumor necrosis factor α. These data indicated that the use of ERAI-Luc mice was effective in the detection of ER stress in the liver. Moreover, the NASH model using ERAI-Luc mice can be a useful tool to clarify the role of ER stress in pathogenesis of NASH and to evaluate effects of drugs targeted against ER stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Trypanosoma cruzi Infection Is a Potent Risk Factor for Non-alcoholic Steatohepatitis Enhancing Local and Systemic Inflammation Associated with Strong Oxidative Stress and Metabolic Disorders

    PubMed Central

    Onofrio, Luisina I.; Arocena, Alfredo R.; Paroli, Augusto F.; Cabalén, María E.; Andrada, Marta C.; Cano, Roxana C.; Gea, Susana

    2015-01-01

    Background The immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH), and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood. Methodology/Principal Findings We evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficient mice fed with a standard, low fat diet, LFD (3% fat) as control group, or a medium fat diet, MFD (14% fat) in order to induce NASH, or mice infected intraperitoneally with 100 blood-derived trypomastigotes of Tulahuen strain and also fed with LFD (I+LFD) or MFD (I+MFD) for 24 weeks. We demonstrated that MFD by itself was able to induce NASH in WT mice and that parasitic infection induced marked metabolic changes with reduction of body weight and steatosis revealed by histological studies. The I+MFD group also improved insulin resistance, demonstrated by homeostasis model assessment of insulin resistance (HOMA-IR) analysis; although parasitic infection increased the triglycerides and cholesterol plasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cells showed intracellular inflammatory cytokines which were associated with high levels of IL6, IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with an increase in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitment of hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and it was intensified by parasitic infection. These results were TLR4 signaling dependent. Flow cytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbated by parasitic infection in our NASH model. Conclusions We highlight that a medium fat diet by itself is able to induce steatohepatitis. Our results also suggest a synergic effect between damage associated with molecular patterns

  1. Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions.

    PubMed

    Kochi, Takahiro; Shimizu, Masahito; Terakura, Daishi; Baba, Atsushi; Ohno, Tomohiko; Kubota, Masaya; Shirakami, Yohei; Tsurumi, Hisashi; Tanaka, Takuji; Moriwaki, Hisataka

    2014-01-01

    Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin-angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST-P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non-obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial.

    PubMed

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-11-04

    Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m(2)) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. The protocol was approved by the National Research Ethics Service (East Midlands-Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is

  3. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

    PubMed Central

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-01-01

    Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52

  4. Development of poly(vinyl acetate-methylacrylic acid)/chitosan/Fe3O4 nanoparticles for the diagnosis of non-alcoholic steatohepatitis with magnetic resonance imaging.

    PubMed

    Luo, Xiadan; Song, Xiaoli; Zhu, Aiping; Si, Yunfeng; Ji, Lijun; Ma, Zhanrong; Jiao, Zhiyun; Wu, Jingtao

    2012-12-01

    Non-alcoholic steatohepatitis is a burgeoning health problem. To diagnose NASH with magnetic resonance imaging (MRI), an effective contrast agent, a stable suspension of superparamagnetic Fe(3)O(4) nanoparticles, were newly developed. The negatively charged Fe(3)O(4) nanoparticles were coated with positive chitosan (CS) firstly, and then assembled with poly(vinyl acetate-methylacrylic acid) (P(VAc-MAA)). Transmission electron microscope and dynamic light scattering confirmed that the obtained P(VAc-MAA)/CS/Fe(3)O(4) nanoparticles had a spherical or ellipsoidal morphology with an average diameter in the range of 14-20 nm. The superparamagnetic property and spinel structure of the Fe(3)O(4) nanoparticles were well preserved due to the protection of the P(VAc-MAA)/CS layers on the surface of the Fe(3)O(4) nanoparticles. The in vivo rat experiments confirmed that the P(VAc-MAA)/CS/Fe(3)O(4) nanoparticles were an effective contrast agent for MRI to diagnose NASH.

  5. Epidemiological Trends Strongly Suggest Exposures as Etiologic Agents in the Pathogenesis of Sporadic Alzheimer's Disease, Diabetes Mellitus, and Non-Alcoholic Steatohepatitis

    PubMed Central

    de la Monte, Suzanne M.; Neusner, Alexander; Chu, Jennifer; Lawton, Margot

    2015-01-01

    Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the “unbuilding” blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance. PMID:19363256

  6. Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: A pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis

    PubMed Central

    Bocca, Claudia; Foglia, Beatrice; Benetti, Elisa; Novo, Erica; Chiazza, Fausto; Rogazzo, Mara; Fantozzi, Roberto; Povero, Davide; Sutti, Salvatore; Bugianesi, Elisabetta; Feldstein, Ariel E.; Albano, Emanuele; Collino, Massimo; Parola, Maurizio

    2017-01-01

    Non-Alcoholic Fatty Liver Disease (NAFLD) is a major form of chronic liver disease in the general population in relation to its high prevalence among overweight/obese individuals and patients with diabetes type II or metabolic syndrome. NAFLD can progress to steatohepatitis (NASH), fibrosis and cirrhosis and end-stage of liver disease but mechanisms involved are still incompletely characterized. Within the mechanisms proposed to mediate the progression of NAFLD, lipotoxicity is believed to play a major role. In the present study we provide data suggesting that microvesicles (MVs) released by fat-laden cells undergoing lipotoxicity can activate NLRP3 inflammasome following internalization by either cells of hepatocellular origin or macrophages. Inflammasome activation involves NF-kB-mediated up-regulation of NLRP3, pro-caspase-1 and pro-Interleukin-1, then inflammasome complex formation and Caspase-1 activation leading finally to an increased release of IL-1β. Since the release of MVs from lipotoxic cells and the activation of NLRP3 inflammasome have been reported to occur in vivo in either clinical or experimental NASH, these data suggest a novel rational link between lipotoxicity and increased inflammatory response. PMID:28249038

  7. Anti-oxidative and anti-inflammatory effects of spirulina on rat model of non-alcoholic steatohepatitis

    PubMed Central

    Pak, Wing; Takayama, Fusako; Mine, Manaka; Nakamoto, Kazuo; Kodo, Yasumasa; Mankura, Mitsumasa; Egashira, Toru; Kawasaki, Hiromu; Mori, Akitane

    2012-01-01

    The pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear, but accumulating data suggest oxidative stress and the relationship between inflammation and immunity plays a crucial role. The aim of this study is to investigate the spirulina, which is a blue-green algae rich in proteins and other nutritional elements, and its component-phycocyanin effect on a rat model of NASH. NASH model rats were established by feeding male Wistar rats with choline-deficient high-fat diet (CDHF) and intermittent hypoxemia by sodium nitrite challenge after 5 weeks of CDHF. After experimental period of 10 weeks, blood and liver were collected to determine oxidative stress injuries and efficacies of spirulina or phycocyanin on NASH model rats. In the NASH model rats, increase in plasma liver enzymes and liver fibrosis, increases in productions of reactive oxygen species from liver mitochondria and from leukocytes, the activation of nuclear factor-kappa B, and the change in the lymphocyte surface antigen ratio (CD4+/CD8+) were observed. The spirulina and phycocyanin administration significantly abated these changes. The spirulina or phycocyanin administration to model rats of NASH might lessen the inflammatory response through anti-oxidative and anti-inflammatory mechanisms, breaking the crosstalk between oxidative stress and inflammation, and effectively inhibit NASH progression. PMID:23170052

  8. Role of Serum Biomarkers in Early Detection of Non-Alcoholic Steatohepatitis and Fibrosis in West Virginian Children.

    PubMed

    Sodhi, Komal; Bracero, Lucas; Feyh, Andrew; Nichols, Alexandra; Srikanthan, Krithika; Latif, Tariq; Preston, Deborah; Shapiro, Joseph I; Elitsur, Yoram

    2016-02-01

    Obesity, an epidemic among West Virginia children, as well as insulin resistance (IR), is well-established contributors to nonalcoholic steatohepatitis (NASH). Progression of NASH can lead to hepatic fibrosis and cirrhosis, making early detection imperative. The standard for diagnosing NASH is histologically via liver biopsy, which is highly invasive and generally contraindicated in children. By studying serum biomarkers associated with NASH, we aim to identify high risk children who can benefit from a less invasive, alternative approach to the early detection of NASH. Seventy one children were prospectively recruited and divided into 3 groups: normal weight without IR (control), obese without IR, and obese with IR. Serum samples were drawn for each patient and biomarker levels were assessed via ELISA kits. Obese without IR and obese with IR patients had significantly elevated levels of lipid metabolism and accumulation markers (FGF-21, NEFA, FATP5, ApoB), oxidative stress markers (dysfunctional HDL, 8-Isoprostane), inflammatory markers(dysfunctional HDL, CK-18) and apoptosis markers (CK-18) compared to control patients (p<0.02). Bilirubin (an antioxidant) was significantly decreased in the obese without IR and obese with IR patients compared to control (p<0.02). This study showed a correlation between obesity, IR, and biomarkers associated with NASH in pediatrics patients from West Virginia, with obese with IR patients showing the strongest correlation. These findings support the clinical application of these serum biomarkers as a less invasive method for early detection of NASH and hepatic fibrosis.

  9. Role of Serum Biomarkers in Early Detection of Non-Alcoholic Steatohepatitis and Fibrosis in West Virginian Children

    PubMed Central

    Sodhi, Komal; Bracero, Lucas; Feyh, Andrew; Nichols, Alexandra; Srikanthan, Krithika; Latif, Tariq; Preston, Deborah; Shapiro, Joseph I; Elitsur, Yoram

    2016-01-01

    Background Obesity, an epidemic among West Virginia children, as well as insulin resistance (IR), is well-established contributors to nonalcoholic steatohepatitis (NASH). Progression of NASH can lead to hepatic fibrosis and cirrhosis, making early detection imperative. The standard for diagnosing NASH is histologically via liver biopsy, which is highly invasive and generally contraindicated in children. By studying serum biomarkers associated with NASH, we aim to identify high risk children who can benefit from a less invasive, alternative approach to the early detection of NASH. Methods Seventy one children were prospectively recruited and divided into 3 groups: normal weight without IR (control), obese without IR, and obese with IR. Serum samples were drawn for each patient and biomarker levels were assessed via ELISA kits. Results Obese without IR and obese with IR patients had significantly elevated levels of lipid metabolism and accumulation markers (FGF-21, NEFA, FATP5, ApoB), oxidative stress markers (dysfunctional HDL, 8-Isoprostane), inflammatory markers(dysfunctional HDL, CK-18) and apoptosis markers (CK-18) compared to control patients (p<0.02). Bilirubin (an antioxidant) was significantly decreased in the obese without IR and obese with IR patients compared to control (p<0.02). Conclusion This study showed a correlation between obesity, IR, and biomarkers associated with NASH in pediatrics patients from West Virginia, with obese with IR patients showing the strongest correlation. These findings support the clinical application of these serum biomarkers as a less invasive method for early detection of NASH and hepatic fibrosis. PMID:27182456

  10. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH).

    PubMed

    Jindal, Aastha; Bruzzì, Stefania; Sutti, Salvatore; Locatelli, Irene; Bozzola, Cristina; Paternostro, Claudia; Parola, Maurizio; Albano, Emanuele

    2015-08-01

    Nonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine-choline deficient (MCD) diet up to 8weeks. In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat-laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-α) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolated macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80(+) cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size. We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses.

  11. A Vaccine Targeted at CETP Alleviates High Fat and High Cholesterol Diet-Induced Atherosclerosis and Non-Alcoholic Steatohepatitis in Rabbit

    PubMed Central

    Liaw, Yi-Wei; Lin, Chi-Yu; Lai, Yu-Sheng; Yang, Tzu-Chung; Wang, Chau-Jong; Whang-Peng, Jacqueline; Liu, Leroy F.; Lin, Chia-Po; Nieh, Shin; Lu, Shao-Chun; Hwang, Jaulang

    2014-01-01

    Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use. PMID:25486007

  12. A vaccine targeted at CETP alleviates high fat and high cholesterol diet-induced atherosclerosis and non-alcoholic steatohepatitis in rabbit.

    PubMed

    Liaw, Yi-Wei; Lin, Chi-Yu; Lai, Yu-Sheng; Yang, Tzu-Chung; Wang, Chau-Jong; Whang-Peng, Jacqueline; Liu, Leroy F; Lin, Chia-Po; Nieh, Shin; Lu, Shao-Chun; Hwang, Jaulang

    2014-01-01

    Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.

  13. Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway.

    PubMed

    Hur, Wonhee; Lee, Joon Ho; Kim, Sung Woo; Kim, Jung-Hee; Bae, Si Hyun; Kim, Minhyung; Hwang, Daehee; Kim, Young Seok; Park, Taesun; Um, Soo-Jong; Song, Byoung-Joon; Yoon, Seung Kew

    2015-07-01

    Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes. Although recent studies have shown that microRNAs play important roles in hepatic metabolic functions, the pivotal role of microRNAs in the progression of NAFLD is not fully understood. We investigated the functions of miR-451, which was identified as a target gene in the inflammatory process in NAFLD. miR-451 expression was significantly decreased in the palmitate (PA)-exposed HepG2 cells and in liver tissues of HFD-induced non-alcoholic steatohepatitis (NASH) mice. Its decreased expressions were also observed in liver specimens of NASH patients. In vitro analysis of the effect of miR-451 on proinflammatory cytokine provided evidence for negative regulation of PA-induced interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) production. Furthermore, miR-451 over-expression inhibited translocation of the PA-induced NF-κB p65 subunit into the nucleus. Our result showed that Cab39 is a direct target of miRNA-451 in steatotic cells. Further study showed that AMPK activated through Cab39 inhibits NF-κB transactivation induced in steatotic HepG2 cells. miR-451 over-expression in steatotic cells significantly suppressed PA-induced inflammatory cytokine. These results provide new insights into the negative regulation of miR-451 in fatty acid-induced inflammation via the AMPK/AKT pathway and demonstrate potential therapeutic applications for miR-451 in preventing the progression from simple steatosis to severely advanced liver disease.

  14. Ameliorative potential of omega 3 fatty acids and HMG-CoA reductase inhibitors on experimentally-induced non-alcoholic steatohepatitis.

    PubMed

    Kabel, Ahmed M; Abd Elmaaboud, Maaly A; Albarraq, Ahmed A

    2015-05-01

    Non-alcoholic steatohepatitis (NASH) has a relation to obesity. It may lead to hepatocellular carcinoma. To date, the therapeutic options are limited due to complex pathogenesis. This study aimed to investigate the effect of atorvastatin and omega 3 fatty acids on experimentally-induced NASH. Sixty male albino rats were divided into 6 equal groups; control group, high fat emulsion/sucrose (HFE/S) diet, HFE/S+carboxymethyl cellulose, HFE/S +Atorvastatin, HFE/S+Fish oil and HFE/S+Atorvastatin+Fish oil. Serum alanine aminotransferase, total cholesterol (TC), triglycerides (TG), high density lipoproteins, insulin, glucose, C-reactive protein and quantitative insulin sensitivity check index were measured. Also, hepatic TC, TG, malondialdehyde, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF-β1) were determined. Liver sections were examined histopathologically. Atorvastatin improved lipid profile, inflammation and oxidative stress but did not improve insulin resistance, hepatic TGF-β1 or body weight while fish oil improved lipid profile, decreased inflammation and oxidative stress, improved insulin resistance, hepatic TGF-β1 and body weight compared to HFE/S group. Atorvastatin/fish oil combination produced significant improvement in the lipid profile, inflammation, oxidative stress, insulin resistance, hepatic TGF-β1 and body weight compared to the use of each of these drugs alone. This might be attributed to the effect of fish oil on the lipid profile, inflammatory cytokines, insulin resistance and TGF-β1 which potentiates the effect of atorvastatin on NASH.

  15. Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice.

    PubMed

    Ganz, Michal; Bukong, Terence N; Csak, Timea; Saha, Banishree; Park, Jin-Kyu; Ambade, Aditya; Kodys, Karen; Szabo, Gyongyi

    2015-06-16

    Non-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple 'hits' have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger signals, inflammation, inflammasome activation and NAFLD progression. Male C57Bl/6 mice were fed a high fat diet with high cholesterol and a high sugar supplement (HF-HC-HSD) for 8, 27, and 49 weeks and the extent of steatosis, liver inflammation, fibrosis and tumor development were evaluated at each time point. The HF-HC-HSD resulted in liver steatosis at 8 weeks, progressing to steatohepatitis and early fibrosis at 27 weeks, and steatohepatitis, fibrosis, and tumor development at 49 weeks compared to chow diet. Steatohepatitis was characterized by increased levels of MCP-1, TNFα, IL-1β and increased liver NASH histological score. We found increased serum levels of sterile danger signals, uric acid and HMGB1, as early as 8 weeks, while endotoxin and ATP levels increased only after 49 weeks. Increased levels of these sterile and microbial danger signals paralleled upregulation and activation of the multiprotein complex inflammasome. At 27, 49 weeks of HF-HC-HSD, activation of M1 macrophages and loss of M2 macrophages as well as liver fibrosis were present. Finally, similar to human NASH, liver tumors occurred in 41% of mice in the absence of cirrhosis and livers expressed increased p53 and detectable AFP. HF-HC-HSD over 49 weeks induces the full spectrum

  16. High carbohydrate diet induces nonalcoholic steato-hepatitis (NASH) in a desert gerbil.

    PubMed

    Semiane, Nesrine; Foufelle, Fabienne; Ferré, Pascal; Hainault, Isabelle; Ameddah, Souad; Mallek, Aicha; Khalkhal, Ali; Dahmani, Yasmina

    2017-01-01

    A high intake of sugars has been linked to diet-induced health problems. The aim of this study was to assess whether the long-term consumption of a high-carbohydrate diet (HCD) would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH) in a desert gerbil, Gerbillus gerbillus. Compared to natural diet, HCD leads to several metabolic disorders including adiposity, dyslipidemia, insulin resistance, ectopic fat deposition in the liver, which were associated with higher levels of transcripts of genes involved with fat synthesis, endoplasmic reticulum (ER) stress, and fibrosis. In the same way, the experimented animals showed enhanced oxidative stress. Taken together, these results demonstrate that HCD consumption in gerbils induces metabolic disorders and damaged liver, which are key contributors to NASH development. These results suggest that this rodent represents a valuable natural model for human diet-induced metabolic disorders and nonalcoholic fatty liver disease (NAFLD).

  17. Treatment of experimental non-alcoholic steatohepatitis by targeting α7 nicotinic acetylcholine receptor-mediated inflammatory responses in mice.

    PubMed

    Zhou, Zhou; Liu, Ying-Chao; Chen, Xiao-Mei; Li, Fu-Qiang; Tong, Xiao-Juan; Ding, Yue-Ping; Tang, Cui-Lan

    2015-11-01

    Non‑alcoholic fatty liver disease (NAFLD) is one of the most common types of liver disease, affecting up to 30% of the general population worldwide. Non‑alcoholic steatohepatitis (NASH) is a severe form of NAFLD without any effective therapies available. The present study showed that activation of α7‑nicotinic acetylcholine receptor (α7 nAChR) may be a novel potential strategy for NASH therapy. Treatment with the α7 nAChR agonist nicotine for three weeks obviously attenuated hepatic steatosis in a high-fat diet‑induced mouse model of NASH. Investigation of the underlying mechanism showed that nicotine reduced the secretion of the pro‑inflammatory cytokines tumor necrosis factor α and interleukin 6 in vitro and in vivo. Inflammation is an integral part of NASH and is the most prevalent form of hepatic pathology found in the general population; therefore, the effect of α7 nAChR activation against NASH may be ascribed to its anti‑inflammatory effects. In addition, the present study showed that nicotine‑stimulated α7 nAChR activation led to a significant downregulation of nuclear factor kappa B (NK‑κB) and extracellular signal-regulated kinase (ERK). It therefore appeared that activation of α7 nAChR suppressed the production of pro‑inflammatory cytokines through NK‑κB and ERK pathways. In conclusion, the present study indicated that targeting α7 nAChR may represent a novel treatment strategy for NASH.

  18. [Non-alcoholic fatty liver disease (NAFLD)].

    PubMed

    Rau, Monika; Weiss, Johannes; Geier, Andreas

    2015-07-01

    Non-alcoholic fatty liver disease is the most common chronic liver disease in Europe and in the USA with rising prevalence. Patients with a metabolic syndrome (diabetes mellitus, obesity, dyslipidemia) are patients at risk with the highest prevalence for NAFLD. Progression from a non-alcoholic fatty liver (NAFL) to a non-alcoholic steatohepatitis (NASH) occurs in 5-20% of patients with the potential to develop a liver fibrosis/cirrhosis. NASH patients and NAFLD patients with higher fibrosis should be identified because they are at risk of a higher mortality. A specific treatment for NASH is not available at the moment. Therefore, the treatment of risk factors and metabolic syndrome has high priority.

  19. [Non-canonical Wnt signaling contributes to development of non-alcoholic steatohepatitis in a rat model of type 2 diabetes mellitus].

    PubMed

    Tian, Feng; Zhang, Ya-jie; Wang, Lin

    2013-07-01

    To investigate the role of the non-canonical Wnt signaling pathway in development of non-alcoholic steatohepatitis (NASH) related to type 2 diabetes mellitus (T2DM) using a rat model. Twenty-four male Sprague-Dawley rats were randomly divided into two equal groups: control group, fed a stand diet; T2DM-NASH model group, fed a high sucrose and fat diet for 4 weeks and intraperitoneally injected with streptozotocin (30 mg/kg). Twelve weeks after model establishment, all rats were sacrificed. Serum levels of glucose, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by biochemical analysis. Liver pathological changes were assessed microscopically by hematoxylin-eosin and oil red O staining. The liver expression of Wnt5a and NF-kB p65 were detected by immunohistochemistry and western blotting (protein), and quantitative real-time PCR (mRNA). The T2DM-NASH model group showed significantly higher levels of glucose (control group: 6.25 +/- 1.28 vs. 31.21 +/- 0.86 mmol/L, t = -36.204, P less than 0.01), ALT (31.00 +/- 3.69 vs. 301.50 +/- 8.62 U/L, t = -99.94, P less than 0.01), and AST (77.58 +/- 1.83 vs. 344.75 +/- 1.82 U/L, t = -358.85, P less than 0.01). The T2DM-NASH group also showed remarkable signs of steatosis and inflammation in hepatic tissues. The T2DM-NASH group had significantly higher integral optical density (IOD) detection of Wnt5a (control group: 1.15E4 +/- 577.45 vs. 4.04E5 +/- 2.42E4, t = -56.24, P less than 0.01) and NF-kB p65 (1.28E4 +/- 1.59E3 vs. 4.21E5 +/- 1.68E4, t = -83.895, P less than 0.01), as well as protein levels detected by western blot (Wnt5a: 4.21 +/- 0.34 vs. 1.00 +/- 0.25, t = 17.030, P less than 0.01; NF-kB p65: 4.93 +/- 0.76 vs. 1 +/- 0.13, t = 11.438, P less than 0.01). The hepatic mRNA levels followed the same trend (Wnt5a: 9.53 +/- 0.64 vs. 1.04 +/- 0.35, t = 20.165, P less than 0.01; NF-kB p65: 0.60 +/- 0.13 vs. 0.74 +/- 0.10, t = -1.802, P = 0.125). In the T2DM-NASH group, hepatic Wnt5a protein

  20. Impact of family history of metabolic traits on severity of non-alcoholic steatohepatitis related cirrhosis: A cross-sectional study.

    PubMed

    Bhadoria, Ajeet S; Kedarisetty, Chandan K; Bihari, Chhagan; Kumar, Guresh; Jindal, Ankur; Bhardwaj, Ankit; Shasthry, Varsha; Vyas, Tanmay; Benjamin, Jaya; Sharma, Shvetank; Sharma, Manoj K; Sarin, Shiv K

    2017-09-01

    Familial aggregation of metabolic traits with fatty liver disease is well documented. However, there is scarcity of data regarding such association with non-alcoholic steatohepatitis (NASH)-related cirrhosis. This study was aimed to explore the association of family history of metabolic traits with severity of cirrhosis. In a cross-sectional study, all consecutive patients with NASH-related cirrhosis presenting to our tertiary care centre were included. Family history, personal history, demographic characteristics, medical history, anthropometric measurements and laboratory data were recorded. Of the 1133 cirrhotics (68.1% males, age 51.4±10.9 years); 779 (68.8%) had family history for metabolic traits. These patients had lower age at diagnosis (45.4±10.6 vs 49.6±11.2 years), higher Child-Turcotte-Pugh (CTP) score (7.8±1.9 vs 6.6±1.5), higher model for end stage liver disease (MELD) score (12.9±6.1 vs 10.9±4.1) and more incidence of decompensation in the form of ascites (46.3% vs 25.7%), jaundice (12.1% vs 6.2%) and hepatic encephalopathy (26.1% vs 11.0%). Patients with family and personal history of metabolic traits, had an increased risk of an early diagnosis of cirrhosis at<45 years of age (OR: 3.1, 95% CI 2.1-4.4), CTP≥10 (OR: 4.6, 95% CI 2.3-9.1), MELD>15 (OR: 6.6, 95% CI 3.8-11.5) with ≥1 features of decompensation (OR: 4.2, 95% CI 2.9-6.1). Family history of diabetes alone, also had higher risk of cirrhosis with MELD>15 (OR: 4.3, 95% CI 2.4-5.3, P<.001). Family and personal history of metabolic traits are associated with early age at diagnosis of cirrhosis with more severity and decompensation and so, has a prognostic importance in NASH-related cirrhotics. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs).

    PubMed

    Okazaki, Isao; Noro, Takuji; Tsutsui, Nobuhiro; Yamanouchi, Eigoro; Kuroda, Hajime; Nakano, Masayuki; Yokomori, Hiroaki; Inagaki, Yutaka

    2014-06-27

    Nonalcoholic steatohepatitis (NASH) is emerging worldwide because life-styles have changed to include much over-eating and less physical activity. The clinical and pathophysiological features of NASH are very different from those of HBV- and HCV-chronic liver diseases. The prognosis of NASH is worse among those with nonalcoholic fatty liver diseases (NAFLD), and some NASH patients show HCC with or without cirrhosis. In the present review we discuss fibrogenesis and the relationship between fibrosis and HCC occurrence in NASH to clarify the role of MMPs and TIMPs in both mechanisms. Previously we proposed MMP and TIMP expression in the multi-step occurrence of HCC from the literature based on viral-derived HCC. We introduce again these expressions during hepatocarcinogenesis and compare them to those in NASH-derived HCC, although the relationship with hepatic stem/progenitor cells (HPCs) invasion remains unknown. Signal transduction of MMPs and TIMPs is also discussed because it is valuable for the prevention and treatment of NASH and NASH-derived HCC.

  2. [Non-alcoholic fatty liver disease in children and adolescents].

    PubMed

    Björklund, Jessica; Laursen, Tea Lund; Kazankov, Konstantin; Thomsen, Karen Louise; Hamilton-Dutoit, Stephen; Stenbøg, Elisabeth; Grønbæk, Henning

    2017-07-03

    Non-alcoholic fatty liver disease (NAFLD) is characterized by liver fat accumulation and non-alcoholic steatohepatitis (NASH) with inflammation and fibrosis, which may lead to cirrhosis also in childhood. NAFLD/NASH in children are related to obesity and the metabolic syndrome, and incidence and prevalence are expected to increase. Children having liver steatosis and elevated liver enzymes are most often asymptomatic, and a liver biopsy is necessary for correct diagnosis and staging. The treatment should focus on lifestyle changes, as pharmacological therapy needs further evaluation.

  3. The Role of Morbid Obesity in the Promotion of Metabolic Disruptions and Non-Alcoholic Steatohepatitis by Helicobacter Pylori

    PubMed Central

    Valladares, Silvia; López-Cano, Carolina; Gutiérrez, Liliana; Ciudin, Andreea; Fort, José Manuel; Reñé, Josep Maria; Matias-Guiu, Xavier; de Torres, Inés; Bueno, Marta; Pallarés, Judit; Baena, Juan Antonio

    2016-01-01

    Background Helicobacter pylory (HP) infection has been associated to an increased rate of type 2 diabetes (T2D) and liver disease through its effect on insulin resistance and systemic inflammation. However, results are inconstant and no studies exist in morbidly obese patients, in which both insulin resistance and inflammation coexist. Material and Methods Cross-sectional study to evaluate the relationship between HP infection and alterations in carbohydrate metabolism, lipid profile, inflammation markers, and liver disease in patients awaiting for bariatric surgery. HP infection was histologically assessed in gastric antrum biopsy from 416 subjects. Liver biopsy was also available in 93 subjects. Results Both impaired fasting glucose and T2D were similar when comparing subjects with and without HP infection (24.2% vs. 22%, p = 0.290 and 29.4% vs. 29.1%, p = 0.916, respectively), with no differences between groups in the HOMA-IR, lipid profile neither inflammatory parameters. However, HP infection was higher among subjects with a BMI ≥ 40.0 kg/m2 in comparison with lower degrees of obesity (71.7% vs. 60.0%, p = 0.041). In addition, subjects without HP infection showed higher degrees of steatosis (44.1±26.4% vs. 32.0±20.7%, p = 0.038), as well as a lower prevalence of non-alcoholic steatohepatitis (9.3% vs. 30.7%, p = 0.023). Conclusions In patients with morbid obesity, HP infection does not seem to be associated with abnormal carbohydrate metabolism. In addition, less advanced degrees of non-alcoholic fatty disease were observed. We suggest that low-grade inflammation that accompanies obesity mitigates the diabetogenic effect of HP, so the presence of obesity should be considered in studies that evaluate the HP metabolic effects. PMID:27893763

  4. The Role of Morbid Obesity in the Promotion of Metabolic Disruptions and Non-Alcoholic Steatohepatitis by Helicobacter Pylori.

    PubMed

    Lecube, Albert; Valladares, Silvia; López-Cano, Carolina; Gutiérrez, Liliana; Ciudin, Andreea; Fort, José Manuel; Reñé, Josep Maria; Matias-Guiu, Xavier; de Torres, Inés; Bueno, Marta; Pallarés, Judit; Baena, Juan Antonio

    2016-01-01

    Helicobacter pylory (HP) infection has been associated to an increased rate of type 2 diabetes (T2D) and liver disease through its effect on insulin resistance and systemic inflammation. However, results are inconstant and no studies exist in morbidly obese patients, in which both insulin resistance and inflammation coexist. Cross-sectional study to evaluate the relationship between HP infection and alterations in carbohydrate metabolism, lipid profile, inflammation markers, and liver disease in patients awaiting for bariatric surgery. HP infection was histologically assessed in gastric antrum biopsy from 416 subjects. Liver biopsy was also available in 93 subjects. Both impaired fasting glucose and T2D were similar when comparing subjects with and without HP infection (24.2% vs. 22%, p = 0.290 and 29.4% vs. 29.1%, p = 0.916, respectively), with no differences between groups in the HOMA-IR, lipid profile neither inflammatory parameters. However, HP infection was higher among subjects with a BMI ≥ 40.0 kg/m2 in comparison with lower degrees of obesity (71.7% vs. 60.0%, p = 0.041). In addition, subjects without HP infection showed higher degrees of steatosis (44.1±26.4% vs. 32.0±20.7%, p = 0.038), as well as a lower prevalence of non-alcoholic steatohepatitis (9.3% vs. 30.7%, p = 0.023). In patients with morbid obesity, HP infection does not seem to be associated with abnormal carbohydrate metabolism. In addition, less advanced degrees of non-alcoholic fatty disease were observed. We suggest that low-grade inflammation that accompanies obesity mitigates the diabetogenic effect of HP, so the presence of obesity should be considered in studies that evaluate the HP metabolic effects.

  5. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock?

    PubMed

    Chitturi, Shivakumar; Farrell, Geoffrey C; George, Jacob

    2004-04-01

    Clinicians in both the developed and also the newer industrial economies in the Asia-Pacific region will encounter non-alcoholic fatty liver disease (NAFLD) with increasing frequency. Although the region has been a significant contributor to the current state of knowledge, the spectrum of NAFLD, its severity and the potential for significant future morbidity and health costs are not widely recognized. Lifestyle changes, the epidemic of childhood and adult obesity and type 2 diabetes sweeping the Asia-Pacific represent the key substrates for the rising prevalence of NAFLD. Physicians in all disciplines need to be aware of clinical clues to the presence of NAFLD in the absence of other liver disease and in those with chronic viral hepatitis and they should be able to identify subsets at risk for liver-related morbidity. Given the scope of the problem, efforts should focus primarily on preventing or ameliorating the impact of risk factors; the key one is insulin resistance and its associates of diabetes and central obesity. Pharmacotherapy may play a role in selected individuals. A regional agenda for case definition, future study and public health initiatives is urgently required.

  6. The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis

    PubMed Central

    2011-01-01

    Introduction Mitochondrial dysfunction plays a central role in the general pathogenesis of non-alcoholic fatty liver disease (NAFLD), increasing the risk of developing steatosis and subsequent hepatocellular inflammation. We aimed to assess hepatic mitochondrial function by a non-invasive 13C-methionine breath test (MeBT) in patients with histologically proven NAFLD. Methods 118 NAFLD-patients and 18 healthy controls were examined by MeBT. Liver biopsy specimens were evaluated according to the NASH scoring system. Results Higher grades of NASH activity and fibrosis were independently associated with a significant decrease in cumulative 13C-exhalation (expressed as cPDR(%)). cPDR1.5h was markedly declined in patients with NASH and NASH cirrhosis compared to patients with simple steatosis or borderline diagnosis (cPDR1.5h: 3.24 ± 1.12% and 1.32 ± 0.94% vs. 6.36 ± 0.56% and 4.80 ± 0.88% respectively; p < 0.001). 13C-exhalation further declined in the presence of advanced fibrosis which was correlated with NASH activity (r = 0.36). The area under the ROC curve (AUROC) for NASH diagnosis was estimated to be 0.87 in the total cohort and 0.83 in patients with no or mild fibrosis (F0-1). Conclusion The 13C-methionine breath test indicates mitochondrial dysfunction in non-alcoholic fatty liver disease and predicts higher stages of disease activity. It may, therefore, be a valuable diagnostic addition for longitudinal monitoring of hepatic (mitochondrial) function in non-alcoholic fatty liver disease. PMID:21810560

  7. N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis

    USDA-ARS?s Scientific Manuscript database

    A "two-hit" model for non-alcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the "first hit" and sensitizes the liver to potential "second hits" resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, ...

  8. Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study.

    PubMed

    Miglio, F; Rovati, L C; Santoro, A; Setnikar, I

    2000-08-01

    In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective.

  9. Non-alcoholic Fatty liver disease in children.

    PubMed

    Singer, Cristina; Stancu, Polixenia; Coşoveanu, Simona; Botu, Alina

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children.

  10. Non-Alcoholic Fatty Liver Disease in Children

    PubMed Central

    SINGER, CRISTINA; STANCU, POLIXENIA; COŞOVEANU, SIMONA; BOTU, ALINA

    2014-01-01

    In the last years, there has been extremely much information which reveals an alarming increase of obesity in children and, at the same time, an increase of the incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD implies a wide range of affections starting from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH); the latter can evolve to cirrhosis and hepatic carcinoma. All these affections were noticed in children, too. The article presents data on the epidemiology, pathogeny, clinical and paraclinical findings, and treatment of NAFLD in children. PMID:25729601

  11. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

    PubMed Central

    Neuschwander-Tetri, Brent A; Loomba, Rohit; Sanyal, Arun J; Lavine, Joel E; Van Natta, Mark L; Abdelmalek, Manal F; Chalasani, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Hameed, Bilal; Kowdley, Kris V; McCullough, Arthur; Terrault, Norah; Clark, Jeanne M; Tonascia, James; Brunt, Elizabeth M; Kleiner, David E; Doo, Edward

    2015-01-01

    Summary Background The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Methods We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Findings Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group

  12. Prevalence and outcome of non-alcoholic fatty liver disease in adolescents and young adults undergoing weight loss surgery.

    PubMed

    Corey, K E; Stanley, T L; Misdraji, J; Scirica, C; Pratt, J; Hoppin, A; Misra, M

    2014-10-01

    We evaluated the prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in 27 adolescents referred for weight loss surgery (WLS). On biopsy, 18 patients (66.7%) had NAFLD, and of those, 10 (37.0%) had NASH and 11 (40.7%) had fibrosis. Insulin, HbA1C and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with NASH than those without NASH. Following WLS, 40% of patients with NASH had persistently elevated aminotransferase levels despite weight loss. We found that NASH is underdiagnosed in adolescents referred for WLS, and that hyperinsulinaemia, HOMA-IR and HbA1c can aid in identifying high-risk patients. © 2014 The Authors. Pediatric Obesity © 2014 International Association for the Study of Obesity.

  13. Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD).

    PubMed

    Doycheva, Iliana; Loomba, Rohit

    2014-01-01

    The key histologic feature of nonalcoholic steatohepatitis (NASH) is hepatocellular ballooning (HB). It plays an important role in NASH progression and is an independent predictor of liver mortality. In this review, we identified all studies using metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) that included pre- and post-treatment liver biopsies. We specifically reviewed the effects of metformin on HB. Improved HB was noted in pediatric populations and in those adult patients who were able to lose weight and improve or normalize transaminases during therapy. Previous studies have supported the beneficial effects of metformin in reduction of body weight, improvement of insulin resistance, prevention of complications related to diabetes and chemo-preventive benefits in reducing hepatocellular carcinoma. All these effects make it an attractive treatment consideration for patients with diabetes, and prediabetes who have co-existing NAFLD. Future studies are warranted in order to confirm this effect of metformin on HB and its association with improving long-term outcomes in patients with NAFLD.

  14. Early diagnosis of NAFLD-NASH transition using mid infrared spectroscopy.

    PubMed

    Bensaid, Siouar; Kachenoura, Amar; Costet, Nathalie; De Ledinghen, Victor; Vergniol, Julien; Laine, Fabrice; Turlin, Bruno; Tariel, Hugues; Senhadji, Lotfi

    2016-08-01

    Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of fat in the liver in the absence of excessive drinking of alcohol. Initially considered as benign and self-limited, NAFLD may progress to the malignant stage of non-alcoholic steatohepatitis (NASH) characterized by degenerate hepatocellular ballooning and lobular inflammation. NASH can lead to hepatic fibrosis and ultimately to cirrhosis and hepatocellular carcinoma. Unfortunately, the transition from NAFLD to NASH is difficult to detect so far. In this paper, we propose to evaluate the characterization of NASH using mid infrared fiber evanescent wave spectroscopy on blood serum. We used an heuristic variable selection method and a generalized linear model to classify NAFLD and NASH spectra. The obtained results proved that this technique is a promising non-invasive and simple diagnosis tool for NASH.

  15. Non-alcoholic fatty liver disease and childhood obesity.

    PubMed

    Mathur, Prashant; Das, Manoja K; Arora, Narendra K

    2007-04-01

    Obesity has emerged as a significant global health problem in the pediatric population. Pediatric liver disease is a serious complication of childhood obesity. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver--simple steatosis, NASH/ steatohepatitis--fat with in.ammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. The important message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.

  16. Nonalcoholic steatohepatitis is associated with increased hepatocyte apoptosis, JNK activation and Bax protein

    USDA-ARS?s Scientific Manuscript database

    High-fat diet enriched in omega-6 polyunsaturated fatty acids (PUFA) induces non-alcoholic steatohepatitis (NASH). The potential mechanisms involved in this process have not been defined. Male Sprague-Dawley rats were fed ad libitum Lieber-DeCarli diet at either 35% energy from fat (control) or 71% ...

  17. Spirulina improves non-alcoholic steatohepatitis, visceral fat macrophage aggregation, and serum leptin in a mouse model of metabolic syndrome.

    PubMed

    Fujimoto, Makoto; Tsuneyama, Koichi; Fujimoto, Takako; Selmi, Carlo; Gershwin, M Eric; Shimada, Yutaka

    2012-09-01

    Nutritional approaches are sought to overcome the limits of pioglitazone in metabolic syndrome and non-alcoholic fatty liver disease. Spirulina, a filamentous unicellular alga, reduces serum lipids and blood pressure while exerting antioxidant effects. To determine whether Spirulina may impact macrophages infiltrating the visceral fat in obesity characterizing our metabolic syndrome mouse model induced by the subcutaneous injection treatment of monosodium glutamate. Mice were randomized to receive standard food added with 5% Spirulina, 0.02% pioglitazone, or neither. We tested multiple biochemistry and histology (both liver and visceral fat) readouts at 24 weeks of age. Data demonstrate that both the Spirulina and the pioglitazone groups had significantly lower serum cholesterol and triglyceride levels and liver non-esterified fatty acid compared to untreated mice. Spirulina and pioglitazone were associated with significantly lower leptin and higher levels, respectively, compared to the control group. At liver histology, non-alcoholic fatty liver disease activity score and lipid peroxide were significantly lower in mice treated with Spirulina. Spirulina reduces dyslipidaemia in our metabolic syndrome model while ameliorating visceral adipose tissue macrophages. Human studies are needed to determine whether this safe supplement could prove beneficial in patients with metabolic syndrome. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  18. Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation.

    PubMed

    Aizawa, Koichi; Liu, Chun; Tang, Sanyuan; Veeramachaneni, Sudipta; Hu, Kang-Quan; Smith, Donald E; Wang, Xiang-Dong

    2016-09-01

    Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury. © 2016 UICC.

  19. Steatosis and Steatohepatitis: Complex Disorders

    PubMed Central

    Bettermann, Kira; Hohensee, Tabea; Haybaeck, Johannes

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) which includes steatosis and steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), is a rising health problem world-wide and should be separated from alcoholic steatohepatitis (ASH). NAFLD is regarded as hepatic manifestation of the metabolic syndrome (MetSy), being tightly linked to obesity and type 2 diabetes mellitus (T2DM). Development of steatosis, liver fibrosis and cirrhosis often progresses towards hepatocellular carcinogenesis and frequently results in the indication for liver transplantation, underlining the clinical significance of this disease complex. Work on different murine models and several human patients studies led to the identification of different molecular key players as well as epigenetic factors like miRNAs and SNPs, which have a promoting or protecting function in AFLD/ASH or NAFLD/NASH. To which extent they might be translated into human biology and pathogenesis is still questionable and needs further investigation regarding diagnostic parameters, drug development and a better understanding of the genetic impact. In this review we give an overview about the currently available knowledge and recent findings regarding the development and progression of this disease. PMID:24897026

  20. Cardiovascular assessment in liver transplant for non-alcoholic steatohepatitis patients: What we do, what we should do

    PubMed Central

    Sanchez-Torrijos, Yolanda; Ampuero, Javier; Romero-Gómez, Manuel

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is increasing considerably due to the current lifestyle, which means that it is becoming one of the main indications for liver transplantation. On the other hand, there is a strong association between NAFLD and cardiovascular disease. This has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness, leading to cardiovascular events and, ultimately, mortality. According to the liver transplant guidelines, screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years old. However, there are no specific recommendations in NAFLD patients requiring a liver transplantation, despite its well-known cardiovascular risk association. Many studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or nutritionists. Also, the incidence of cardiovascular disease is also increased in NAFLD patients in the post-transplantation period in comparison with other etiologies, because of the pre-existent risk factors together with the immunosuppressive therapy. Therefore, an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in NAFLD patients requiring a liver transplantation. PMID:28596817

  1. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer

    PubMed Central

    Asgharpour, Amon; Cazanave, Sophie C.; Pacana, Tommy; Seneshaw, Mulugeta; Vincent, Robert; Banini, Bubu A.; Kumar, Divya Prasanna; Daita, Kalyani; Min, Hae-Ki; Mirshahi, Faridoddin; Bedossa, Pierre; Sun, Xiaochen; Hoshida, Yujin; Koduru, Srinivas V.; Contaifer, Daniel; Warncke, Urszula Osinska; Wijesinghe, Dayanjan S.; Sanyal, Arun J.

    2016-01-01

    Background & Aims The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. Methods A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. Results Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4–8 weeks), steatohepatitis (16–24 weeks), progressive fibrosis (16 weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. Conclusions We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. Lay summary We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH. PMID:27261415

  2. Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model

    PubMed Central

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

    2016-01-01

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

  3. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis

    PubMed Central

    Alisi, A.; Bedogni, G.; Baviera, G.; Giorgio, V.; Porro, E.; Paris, C.; Giammaria, P.; Reali, L.; Anania, F.; Nobili, V.

    2014-01-01

    SUMMARY Background Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children. Aim We performed a double-blind RCT of VSL#3 vs. placebo in obese children with biopsy-proven NAFLD. Methods Of 48 randomised children, 44 (22 VSL#3 and 22 placebo) completed the study. The main outcome was the change in fatty liver severity at 4 months as detected by ultrasonography. Secondary outcomes were the changes in triglycerides, insulin resistance as detected by the homoeostasis model assessment (HOMA), alanine transaminase (ALT), body mass index (BMI), glucagon-like peptide 1 (GLP-1) and activated GLP-1 (aGLP-1). Ordinal and linear models with cluster confidence intervals were used to evaluate the efficacy of VSL#3 vs. placebo at 4 months. Results At baseline, moderate and severe NAFLD were present in 64% and 36% of PLA children and in 55% and 45% of VSL#3 children. The probability that children supplemented with VSL#3 had none, light, moderate or severe FL at the end of the study was 21%, 70%, 9% and 0% respectively with corresponding values of 0%, 7%, 76% and 17% for the placebo group (P < 0.001). No between-group differences were detected in triglycerides, HOMA and ALT while BMI decreased and GLP-1 and aGLP1 increased in the VSL#3 group (P < 0.001 for all comparisons). Conclusions A 4-month supplement of VSL#3 significantly improves NAFLD in children. The VSL#3-dependent GLP-1 increase could be responsible for these beneficial effects. Trial identifier: NCT01650025 (www.clinicaltrial.gov) PMID:24738701

  4. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    SciTech Connect

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  5. Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

    USDA-ARS?s Scientific Manuscript database

    Non-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated. Two independent studies were performed to...

  6. Obesity, insulin resistance, NASH and hepatocellular carcinoma.

    PubMed

    Yu, Jun; Shen, Jiayun; Sun, Ting Ting; Zhang, Xiang; Wong, Nathalie

    2013-12-01

    Epidemiological and clinical data have clearly demonstrated that non-alcoholic steatohepatitis (NASH) predisposes risk to the development of hepatocellular carcinoma (HCC). NASH is the liver manifestation of metabolic syndrome, which constellates obesity, insulin resistance and dyslipidemia. Although the percentage of patients diagnosed annually with NASH-associated HCC is still relatively low, this number signifies a large population due to the rapidly increasing incidence of obesity and diabetes globally. Fundamental studies on lipid storage, regulation of adipose factors, inflammatory cytokine recruitments and oxidative stress have provided insights into NASH as well as metabolic syndrome. Recent evidence also indicates the significant role of genetic factors in contributing to the pathogenesis of NASH and induced hepatic malignancy. In this review, we attempt to collate current research on NASH biology that lead to our understandings on how metabolic disorders may intersect with cancer development. We also discuss study models that have supported discoveries of molecular and cellular defects, and offered a perspective on therapeutic developments. These studies have collectively increased our knowledge on the complex signaling pathways involved in NASH and cancer, and provided the foundation for improved clinical management of patients with metabolic diseases.

  7. NASH: A global health problem.

    PubMed

    Sanyal, Arun J

    2011-07-01

    Non-alcoholic fatty liver disease (NAFLD) is a major public health problem both in the Western world and in the East. This is mainly due to the high prevalence of the disease and its effects on the individual with NAFLD. In the USA, it is estimated that approximately a third of the general population has NAFLD. Increasing age, obesity and the presence of multiple features of metabolic syndrome, especially diabetes, are associated with a higher probability of having non-alcoholic steatohepatitis (NASH). In the individual with NAFLD, excess hepatic fat is associated with an increased risk of developing diabetes, hypertension, cardiovascular events, abnormal resting electrocardiography and endothelial dysfunction. These findings have been corroborated in studies in teenagers as well as adults. There is also an increase in cardiovascular mortality, especially in those with NASH. In addition, there is an increased risk of death from a variety of non-hepatocellular cancers. From a liver perspective, NAFLD is associated with a 15-20% risk of progression to cirrhosis. The disease progresses more rapidly in those with diabetes, increasing age and obesity. The PNPLA3 gene mutation at position 148 is associated with not only steatosis, but with the likelihood of having steatohepatitis and increased inflammation and fibrosis. Once cirrhosis develops, the liver disease decompensates at the rate of 3-4% per year. NASH-related cirrhosis is a risk factor for hepatocellular cancer. All of these factors indicate that NAFLD is a common condition that has significant adverse health consequences for those who are afflicted. It is therefore a major public health hazard throughout the world.

  8. Nonalcoholic Fatty Liver Disease & NASH

    MedlinePlus

    ... liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Weight loss can reduce fat in the liver, inflammation, and fibrosis. No medicines have been approved to treat NAFLD and NASH. Eating, ... Clinical Trials The National Institute ...

  9. Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model.

    PubMed

    Takegoshi, Kai; Honda, Masao; Okada, Hikari; Takabatake, Riuta; Matsuzawa-Nagata, Naoto; Campbell, Jean S; Nishikawa, Masashi; Shimakami, Tetsuro; Shirasaki, Takayoshi; Sakai, Yoshio; Yamashita, Taro; Takamura, Toshinari; Tanaka, Takuji; Kaneko, Shuichi

    2017-02-13

    Oral supplementation with branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in patients with liver cirrhosis potentially suppresses the incidence of hepatocellular carcinoma (HCC) and improves event-free survival. However, the detailed mechanisms of BCAA action have not been fully elucidated. BCAA were administered to atherogenic and high-fat (Ath+HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice. Liver histology, tumor incidence, and gene expression profiles were evaluated. Ath+HF diet mice developed hepatic tumors at a high frequency at 68 weeks. BCAA supplementation significantly improved hepatic steatosis, inflammation, fibrosis, and tumors in Ath+HF mice at 68 weeks. GeneChip analysis demonstrated the significant resolution of pro-fibrotic gene expression by BCAA supplementation. The anti-fibrotic effect of BCAA was confirmed further using platelet-derived growth factor C transgenic mice, which develop hepatic fibrosis and tumors. In vitro, BCAA restored the transforming growth factor (TGF)-β1-stimulated expression of pro-fibrotic genes in hepatic stellate cells (HSC). In hepatocytes, BCAA restored TGF-β1-induced apoptosis, lipogenesis, and Wnt/β-Catenin signaling, and inhibited the transformation of WB-F344 rat liver epithelial stem-like cells. BCAA repressed the promoter activity of TGFβ1R1 by inhibiting the expression of the transcription factor NFY and histone acetyltransferase p300. Interestingly, the inhibitory effect of BCAA on TGF-β1 signaling was mTORC1 activity-dependent, suggesting the presence of negative feedback regulation from mTORC1 to TGF-β1 signaling. Thus, BCAA induce an anti-fibrotic effect in HSC, prevent apoptosis in hepatocytes, and decrease the incidence of HCC; therefore, BCAA supplementation would be beneficial for patients with advanced liver fibrosis with a high risk of HCC.

  10. Republished: Non-alcoholic fatty liver disease: a practical approach to treatment

    PubMed Central

    Dyson, J K; Anstee, Q M; McPherson, S

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis. PMID:25655252

  11. Non-alcoholic fatty liver disease: a practical approach to treatment

    PubMed Central

    Dyson, J K; Anstee, Q M; McPherson, S

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the population in many developed countries. Between 10% and 30% of patients with NAFLD have non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis. There are metabolic risk factors common to both NAFLD and cardiovascular disease, so patients with NASH have an increased risk of liver-related and cardiovascular death. Management of patients with NAFLD depends largely on the stage of disease, emphasising the importance of careful risk stratification. There are four main areas to focus on when thinking about management strategies in NAFLD: lifestyle modification, targeting the components of the metabolic syndrome, liver-directed pharmacotherapy for high risk patients and managing the complications of cirrhosis. PMID:25285192

  12. An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present.

    PubMed

    Jacobs, Ans; Warda, Anne-Sophie; Verbeek, Jef; Cassiman, David; Spincemaille, Pieter

    2016-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc.

  13. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

    PubMed

    Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

    2016-10-21

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH.

  14. Novel antidiabetic medications for non-alcoholic fatty liver disease with type 2 diabetes mellitus.

    PubMed

    Sumida, Yoshio; Seko, Yuya; Yoneda, Masashi

    2016-12-26

    Liver-related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non-alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non-alcoholic steatohepatitis can be called "diabetic hepatopathy". There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first-line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver-related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM.

  15. Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review.

    PubMed

    Nseir, William; Mahamid, Mahmud

    2013-03-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The most common cause of mortality in patients with NAFLD or NASH is cardiovascular disease (CVD). Currently, the treatment of NAFLD focuses on gradual weight loss and life style modifications. However, multifactorial treatment of NAFLD or NASH risk factors may be needed to reduce the likelihood of these patients developing CVD. This review discusses the mechanisms that link hyperlipidemia and NAFLD. In addition, the review focuses on the safety and efficacy of statins in patients with NAFLD or NASH, and their effect on the extent of hepatic steatosis and fibrosis based on human studies.

  16. [Effects of celecoxib on expression of PPARγ and NF-κB in type 2 diabetes rats with non-alcoholic steatohepatitis].

    PubMed

    Tian, F; Zhang, Y J; Wang, Y H

    significantly higher than those in the control group (1.00±0.13 and 1.00±0.15) (t= 11.44 and 16.64, bothP< 0.01) and those in the model+celecoxib group (2.44±0.32 and 1.26±0.11) (t= 6.80 and 15.81, bothP< 0.01). The relative protein level of hepatic PPARγin the model+celecoxib group (0.98±0.09) was significantly higher than that in the model group (0.37±0.03) (t= 15.08,P< 0.01). Conclusion: Celecoxib protects type 2 diabetes rats against non-alcoholic steatohepatitis probably via modulating the expression of PPARγand NF-κB.

  17. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Cusi, Kenneth; Chang, Zhi; Harrison, Steve; Lomonaco, Romina; Bril, Fernando; Orsak, Beverly; Ortiz-Lopez, Carolina; Hecht, Joan; Feldstein, Ariel E; Webb, Amy; Louden, Christopher; Goros, Martin; Tio, Fermin

    2014-01-01

    Liver biopsy is the only reliable way of diagnosing and staging NASH but its invasive nature limits its use. Plasma caspase-generated cytokeratin-18 fragments (CK-18) have been proposed as a non-invasive alternative. We studied its clinical value in a large multiethnic NAFLD population and examined its relationship to clinical/metabolic/histological parameters. 424 middle-aged subjects in whom we measured adipose tissue, liver and muscle insulin resistance (IR), liver fat by MRS (n=275) and histology (n=318). Median CK-18 were elevated in patients with vs. without NAFLD by MRS (209 [IQR: 137-329] vs. 122 [IQR: 98-155]U/L) or with vs. without NASH (232 [IQR: 151-387] vs. 170 [IQR: 135-234]U/L, both p<0.001). Plasma CK-18 raised significantly with any increase in steatosis, inflammation and fibrosis, but there was a significant overlap across disease severity. The CK-18 AUROC to predict NAFLD, NASH or fibrosis were 0.77 (95% CI=0.71-0.84), 0.65 (95% CI=0.59-0.71) and 0.68 (95% CI=0.61-0.75), respectively. The overall sensitivity/specificity for NAFLD, NASH and fibrosis were 63% (57-70%)/83% (69-92%), 58% (51-65%)/68% (59-76%) and 54% (44-63%)/85% (75-92%), respectively. CK-18 correlated most strongly with ALT (r=0.57, p<0.0001) and adipose tissue IR (insulin-suppression of FFA: r=-0.43; p<0.001), less with steatosis, lobular inflammation and fibrosis (r=0.28-0.34, all p<0.001), but not with ballooning, BMI, metabolic syndrome or T2DM. Plasma CK-18 has a high specificity for NAFLD and fibrosis, but its limited sensitivity makes it inadequate as a screening test for staging NASH. Whether combined as a diagnostic panel with other biomarkers or clinical/laboratory tests may prove useful requires further study. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. Pediatric Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Bush, Haley; Golabi, Pegah; Younossi, Zobair M.

    2017-01-01

    With the increase in the prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become among the leading causes of chronic liver disease in the pediatric age group. Once believed to be a “two-hit process”, it is now clear that the actual pathophysiology of NAFLD is complex and involves multiple pathways. Moreover, NAFLD is not always benign, and patients with non-alcoholic steatohepatitis (NASH) are at increased risk of developing advanced stages of liver disease. It has also been shown that NAFLD is not only a liver disease, but is also associated with multiple extrahepatic manifestations, including cardiovascular diseases, type 2 diabetes, and low bone mineral density. Although the data is scarce in the pediatric population, some studies have suggested that long-term mortality and the requirement of liver transplantation will continue to increase in patients with NAFLD. More studies are needed to better understand the natural history of NAFLD, especially in the pediatric age group. PMID:28598410

  19. [Non-alcoholic fatty liver disease in obese children and adolescents].

    PubMed

    Denzer, C

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adolescents in industrialized countries. Recent studies have demonstrated a prevalence rate of NAFLD in overweight and obese children and adolescents in Germany of up to 30%. The spectrum of NAFLD ranges from pure fatty infiltration (simple steatosis) to inflammation (steatohepatitis, synonymous NASH) to fibrosis and cirrhosis. Age, gender, ethnicity, insulin resistance, and sex steroids are implicated in the pathogenesis of NAFLD in childhood and adolescence. Moreover, NAFLD in the pediatric age group is associated with marked cardiovascular comorbidities. This review focuses on current data regarding epidemiology, pathophysiology, comorbidities, and treatment of NAFLD in children and adolescents.

  20. Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation

    USDA-ARS?s Scientific Manuscript database

    Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carc...

  1. Epigenetics in non-alcoholic fatty liver disease.

    PubMed

    Lee, Jooho; Kim, Yuri; Friso, Simonetta; Choi, Sang-Woon

    2017-04-01

    Non-alcoholic fatty liver disease (NAFLD), a common hepatic disorder ranging from simple steatosis through steatohepatitis to fibrosis and cirrhosis, is an emerging health concern. NAFLD is a pathologic condition characterized by the buildup of extra fat in liver cells that is not caused by alcohol consumption. Excess hepatic fat accumulation results from increased delivery of triglycerides (TG) to the liver or conversion of surplus carbohydrates to TG. Importantly, a subgroup of NAFLD results in hepatocellular injury and inflammation, which is referred to as non-alcoholic steatohepatitis (NASH), and may progress to irreversible cirrhosis and hepatocellular carcinoma (HCC). NAFLD shares, in part, the common pathogenesis of metabolic syndrome including obesity, hyperlipidemia, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines. Epigenetics, an inheritable phenomenon that affects gene expression without altering the DNA sequence, provides a new perspective on the pathogenesis of NAFLD. Reversible epigenetic changes take place at the transcriptional level and provide a phenotypic connection between the host and environment. An accumulating body of evidence suggests the importance of epigenetic roles in NAFLD, which in turn can be identified as potential therapeutic targets and non-invasive biomarkers of NAFLD. It is anticipated that the epigenetic modifiers in NAFLD may provide novel molecular indicators that can determine not only the initial risk but also the disease progression and prognosis. In the present review, we update the roles of epigenetics as pathologic mechanisms, therapeutic targets and biomarkers in NAFLD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. [Dislipidemia and steatohepatitis with visceral fat].

    PubMed

    Yasuda, Daijiro; Maeda, Tomomi; Teramoto, Tamio

    2009-02-01

    The prevalence of metabolic syndrome has been increased recently because of westernized dietary habits and low physical activity in Japan. Metabolic syndrome is diagnosed by the accumulation of dislipidemia, glucose intolerance and/or high blood pressure caused by visceral obesity. The dislipidemia in metabolic syndrome is characterized by the presence of high plasma triglyceride and low HDL-cholesterol, which are associated with increase in small dense LDL and remnant lipoproteins, highly atherogenic lipoproteins. Metabolic syndrome is also often associated with fatty liver, which may be led to non-alcoholic steatohepatitis (NASH). Reduction of body weight and increase in physical activities are highly recommended in overweight patients to inhibit the development of metabolic syndrome, the dislipidemia and NASH.

  3. The Natural Course of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Calzadilla Bertot, Luis; Adams, Leon Anton

    2016-05-20

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, paralleling the epidemic of obesity and Type 2 diabetes mellitus (T2DM). NAFLD exhibits a histological spectrum, ranging from "bland steatosis" to the more aggressive necro-inflammatory form, non-alcoholic steatohepatitis (NASH) which may accumulate fibrosis to result in cirrhosis. Emerging data suggests fibrosis, rather than NASH per se, to be the most important histological predictor of liver and non-liver related death. Nevertheless, only a small proportion of individuals develop cirrhosis, however the large proportion of the population affected by NAFLD has led to predictions that NAFLD will become a leading cause of end stage liver disease, hepatocellular carcinoma (HCC), and indication for liver transplantation. HCC may arise in non-cirrhotic liver in the setting of NAFLD and is associated with the presence of the metabolic syndrome (MetS) and male gender. The MetS and its components also play a key role in the histological progression of NAFLD, however other genetic and environmental factors may also influence the natural history. The importance of NAFLD in terms of overall survival extends beyond the liver where cardiovascular disease and malignancy represents additional important causes of death.

  4. Paediatric non-alcoholic fatty liver disease: an overview.

    PubMed

    AlKhater, S A

    2015-05-01

    Non-alcoholic fatty liver disease (NAFLD) is a progressive disease that encompasses a spectrum of liver diseases, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Data related to survival in children are scarce, but these data firmly associate NAFLD with higher risks of hepatic and non-hepatic morbidities and mortalities compared with the general population. More recently, the association between NAFLD and cardiovascular disease among children has increasingly been recognized. Given that obesity is a major risk factor for the disease, paediatric NAFLD is becoming a global issue, paralleling the dramatic rise in obesity worldwide. NASH, which is more common in obese children, has the potential to advance to liver fibrosis and failure. It is unclear why certain patients undergo such transformation but this susceptibility is likely related to an interaction between a genetically susceptible host and the surrounding environment. Currently, treatment is largely conservative and includes lifestyle modification, attainable through healthy weight reduction via diet and exercise. In this review, current knowledge about NAFLD in children is summarized. This review aims to increase the awareness of the medical community about a hidden public health issue and to identify current gaps in the literature while providing directions for future research. © 2015 World Obesity.

  5. Non-alcoholic Fatty Liver Disease (NAFLD)--A Review.

    PubMed

    Karim, M F; Al-Mahtab, M; Rahman, S; Debnath, C R

    2015-10-01

    Non-alcoholic fatty liver disease (NAFLD) is an emerging problem in Hepatology clinics. It is closely related to the increased frequency of overweight or obesity. It has recognised association with metabolic syndrome. Central obesity, diabetes mellitus, dyslipidemia are commonest risk factors. Association with hepatitis C genotype 3 is also recognised. NAFLD is an important cause of cyptogenic cirrhosis of liver. It affects all populations and all age groups. Most patients with NAFLD are asymptomatic or vague upper abdominal pain. Liver function tests are mostly normal or mild elevation of aminotranferases. Histological features almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. Two hit hypothesis is prevailing theory for the development of NAFLD. Diagnosis is usually made by imaging tools like ultrasonogram which reveal a bright liver while liver biopsy is gold standard for diagnosis as well as differentiating simple fatty liver and non-alcoholic steatohepatitis (NASH). Prognosis is variable. Simple hepatic steatosis generally has a benign long-term prognosis. However, one to two third of NASH progress to fibrosis or cirrhosis and may have a similar prognosis as cirrhosis from other liver diseases. Treatment is mostly control of underlying disorders and dietary advice, exercise, insulin sensitizers, antioxidants, or cytoprotective agents. The prevalence of NAFLD is increasing. So it needs more research to address this problem.

  6. Pathophysiology of NASH: perspectives for a targeted treatment

    PubMed Central

    Marra, Fabio; Lotersztajn, Sophie

    2013-01-01

    Non alcoholic steatohepatitis (NASH) is the more severe form of nonalcoholic fatty liver disease. In NASH, fatty liver, hepatic inflammation, hepatocyte injury and fibrogenesis are associated, and thi condition may eventually lead to cirrhosis. Current treatment of NASH relies on the reduction of body weight and increase in physical activity, but there is no pharmacologic treatment approved as yet. Emerging data indicate that NASH progression results from parallel events originating from the liver as well as from the adipose tissue, the gut and the gastrointestinal tract. Thus, dysfunction of the adipose tissue through enhanced flow of free fatty acids and release of adipocytokines, and alterations in the gut microbiome generate proinflammatory signals that underly NASH progression. Additional ‘extrahepatic hits’ include dietary factors and gastrointestinal hormones. Within the liver, hepatocyte apoptosis, ER stress and oxidative stress are key contributors to hepatocellular injury. In addition, lipotoxic mediators and danger signals activate Kupffer cells which initiate and perpetuate the inflammatory response by releasing inflammatory mediators that contribute to inflammatory cell recruitment and development of fibrosis. Inflammatory and fibrogenic mediators include chemokines, the cannabinoid system, the inflammasome and activation of pattern-recognition receptors. Here we review the major mechanisms leading to appearance and progression of NASH, focusing on both extrahepatic signals and local inflammatory mechanisms, in an effort to identify the most promising molecular targets for the treatment of this condition. PMID:23394092

  7. Non alcoholic fatty liver disease and metabolic syndrome

    PubMed Central

    Paschos, P; Paletas, K

    2009-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic entity increasingly recognized as a major health burden in developed countries. It includes a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and rarely, progression to cirrhosis. Recent studies emphasize the role of insulin resistance, oxidative stress and subsequent lipid peroxidation, proinflammatory cytokines, adipokines and mitochondrial dysfunction in the development and progression of NAFLD. Furthermore, accumulating evidence supports an association between NAFLD and metabolic syndrome. Although the data are mainly epidemiological, the pathogenesis of NAFLD and metabolic syndrome seems to have common pathophysiological mechanisms, with focus on insulin resistance as a key factor. This review summarizes the current knowledge on the epidemiology, pathophysiology and diagnosis of both NAFLD and metabolic syndrome and the findings that strongly support the association of nonalcoholic fatty liver disease as a possible component in the cluster of metabolic syndrome. PMID:19240815

  8. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging

    PubMed Central

    Dyson, Jessica K; Anstee, Quentin M; McPherson, Stuart

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of abnormal liver function tests (LFTs) in the UK with approximately a third of the population being affected. The exact prevalence is not known, but population studies from the USA and China using magnetic resonance spectroscopy estimate that approximately 30% of the general population have steatosis. It is a spectrum of disease ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH), through to advanced fibrosis and cirrhosis. The majority have simple steatosis, but approximately 10–30% develop NASH and the development of NASH cirrhosis is associated with a poor long-term prognosis. Patients with NASH have increased liver-related and cardiovascular mortality. Many patients with NAFLD remain undiagnosed, and recognising those at risk is the first step. Clinicians overly rely on abnormal liver enzymes to identify patients with NAFLD, so patients with significant liver disease can be overlooked, potentially missing opportunities for intervention. Although liver biopsy is the gold standard method for diagnosing and staging NAFLD, the majority of patients can be effectively diagnosed non-invasively with tests that are routinely available in the clinic today. This review discusses a pragmatic approach to diagnosis and staging of NAFLD so that patients at the highest risk of liver-related complications can be identified. PMID:25018867

  9. [Non-alcoholic fatty liver disease--new view].

    PubMed

    Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

    2008-06-01

    Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

  10. Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Bandsma, Robert; Comelli, Elena M.; Arendt, Bianca M.; Zhang, Ling; Fung, Scott; Fischer, Sandra E.; McGilvray, Ian G.; Allard, Johane P.

    2016-01-01

    Background & Aims Non-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied by an altered bile acid (BA) homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data. Methods This was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH) and healthy controls (HC). Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) and intestinal BA signalling, as well as IM composition were assessed. Results 53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA), chenodeoxycholic acid (CDCA) and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons). The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004), but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively). C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA) (r = 0.526, p = 0.003) and inversely with unconjugated CA (r = -0.669, p<0.0001) and unconjugated CDCA (r = - 0.630, p<0.0001). FGF19 levels were not different between the groups (p = 0.114). Conclusions In adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury. PMID:27203081

  11. Clinical approaches to non-alcoholic fatty liver disease

    PubMed Central

    Schwenger, Katherine JP; Allard, Johane P

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leading to fibrosis and potentially cirrhosis, and it is one of the most common causes of liver disease worldwide. NAFLD is associated with other medical conditions such as metabolic syndrome, obesity, cardiovascular disease and diabetes. NASH can only be diagnosed through liver biopsy, but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis, reducing the need for liver biopsy and risk to patients. Disease progression varies between individuals and is linked to a number of risk factors. Mechanisms involved in the pathogenesis are associated with diet and lifestyle, influx of free fatty acids to the liver from adipose tissue due to insulin resistance, hepatic oxidative stress, cytokines production, reduced very low-density lipoprotein secretion and intestinal microbiome. Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD. Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial. Omega 3 polyunsaturated fatty acids and statins may offer additional benefits. Bariatric surgery should be considered in morbidly obese patients. More research is needed to assess the impact of these treatments on a long-term basis. The objective of this article is to briefly review the diagnosis, management and treatment of this disease in order to aid clinicians in managing these patients. PMID:24587650

  12. Resolution of NASH with weight loss documented by hepatic MRI.

    PubMed

    Singh, Vasvi; Luthra, Saurav; Elajami, Tarec K; Welty, Francine K

    2015-01-06

    A 57-year-old Asian woman with type 2 diabetes mellitus, hypertension, obesity, dyslipidaemia and history of breast cancer, was referred to the cardiovascular health and lipid centre for evaluation and management of dyslipidaemia and NASH (Non-alcoholic steatohepatitis) in 2010. She originally had a detailed work up at the liver clinic for elevated liver enzymes, with no associated symptoms. Initial hepatic MRI on 22 January 2007 showed diffuse fatty infiltration quantitated at 15%. We counselled her on lifestyle modifications, including dietary measures and exercise, geared toward weight loss. Over the next 2 years, she lost 24.5 lbs; repeat hepatic MRI on 22 December 2011 showed 6% hepatic fat, which is within the normal range. This case demonstrates the efficacy of significant weight loss in the improvement and resolution of NASH. We believe that this is the first case report documenting this through liver MRI. 2015 BMJ Publishing Group Ltd.

  13. Resolution of NASH with weight loss documented by hepatic MRI

    PubMed Central

    Singh, Vasvi; Luthra, Saurav; Elajami, Tarec K; Welty, Francine K

    2015-01-01

    A 57-year-old Asian woman with type 2 diabetes mellitus, hypertension, obesity, dyslipidaemia and history of breast cancer, was referred to the cardiovascular health and lipid centre for evaluation and management of dyslipidaemia and NASH (Non-alcoholic steatohepatitis) in 2010. She originally had a detailed work up at the liver clinic for elevated liver enzymes, with no associated symptoms. Initial hepatic MRI on 22 January 2007 showed diffuse fatty infiltration quantitated at 15%. We counselled her on lifestyle modifications, including dietary measures and exercise, geared toward weight loss. Over the next 2 years, she lost 24.5 lbs; repeat hepatic MRI on 22 December 2011 showed 6% hepatic fat, which is within the normal range. This case demonstrates the efficacy of significant weight loss in the improvement and resolution of NASH. We believe that this is the first case report documenting this through liver MRI. PMID:25564638

  14. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update

    PubMed Central

    Athyros, Vasilios G; Tziomalos, Konstantinos; Katsiki, Niki; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is considered to be an independent cardiovascular disease (CVD) risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis (NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease (CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness (AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis (mainly by simple non-invasive tests), CKD, and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above. PMID:26078558

  15. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update.

    PubMed

    Athyros, Vasilios G; Tziomalos, Konstantinos; Katsiki, Niki; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-06-14

    Non-alcoholic fatty liver disease (NAFLD) is considered to be an independent cardiovascular disease (CVD) risk factor. However, simple steatosis has a benign clinical course without excess mortality. In contrast, the advanced form of NAFLD, non-alcoholic steatohepatitis (NASH) with liver fibrosis increases mortality by approximately 70%, due to an increase in CVD mortality by approximately 300%. Chronic kidney disease (CKD) may be caused by NAFLD/NASH and it substantially increases CVD risk, especially in the presence of type 2 diabetes mellitus. Moreover, CKD may trigger NAFLD/NASH deterioration in a vicious cycle. NAFLD/NASH is also related to increased arterial stiffness (AS), an independent CVD risk factor that further raises CVD risk. Diagnosis of advanced liver fibrosis (mainly by simple non-invasive tests), CKD, and increased AS should be made early in the course of NAFLD and treated appropriately. Lifestyle measures and statin treatment may help resolve NAFLD/NASH and beneficially affect the CVD risk factors mentioned above.

  16. Amelioration by chicory seed extract of diabetes- and oleic acid-induced non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) via modulation of PPARα and SREBP-1.

    PubMed

    Ziamajidi, Nasrin; Khaghani, Shahnaz; Hassanzadeh, Gholamreza; Vardasbi, Safura; Ahmadian, Shahram; Nowrouzi, Azin; Ghaffari, Seyed Mahmood; Abdirad, Afshin

    2013-08-01

    We evaluated the effect of chicory (Cichorium intybus L.) seed extract (CI) on hepatic steatosis caused by early and late stage diabetes in rats (in vivo), and induced in HepG2 cells (in vitro) by BSA-oleic acid complex (OA). Different dosages of CI (1.25, 2.5 and 5 mg/ml) were applied along with OA (1 mM) to HepG2 cells, simultaneously and non-simultaneously; and without OA to ordinary non-steatotic cells. Cellular lipid accumulation and glycerol release, and hepatic triglyceride (TG) content were measured. The expression levels of sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARα) were determined. Liver samples were stained with hematoxylin and eosin (H&E). Significant histological damage (steatosis-inflammation-fibrosis) to the cells and tissues and down-regulation of SREBP-1c and PPARα genes that followed steatosis induction were prevented by CI in simultaneous treatment. In non-simultaneous treatment, CI up-regulated the expression of both genes and restored the normal levels of the corresponding proteins; with a greater stimulating effect on PPARα, CI acted as a PPARα agonist. CI released glycerol from HepG2 cells, and targeted the first and the second hit phases of hepatic steatosis. A preliminary attempt to characterize CI showed caffeic acid, chlorogenic acid, and chicoric acid, among the constituents.

  17. Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr−/− mice

    PubMed Central

    Jump, Donald B.; Depner, Christopher M.; Tripathy, Sasmita; Lytle, Kelli A.

    2015-01-01

    The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr−/− mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr−/− mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr−/− mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects. PMID:26282529

  18. Probiotics as a Novel Treatment for Non-Alcoholic Fatty Liver Disease; A Systematic Review on the Current Evidences

    PubMed Central

    Kelishadi, Roya; Farajian, Sanam; Mirlohi, Maryam

    2013-01-01

    Context Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. Evidence Acquisition We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: “non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver”. Results Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. Conclusions Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up. PMID:23885277

  19. Probiotics as a novel treatment for non-alcoholic Fatty liver disease; a systematic review on the current evidences.

    PubMed

    Kelishadi, Roya; Farajian, Sanam; Mirlohi, Maryam

    2013-04-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: "non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver". Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up.

  20. Fucoidan ameliorates steatohepatitis and insulin resistance by suppressing oxidative stress and inflammatory cytokines in experimental non-alcoholic fatty liver disease.

    PubMed

    Heeba, Gehan H; Morsy, Mohamed A

    2015-11-01

    Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. In the present study, we investigated the therapeutic effect of fucoidan on non-alcoholic fatty liver disease (NAFLD) in rats. Rats were fed a high-fat diet (HFD) for 12 weeks to induce NAFLD. Oral administrations of fucoidan (100mg/kg, orally), metformin (200mg/kg, orally) or the vehicle were started in the last four weeks. Results showed that administration of fucoidan for 4 weeks attenuated the development of NAFLD as evidenced by the significant decrease in liver index, serum liver enzymes activities, serum total cholesterol and triglycerides, fasting serum glucose, insulin, insulin resistance, and body composition index. Further, fucoidan decreased hepatic malondialdehyde as well as nitric oxide concentrations, and concomitantly increased hepatic reduced glutathione level. In addition, the effect of fucoidan was accompanied with significant decrease in hepatic mRNA expressions of tumor necrosis factor-α, interleukins-1β and matrix metalloproteinase-2. Furthermore, histopathological examination confirmed the effect of fucoidan. In conclusion, fucoidan ameliorated the development of HFD-induced NAFLD in rats that may be, at least partly, related to its hypolipidemic, insulin sensitizing, antioxidant and anti-inflammatory mechanisms.

  1. [Prevalence of non-alcoholic esteatohepatitis in adults with metabolic syndrome in Oaxaca].

    PubMed

    Alvarez-Martínez, Héctor Eloy; Pérez-Campos, Eduardo; Leyva-Bohórquez, Paulina

    2005-01-01

    Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that occurs in patients with no significant alcohol consumption, characterized for macrovesicular steatosis, hepatocellular necrosis, mixed inflammatory infiltrate and various grades of fibrosis and, in some cases, Mallory bodies. The prevalence of this disease is unknown; recent studies indicate that in the general population, incidence is about 3%, although the rates are higher in some subpopulations as are obesity and diabetes mellitus. The goal of this work was to determine the prevalence of non-alcoholic steatohepatitis in one sample of patients with the metabolic syndrome, patients at "Presidente Juárez" Regional Hospital. It was a cross-sectional and descriptive study in which, by means of random selection a sample of 110 patients with type 2 diabetes mellitus, arterial hypertension, obesity and dyslipidemia, alone or in combination was chosen. We carried out a clinical and laboratory evaluation, selecting those patients with persistent elevation of aminotransferases for whom additional studies were made, in order to exclude other causes of enzyme abnormality. Five patients were selected for percutaneous liver biopsy, all they had NASH. The prevalence of NASH was 4.54%. The clinical and laboratory characteristics of these patients will be discussed in the article.

  2. Molecular Pathogenesis of NASH

    PubMed Central

    Caligiuri, Alessandra; Gentilini, Alessandra; Marra, Fabio

    2016-01-01

    Nonalcoholic steatohepatitis (NASH) is the main cause of chronic liver disease in the Western world and a major health problem, owing to its close association with obesity, diabetes, and the metabolic syndrome. NASH progression results from numerous events originating within the liver, as well as from signals derived from the adipose tissue and the gastrointestinal tract. In a fraction of NASH patients, disease may progress, eventually leading to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Understanding the mechanisms leading to NASH and its evolution to cirrhosis is critical to identifying effective approaches for the treatment of this condition. In this review, we focus on some of the most recent data reported on the pathogenesis of NASH and its fibrogenic progression, highlighting potential targets for treatment or identification of biomarkers of disease progression. PMID:27657051

  3. Lack of fibroblast growth factor 21 accelerates metabolic liver injury characterized by steatohepatities in mice

    PubMed Central

    Liu, Xingkai; Zhang, Ping; Martin, Robert C; Cui, Guozhen; Wang, Guangyi; Tan, Yi; Cai, Lu; Lv, Guoyue; Li, Yan

    2016-01-01

    Fibroblast growth factor 21 (FGF21) concentrations are increased in human subjects who either have type 2 diabetes or nonalcoholic fatty liver disease (NAFLD). While excessive fat in the liver promotes the release of pro-inflammatory cytokines, NAFLD progresses from steatosis to non alcoholic steatohepatitis (NASH), a more aggressive form of hepatic damage, and lastly toward cirrhosis and HCC. In our previous study, loss of FGF21 is associated with hyper-proliferation, aberrant p53, and HCC development in diabetes mice. In this study, we proposed to investigate the liver metabolic disorders by diabetes and the potential roles of FGF21 played in NASH and potential carcinogenetic transformation of HCC. NASH was induced in FGF21 knockout (FGF21KO) mice by streptozotocin administration or fed with high fat diet (HFD). The pathological transformation of steatohepatities as well as parameters of inflammation, lipid metabolism, cellular events, mesenchymal-epithelial transition (MET) and Wnt/β-catenin signaling was determined in the FGF21 KO diabetic mice and HFD fed mice. We found that mice lacking the FGF21 gene are more prone to develop NASH. A compromised microenvironment of NASH, which could facilitate the HCC carcinogenetic transformation, was found in FGF21 KO mice under metabolic disorders by diabetes and HFD feeding. This study provided further evidence that lack of FGF21 worsened the metabolic disorders in NASH and could render a tumor microenvironment for HCC initiation and progression in the liver of diabetes mice. PMID:27293995

  4. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis.

    PubMed

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-06-24

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.

  5. Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease

    PubMed Central

    Mishra, Alita; Younossi, Zobair M

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden across the world. By definition, although the histopathologic features of NAFLD are identical to that of alcoholic liver disease, its diagnosis requires absence of significant alcohol use and absence of other causes of chronic liver disease. We now know that NAFLD is not simply a disease of the Western world. It is manifested across the world, in varying rates, across gender, across varying ethnicities, and in its association with other host factors. In this review article, the definition of NAFLD, its spectrum, ranging from mild steatosis to hepatocellular injury and inflammation defined as non-alcoholic steatohepatitis (NASH) is discussed. Mild steatosis is generally a stable disease whereas NASH can be progressive. Based on current published literature, current incidence and prevalence of NAFLD and NASH are discussed. It is also accepted that these processes will continue to increase in prevalence with the rise of obesity, type II diabetes, and associated metabolic syndrome. Some of the risk factors have been well-established and are discussed. In addition, this review also presents emerging associations with other risk factors for NAFLD. Natural history of NAFLD is variable depending upon the histologic subtypes and other underlying comorbidities and is discussed in this review as well. PMID:25755422

  6. Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease

    PubMed Central

    Heebøll, Sara; Thomsen, Karen Louise; Pedersen, Steen B; Vilstrup, Hendrik; George, Jacob; Grønbæk, Henning

    2014-01-01

    The prevalence of obesity and related conditions like non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and therapeutic options are limited. Alternative treatment options are therefore intensively sought after. An interesting candidate is the natural polyphenol resveratrol (RSV) that activates adenosinmonophosphate-activated protein kinase (AMPK) and silent information regulation-2 homolog 1 (SIRT1). In addition, RSV has known anti-oxidant and anti-inflammatory effects. Here, we review the current evidence for RSV-mediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis (NASH) pathogenesis with respect to free fatty acid (FFA) flux from adipose tissue, hepatic de novo lipogenesis, inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits. We review the in vivo evidence from animal studies and clinical trials. The abundance of animal studies reports a decrease in hepatic triglyceride accumulation, liver weight and a general improvement in histological fatty liver changes, along with a reduction in circulating insulin, glucose and lipid levels. Some studies document AMPK or SIRT1 activation, and modulation of relevant markers of hepatic lipogenesis, inflammation and oxidation status. However, AMPK/SIRT1-independent actions are also likely. Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes. Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients. PMID:24799987

  7. Epidemiology and Natural History of Non-alcoholic Fatty Liver Disease.

    PubMed

    Mishra, Alita; Younossi, Zobair M

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease burden across the world. By definition, although the histopathologic features of NAFLD are identical to that of alcoholic liver disease, its diagnosis requires absence of significant alcohol use and absence of other causes of chronic liver disease. We now know that NAFLD is not simply a disease of the Western world. It is manifested across the world, in varying rates, across gender, across varying ethnicities, and in its association with other host factors. In this review article, the definition of NAFLD, its spectrum, ranging from mild steatosis to hepatocellular injury and inflammation defined as non-alcoholic steatohepatitis (NASH) is discussed. Mild steatosis is generally a stable disease whereas NASH can be progressive. Based on current published literature, current incidence and prevalence of NAFLD and NASH are discussed. It is also accepted that these processes will continue to increase in prevalence with the rise of obesity, type II diabetes, and associated metabolic syndrome. Some of the risk factors have been well-established and are discussed. In addition, this review also presents emerging associations with other risk factors for NAFLD. Natural history of NAFLD is variable depending upon the histologic subtypes and other underlying comorbidities and is discussed in this review as well.

  8. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis

    PubMed Central

    Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis. PMID:27347998

  9. Pediatric Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Delvin, Edgard; Patey, Natasha; Dubois, Josée; Henderson, Melanie; Lévy, Émile

    2015-01-01

    Summary The rapidly increasing prevalence of childhood obesity and its associated co-morbidities such as hypertriglyceridemia, hyper-insulinemia, hypertension, early atherosclerosis, metabolic syndrome, and non-alcoholic fatty liver disease are major public health concerns in many countries. Therefore the trends in child and adolescent obesity should be closely monitored over time, as in the near future, we may anticipate a major increase of young adults with the stigmata of the metabolic syndrome, and of the related non-alcoholic fatty liver disease (NAFLD), that may lead to non-alcoholic steatohepatitis. PMID:28356817

  10. Potential Epigenetic Mechanism in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Sun, Chao; Fan, Jian-Gao; Qiao, Liang

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the liver. It ranges from simple steatosis to its more aggressive form, non-alcoholic steatohepatitis (NASH), which may develop into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) if it persists for a long time. However, the exact pathogenesis of NAFLD and the related metabolic disorders remain unclear. Epigenetic changes are stable alterations that take place at the transcriptional level without altering the underlying DNA sequence. DNA methylation, histone modifications and microRNA are among the most common forms of epigenetic modification. Epigenetic alterations are involved in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. This review summarizes the current advances in the potential epigenetic mechanism of NAFLD. Elucidation of epigenetic factors may facilitate the identification of early diagnositic biomarkers and development of therapeutic strategies for NAFLD. PMID:25751727

  11. Autophagy and non-alcoholic fatty liver disease.

    PubMed

    Lavallard, Vanessa J; Gual, Philippe

    2014-01-01

    Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma.

  12. Autophagy and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Lavallard, Vanessa J.

    2014-01-01

    Autophagy, or cellular self-digestion, is a catabolic process that targets cell constituents including damaged organelles, unfolded proteins, and intracellular pathogens to lysosomes for degradation. Autophagy is crucial for development, differentiation, survival, and homeostasis. Important links between the regulation of autophagy and liver complications associated with obesity, non-alcoholic fatty liver disease (NAFLD), have been reported. The spectrum of these hepatic abnormalities extends from isolated steatosis to non-alcoholic steatohepatitis (NASH), steatofibrosis, which sometimes leads to cirrhosis, and hepatocellular carcinoma. NAFLD is one of the three main causes of cirrhosis and increases the risk of liver-related death and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of a normal liver to steatosis and then more severe disease are complex and still unclear. The regulation of the autophagic flux, a dynamic response, and the knowledge of the role of autophagy in specific cells including hepatocytes, hepatic stellate cells, immune cells, and hepatic cancer cells have been extensively studied these last years. This review will provide insight into the current understanding of autophagy and its role in the evolution of the hepatic complications associated with obesity, from steatosis to hepatocellular carcinoma. PMID:25295245

  13. Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

    PubMed Central

    Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua; de Almeida, Thiago Pereira; Boursier, Jerome; Bohnic, Brittany; Guy, Cynthia D.; Diehl, Anna Mae

    2015-01-01

    Background and aims Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. Methods Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. Results The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. Conclusion Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID:26017539

  14. Surveillance for Hepatocellular Carcinoma in Patients with NASH.

    PubMed

    Kolly, Philippe; Dufour, Jean-François

    2016-06-07

    European and American guidelines recommend surveillance for hepatocellular carcinoma (HCC) by performing ultrasonography on a six-month basis on an at risk population, defined by presence of cirrhosis. HCC, due to non-alcoholic steatohepatitis (NASH), is rising. Patients with NASH have a high risk of developing HCC and, therefore, have to be enrolled in a screening program. One of the challenges with NASH-induced HCC is that half of the cases arise in non-cirrhotic patients. There is a need to identify those patients in order to screen them for HCC. The obesity of these patients is another challenge, it makes ultrasound screening more difficult. Other radiological methods, such as computer tomography (CT) scans or magnetic resonance imaging (MRI), are available, but the surveillance program would no longer be cost-effective. There is a need to prospectively acquire information on cohorts of patients with NASH in order to improve the tools we have to diagnose early tumors in these patients.

  15. Effect of atorvastatin and diet on non-alcoholic fatty liver disease activity score in hyperlipidemic chickens.

    PubMed

    Martín-Castillo, Antonia; Castells, Maria Teresa; Adánez, Gracia; Polo, Maria Teresa Sánchez; Pérez, Bartolomé García; Ayala, Ignacio

    2010-04-01

    Non-alcoholic steatohepatitis (NASH) is part of the spectrum of non-alcoholic fatty liver disease (NAFLD), which includes from simple steatosis and steatohepatitis, to the most severe cirrhosis and carcinoma, which develops in the absence of excessive alcohol intake. NAFLD is the most common liver disorder in affluent societies. There is no proven treatment for NAFLD/NASH. One of the most frequent adverse effects of statins is an increase in hepatic aminotransferases. Studies that evaluate if the benefits of statins overcome the risks in NASH are lacking. The present study was conceived to explore the effect of both atorvastatin and diet on regression of steatohepatitis, using a chicken experimental model induced by a hyperlipidemic diet (HD). Plasma lipid levels, liver enzymes and hepatic histopathology, as well as image analysis were performed to determine changes in liver lipid deposits and inflammatory infiltration. Features of steatosis, cell-ballooning, and inflammation were scored to obtain the NAFLD activity score (NAS). A severe level of steatosis was found in animals fed on HD. Atorvastatin treated groups showed smaller size of lipid deposits and a lower level of inflammation than non-treated groups. Atorvastatin therapy induced a significant reduction of hepatocellular damage, even though in the animals which continuously received a hyperlipidemic diet. The combination of atorvastatin therapy and a standard diet produced the lowest decrease of NAS. Our results show that atorvastatin therapy not only decreased plasmatic levels of cholesterol and triglycerides, but also induced a reduction of liver steatosis, inflammation and hepatocellular damage, without increasing plasmatic aminotransferase levels.

  16. Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis

    PubMed Central

    Fierbinteanu-Braticevici, Carmen; Dina, Ion; Petrisor, Ana; Tribus, Laura; Negreanu, Lucian; Carstoiu, Catalin

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that have insulin resistance in common and are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD ranges from simple liver steatosis, which follows a benign course, to nonalcoholic steatohepatitis (NASH), a more severe entity, with necroinflammation and fibrosis, which can progress to cryptogenic cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several noninvasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. These markers are currently neither available in all centers nor validated in extensive studies. Examples include high-sensitivity C reactive protein and plasma pentraxin 3, which are associated with extensive liver fibrosis in NASH. Interleukin-6 correlates with inflammation, and cytokeratin-18 represents a marker of hepatocyte apoptosis (prominent in NASH and absent in simple steatosis). Tissue polypeptide specific antigen seems to have a clinical utility in the follow-up of obese patients with NASH. PMID:20939106

  17. Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation

    PubMed Central

    Reid, D. T.; Reyes, J. L.; McDonald, B. A.; Vo, T.; Reimer, R. A.; Eksteen, B.

    2016-01-01

    Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies. PMID:27454866

  18. Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation.

    PubMed

    Reid, D T; Reyes, J L; McDonald, B A; Vo, T; Reimer, R A; Eksteen, B

    2016-01-01

    Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies.

  19. Prevalence of biopsy-proven non-alcoholic fatty liver disease in severely obese subjects without metabolic syndrome.

    PubMed

    Qureshi, K; Abrams, G A

    2016-04-01

    Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses simple fatty liver (FL) and non-alcoholic steatohepatitis (NASH) in its spectrum. NASH can progress to liver cirrhosis and is associated with liver cancer. Not all obese subjects have insulin resistance (IR) or develop metabolic syndrome (MS). This study evaluates the prevalence of NAFLD in severely obese subjects without MS. We retrospectively reviewed 445 charts from our database of severely obese subjects with clinical suspicion of NAFLD and who were selected for laparoscopic Roux-en-Y gastric bypass surgery. One hundred five subjects who did not have MS, as defined by the International Diabetes Foundation, based on comprehensive pre-operative metabolic evaluation were included. Liver biopsy specimens were evaluated for NAFLD. 24% of morbidly obese (mean body mass index [BMI] 48 kg m(-2) ) adult subjects (mean age 38 years) who underwent bariatric surgery did not have MS. NAFLD was identified in 77 (73%) on liver biopsy, out of which 59 (56%) were labelled as FL and 18 (17%) had histological diagnosis of NASH. Age, gender, race and BMI were the same among all groups. Among NAFLD subjects, 22% did not have any additional metabolic component of MS, while 36% had low high-density lipoprotein, 27% had hypertension, 8% had high triglycerides and 6% had hyperglycaemia. IR calculated by HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and diagnosis of hyperglycaemia was statistically higher in NASH group compared to those who did not have NASH. NAFLD is highly prevalent in morbidly obese individuals who undergo bariatric surgery despite the absence of MS. Diagnosis of hyperglycaemia in such subjects suggests the presence of IR and may have underlying NASH, which is a progressive form of NAFLD.

  20. The Effect of Metformin and Standard Therapy Versus Standard Therapy Alone in Nondiabetic Patients with Insulin Resistance and Nonalcoholic Steatohepatitis (NASH): A Pilot Trial

    DTIC Science & Technology

    2009-01-01

    liver patients. Aliment Pharmacol Ther 23: 1643–1647. Hamaguchi, M., Kojima, T., Takeda, N., Nakagawa, T., Taniguchi, H., Fujii, K. et al. (2005) The...J.J. et al. (2009) Clinical trial: pilot study of metformin for the treatment of non-alcoholic steato- hepatitis. Aliment Pharmacol Ther 29: 172–182...patients with non-alcoholic steato- hepatitis. Aliment Pharmacol Ther 19: 537–544. Visit SAGE journals online http://tag.sagepub.com WW Shields, KE Thompson et al. http://tag.sagepub.com 163

  1. Biochemical Evaluation of Patients of Alcoholic Liver Disease and Non-alcoholic Liver Disease.

    PubMed

    Torkadi, Prasad P; Apte, I C; Bhute, A K

    2014-01-01

    Alcoholic liver disease (ALD) is due to excessive alcohol intake for long duration. Distinguishing ALD from non-ALD (non-alcoholic steatohepatitis, hepatitis of viral origin) is difficult as patient may deny alcohol abuse. Clinical examination, histology and serology may not differentiate these conditions. Accurate diagnosis is important as management of ALD differs from non-ALD patients. The aim of our study was (1) To evaluate the patients of ALD and non-ALD by biochemical parameters compared to controls, (2) To assess whether these parameters can differentiate ALD from non-ALD. Study was carried out on 50 patients of ALD in group I and 35 patients of NASH (non-alcoholic steatohepatitis) and acute viral hepatitis each in group II. Age matched healthy controls n = 50. Selection criteria-history of alcohol intake (amount and duration), clinical examination, sonography of abdomen, serum alanine transaminase (ALT) and bilirubin levels. Blood samples were analyzed for bilirubin, aspartate transaminase (AST), ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) by kinetic method. Statistical analysis was done by Student unpaired 't' test. Patients of ALD have raised AST/ALT ratio (De Ritis ratio) (>2), ALP and GGT compared to controls (P < 0.01).There is significant difference in AST/ALT ratio, serum GGT and ALP in ALD group compared to that in NASH and acute viral hepatitis (P < 0.05). This study suggests that De Ritis ratio >2 in ALD patients may be due to alcohol induced hepatic mitochondrial injury and pyridoxine deficiency. High GGT and ALP values may indicate enzyme induction by alcohol and mild cholestasis. Thus ALD patients have severe hepatic damage. De Ritis ratio <1 and normal to mild elevation in GGT level in NASH and acute viral hepatitis suggest mild hepatic injury of non-alcoholic origin. Our study concludes that ALD patients can be differentiated from NASH and acute viral hepatitis with certainty by measuring serum AST/ALT ratio

  2. The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis

    PubMed Central

    2014-01-01

    Background The relationship between resistin and non-alcoholic steatohepatitis (NASH) is not clear, some studies claimed that serum resistin levels were associated with neither the presence of NASH nor its severity, others declared that serum resistin was related with inflammation and fibrosis in NASH. Our animal study verified that the distribution of resistin in the liver is correlated with inflammation in NASH. However, there is no pertinent study in humans. Methods Thirty patients with NASH, 28 simple steatosis, and 43 controls were recruited. Blood was collected for resistin, liver chemistries, fasting insulin and some metabolic parameters. Liver histology was scored according to NAFLD activity scoring system. Hepatic resistin expression was examined by real-time polymerase chain reaction, immunohistochemistry. Resistin protein expression was confirmed by western blotting in 13 patients with concomitant NAFLD and gallstone. Results Serum resistin was significantly elevated in both NASH and simple steatotic subjects compared with controls (all P < 0.05). Hepatic resistin was significantly increased in NASH patients in both mRNA and protein levels than those in simple steatosis and control subjects (all P < 0.05). Both serum and hepatic resistin had a correlation with obesity, but not with insulin resistance. The distribution of resistin positive cells was predominantly in perisinusoidal cells (such as Kupffer cells and hepatic stellate cells) in human NASH. Multivariate analysis revealed that waist-hip ratio, higher serum triglyceride, and hyperresistinemia were independent factors related to higher grade of steatosis; whereas hepatic resistin and serum cytokeratin predict NASH and severity of liver fibrosis. Conclusions Hepatic resistin overexpression in NASH patients is associated with the severity of liver inflammation and fibrosis. Liver-derived resistin may be involved in the pathogenesis of human NASH. PMID:24559185

  3. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis.

    PubMed

    Polimeni, Licia; Del Ben, Maria; Baratta, Francesco; Perri, Ludovica; Albanese, Fabiana; Pastori, Daniele; Violi, Francesco; Angelico, Francesco

    2015-06-08

    Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed.

  4. Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis

    PubMed Central

    Polimeni, Licia; Del Ben, Maria; Baratta, Francesco; Perri, Ludovica; Albanese, Fabiana; Pastori, Daniele; Violi, Francesco; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L-carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed. PMID:26052378

  5. Identification of Lipid Species Linked to the Progression of Non-Alcoholic Fatty Liver Disease.

    PubMed

    Kawano, Yuki; Nishiumi, Shin; Saito, Masaya; Yano, Yoshihiko; Azuma, Takeshi; Yoshida, Masaru

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is histologically characterized by the aberrant accumulation of lipid droplets in the liver, which is positively correlated with insulin resistance. Within the spectrum of this disease, patients can develop hepatitis and cirrhosis; i.e., non-alcoholic steatohepatitis (NASH). The mechanisms responsible for the progression of NAFLD are not fully understood. Triacylglycerol (TAG), which is mainly found in lipid droplets, is currently considered to act as a buffer against the accumulation of non-TAG toxic lipid species. In line with this, recent studies have revealed that insulin resistance is driven by the accumulation of phosphatidic acid and diacylglycerol in hepatocytes and that cholesterol-overloaded stellate cells are associated with fibrosis in the liver. Therefore, it is important to identify the toxic lipid species that contribute to NAFLD progression in order to clarify the pathogenesis of NASH and find novel targets for its treatment. In this review, we divided lipids into five classes; i.e., into fatty acyls, glycerophospholipids, glycerolipids, sphingolipids, and sterol lipids, and described their molecular structures, distributions, and metabolism under physiological conditions, as well as the contributions they make to the progression of NAFLD.

  6. Experimental models of non-alcoholic fatty liver disease in rats.

    PubMed

    Kucera, Otto; Cervinkova, Zuzana

    2014-07-14

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease.

  7. Experimental models of non-alcoholic fatty liver disease in rats

    PubMed Central

    Kucera, Otto; Cervinkova, Zuzana

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease. PMID:25024595

  8. Serum levels of vascular endothelial growth factor in non-alcoholic fatty liver disease

    PubMed Central

    Papageorgiou, Maria-Vasiliki; Hadziyannis, Emilia; Tiniakos, Dina; Georgiou, Anastasia; Margariti, Aikaterini; Kostas, Athanasios; Papatheodoridis, George V.

    2017-01-01

    Background This study aimed to assess the significance of serum levels of vascular endothelial growth factor (VEGF) in non-alcoholic fatty liver disease (NAFLD). Methods Sixty-seven consecutive NAFLD patients and 47 healthy controls who visited our liver clinics between May 2008 and December 2010 were included. The NAFLD diagnosis required elevated alanine aminotransferase and/or gamma-glutamyl transpeptidase levels, evidence of hepatic steatosis on ultrasound and/or liver histology, and exclusion of other causes of liver injury. Serum VEGF levels were determined by an enzyme immunoassay. Liver biopsy was obtained in 34 NAFLD patients. Histological lesions were scored by a liver histopathologist. Results Serum VEGF levels tended to be lower in matched NAFLD patients than in healthy controls (296±146 vs. 365±186 pg/mL, P=0.092); levels in patients with non-alcoholic steatohepatitis (NASH) also tended to be lower than in those with simple fatty liver (FL) (279±149 vs. 359±190 pg/mL, P=0.095); while VEGF levels were significantly lower in NASH patients than in healthy controls (279±149 vs. 365±186 pg/mL, P=0.041). VEGF levels offered poor predictability for the differentiation between NAFLD patients and controls or between NASH and FL patients. However, patients with high VEGF levels (≥300 pg/mL) were significantly more likely to have FL, either in the total NAFLD population (67% vs. 35%, P=0.019) or in the 34 NAFLD patients with liver biopsy (57% vs. 15%, P=0.023), while those with high VEGF levels also had a significantly lower mean fibrosis score (0.7±0.9 vs. 1.6±1.0, P=0.017). Conclusion Our data suggest that serum VEGF levels are equally high in healthy controls and in patients with simple fatty liver, but tend to decrease when NASH develops. PMID:28243042

  9. Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease.

    PubMed

    Dietrich, Christoph G; Rau, Monika; Jahn, Daniel; Geier, Andreas

    2017-06-01

    The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

  10. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation.

    PubMed

    Afrin, Rejina; Arumugam, Somasundaram; Rahman, Azizur; Wahed, Mir Imam Ibne; Karuppagounder, Vengadeshprabhu; Harima, Meilei; Suzuki, Hiroshi; Miyashita, Shizuka; Suzuki, Kenji; Yoneyama, Hiroyuki; Ueno, Kazuyuki; Watanabe, Kenichi

    2017-03-01

    Curcumin, a phenolic compound, has a wide spectrum of therapeutic effects such as antitumor, anti-inflammatory, anti-cancer and so on. The study aimed to investigate the underlying mechanisms of curcumin to protect liver damage and progression of non-alcoholic steatohepatitis (NASH) in a novel NASH-hepatocellular carcinoma (HCC) mouse model. To induce this model neonatal C57BL/6J male mice were exposed to low-dose streptozotocin and were fed a high-fat diet (HFD) from the age of 4weeks to 14weeks. Curcumin was given at 100mg/kg dose daily by oral gavage started at the age of 10weeks and continued until 14weeks along with HFD feeding. We found that curcumin improved the histopathological changes of the NASH liver via reducing the level of steatosis, fibrosis associated with decreasing serum aminotransferases. In addition, curcumin treatment markedly reduced the hepatic protein expression of oxidative stress, pro-inflammatory cytokines, and chemokines including interferon (IFN) γ, interleukin-1β and IFNγ-inducible protein 10, in NASH mice. Furthermore, curcumin treatment significantly reduced the cytoplasmic translocation of high mobility group box 1 (HMGB1) and the protein expression of toll like receptor 4. Nuclear translocation of nuclear factor kappa B (NF-κB) was also dramatically attenuated by the curcumin in NASH liver. Curcumin treatment effectively reduced the progression of NASH to HCC by suppressing the protein expression of glypican-3, vascular endothelial growth factor, and prothrombin in the NASH liver. Our data suggest that curcumin reduces the progression of NASH and liver damage, which may act via inhibiting HMGB1-NF-κB translocation.

  11. Proteomic analysis of mice fed methionine and choline deficient diet reveals marker proteins associated with steatohepatitis.

    PubMed

    Lee, Su Jin; Kang, Jeong Han; Iqbal, Waqas; Kwon, Oh-Shin

    2015-01-01

    The mechanisms underlying the progression of simple steatosis to steatohepatitis are yet to be elucidated. To identify the proteins involved in the development of liver tissue inflammation, we performed comparative proteomic analysis of non-alcoholic steatohepatitis (NASH). Mice fed a methionine and choline deficient diet (MCD) developed hepatic steatosis characterized by increased free fatty acid (FFA) and triglyceride levels as well as alpha-SMA. Two-dimensional proteomic analysis revealed that the change from the normal diet to the MCD diet affected the expressions of 50 proteins. The most-pronounced changes were observed in the expression of proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in NASH model animals. Peroxiredoxin (Prx) is the most interesting among the modulated proteins identified in this study. In particular, cross-regulated Prx1 and Prx6 are likely to participate in cellular defense against the development of hepatitis. Thus, these Prx isoforms may be a useful new marker for early stage steatohepatitis. Moreover, curcumin treatment results in alleviation of the severity of hepatic inflammation in steatohepatitis. Notably, curcumin administration in MCD-fed mice dramatically reduced CYP2E1 as well as Prx1 expression, while upregulating Prx6 expression. These findings suggest that curcumin may have a protective role against MCD fed-induced oxidative stress.

  12. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease

    PubMed Central

    Arora, Anil; Sharma, Praveen

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation. PMID:25755423

  13. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance.

    PubMed

    Yki-Järvinen, Hannele

    2015-11-05

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%-23% fat and 57%-65% carbohydrate lower liver fat compared to diets with 43%-55% fat and 27%-38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

  14. Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

    PubMed Central

    Yki-Järvinen, Hannele

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance. PMID:26556368

  15. Non-invasive Diagnosis of Fibrosis in Non-alcoholic Fatty Liver Disease.

    PubMed

    Arora, Anil; Sharma, Praveen

    2012-06-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in developed as well as in developing countries. Its prevalence continues to rise currently affecting approximately 20-30% of adults and 10% of children in the United States. Non-alcoholic fatty liver disease represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign non-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Liver biopsy remains the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis; however, several non-invasive investigations, such as serum biomarkers, have been developed to establish the diagnosis and also to evaluate treatment response. There has been a substantial development of non-invasive risk scores, biomarker panels, and radiological modalities to identify at risk patients with NAFLD without recourse to liver biopsy on a routine basis. Examples include combination of serum markers like NAFLD fibrosis score (NFS), BARD score, fibrometer, FIB4, and non-invasive tools like fibroscan which assess fibrosis in patients with NAFLD. Other markers of fibrosis that have been evaluated include high-sensitivity C-reactive protein, plasma pentraxin 3, interleukin-6, and cytokeratin-18. This review focuses on the methods currently available in daily clinical practice in hepatology and touches briefly on the potential future markers under investigation.

  16. Glitazones for human nonalcoholic steatohepatitis

    PubMed Central

    Pais, Raluca; Moraru, Ioana; Ratziu, Vlad

    2011-01-01

    The rationale for specific pharmacologic therapy in nonalcoholic steatohepatitis (NASH) is determined by the potential for disease progression and the difficulties, in many patients, of successfully implementing diet and lifestyle changes over the long term. Owing to their ability to correct insulin resistance, insulin-sensitizing agents are attractive candidates for the treatment of NASH. In this review we provide an insight into the mechanism of action, therapeutic efficacy and safety issues regarding the use of glitazones in NASH. PMID:21922031

  17. Impaired N-linked glycosylation of uptake and efflux transporters in human non-alcoholic fatty liver disease.

    PubMed

    Clarke, John D; Novak, Petr; Lake, April D; Hardwick, Rhiannon N; Cherrington, Nathan J

    2017-07-01

    N-linked glycosylation of proteins is critical for proper protein folding and trafficking to the plasma membrane. Drug transporters are one class of proteins that have reduced function when glycosylation is impaired. N-linked glycosylation of plasma proteins has also been investigated as a biomarker for several liver diseases, including non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to assess the transcriptomic expression of genes involved in protein processing and glycosylation, and to determine the glycosylation status of key drug transporters during human NAFLD progression. Human liver samples diagnosed as healthy, steatosis, and non-alcoholic steatohepatitis (NASH) were analysed for gene expression of glycosylation-related genes and for protein glycosylation using immunoblot. Genes involved in protein processing in the ER and biosynthesis of N-glycans were significantly enriched for down-regulation in NAFLD progression. Included in the down regulated N-glycan biosynthesis category were genes involved in the oligosaccharyltransferase complex, N-glycan quality control, N-glycan precursor biosynthesis, N-glycan trimming to the core, and N-glycan extension from the core. N-glycan degradation genes were unaltered in the progression to NASH. Immunoblot analysis of the uptake transporters organic anion transporting polypeptide-1B1 (OATP1B1), OATP1B3, OATP2B1, and Sodium/Taurocholate Co-transporting Polypeptide (NTCP) and the efflux transporter multidrug resistance-associated protein 2 (MRP2) demonstrated a significant loss of glycosylation following the progression to NASH. These data suggest that the loss of glycosylation of key uptake and efflux transporters in humans NASH may influence transporter function and contribute to altered drug disposition observed in NASH. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

    PubMed

    Liang, Wen; Lindeman, Jan H; Menke, Aswin L; Koonen, Debby P; Morrison, Martine; Havekes, Louis M; van den Hoek, Anita M; Kleemann, Robert

    2014-05-01

    The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components

  19. Clinical and histological features of nonalcoholic steatohepatitis in Iranian patients

    PubMed Central

    Bahrami, Hossein; Daryani, Nasser Ebrahimi; Mirmomen, Shahram; Kamangar, Farin; Haghpanah, Babak; Djalili, Mehdi

    2003-01-01

    Background Although several studies have been performed on risk factors and natural course of NASH, it seems that NASH tends to be more than a disease confined to strict boundaries. The objective of this study was to assess the clinical and paraclinical features and risk factors for non-alcoholic steatohepatitis (NASH) patients in an Iranian population Methods Patients with histologically confirmed NASH who had elevated liver aminotransaminases, negative serologic markers of viral or autoimmune hepatitis and no findings in favor of metabolic liver disease were enrolled. A careful history was taken regarding alcohol intake. Results 53 patients consisting of 32 male and 21 female entered the study. The mean age was 37.8 ± 11.3 years. Twenty-six patients (55.3%) were overweight, 15 (31.9%) obese, 40 (75.5%) dyslipidemic, and three patients (5.7%) were diabetic. Liver biopsy showed mild steatosis in 35.7%, moderate steatosis in 53.6%, and severe forms in 10.7%. In 80.2% of patients, portal inflammation was present, and 9.4% had cirrhosis. The amount of increase in liver enzymes bore no relationship with fibrosis, portal inflammation, and degree of steatosis. Conclusions The patients in our study showed a male predominancy and were somewhat younger than other studies. PMID:14561231

  20. Induction of CYP2E1 in non-alcoholic fatty liver diseases

    PubMed Central

    Aljomah, Ghanim; Baker, Susan S.; Liu, Wensheng; Kozielski, Rafal; Oluwole, Janet; Lupu, Benita; Baker, Robert D.; Zhu, Lixin

    2015-01-01

    Mounting evidence supports a contribution of endogenous alcohol metabolism in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is not known whether the expression of alcohol metabolism genes is altered in the livers of simple steatosis. There is also a current debate on whether fatty acids induce CYP2E1 in fatty livers. In this study, expression of alcohol metabolizing genes in the liver biopsies of simple steatosis patients was examined by quantitative real-time PCR (qRT-PCR), in comparison to biopsies of NASH livers and normal controls. Induction of alcohol metabolizing genes was also examined in cultured HepG2 cells treated with ethanol or oleic acid, by qRT-PCR and Western blots. We found that the mRNA expression of alcohol metabolizing genes including ADH1C, ADH4, ADH6, catalase and CYP2E1 were elevated in the livers of simple steatosis, to similar levels found in NASH livers. In cultured HepG2 cells, ethanol induced the expression of CYP2E1 mRNA and protein, but not ADH4 or ADH6; oleic acid did not induce any of these genes. These results suggest that elevated alcohol metabolism may contribute to the pathogenesis of NAFLD at the stage of simple steatosis as well as more severe stages. Our in vitro data support that CYP2E1 is induced by endogenous alcohol but not by fatty acids. PMID:26551085

  1. Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors

    PubMed Central

    Traber, Peter G.; Zomer, Eliezer

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The

  2. Therapy of experimental NASH and fibrosis with galectin inhibitors.

    PubMed

    Traber, Peter G; Zomer, Eliezer

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The

  3. Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis

    PubMed Central

    Komiya, Chikara; Tanaka, Miyako; Tsuchiya, Kyoichiro; Shimazu, Noriko; Mori, Kentaro; Furuke, Shunsaku; Miyachi, Yasutaka; Shiba, Kumiko; Yamaguchi, Shinobu; Ikeda, Kenji; Ochi, Kozue; Nakabayashi, Kazuhiko; Hata, Ken-ichiro; Itoh, Michiko; Suganami, Takayoshi; Ogawa, Yoshihiro

    2017-01-01

    Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH. PMID:28303974

  4. Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease

    PubMed Central

    2012-01-01

    Background In vitro exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new in vitro model of NASH. Methods HuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured. Results FFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species. Conclusions The exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH. PMID:22380754

  5. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

    PubMed Central

    Clemente, Maria Grazia; Mandato, Claudia; Poeta, Marco; Vajro, Pietro

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended

  6. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions.

    PubMed

    Clemente, Maria Grazia; Mandato, Claudia; Poeta, Marco; Vajro, Pietro

    2016-09-28

    Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the "imperfect" gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle

  7. Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice

    PubMed Central

    Nakashima, Hiroyuki; Nakashima, Masahiro; Kinoshita, Manabu; Ikarashi, Masami; Miyazaki, Hiromi; Hanaka, Hiromi; Imaki, Junko; Seki, Shuhji

    2016-01-01

    We have recently reported that Kupffer cells consist of two subsets, radio-resistant resident CD68+ Kupffer cells and radio-sensitive recruited CD11b+ Kupffer cells/macrophages (Mφs). Non-alcoholic steatohepatitis (NASH) is characterized not only by hepatic steatosis but also chronic inflammation and fibrosis. In the present study, we investigated the immunological mechanism of diet-induced steatohepatitis in fibroblast growth factor 5 (FGF5) deficient mice. After consumption of a high fat diet (HFD) for 8 weeks, FGF5 null mice developed severe steatohepatitis and fibrosis resembling human NASH. F4/80+ Mφs which were both CD11b and CD68 positive accumulated in the liver. The production of TNF and FasL indicated that they are the pivotal effectors in this hepatitis. The weak phagocytic activity and lack of CRIg mRNA suggested that they were recruited Mφs. Intermittent exposure to 1 Gy irradiation markedly decreased these Mφs and dramatically inhibited liver inflammation without attenuating steatosis. However, depletion of the resident subset by clodronate liposome (c-lipo) treatment increased the Mφs and tended to exacerbate disease progression. Recruited CD11b+ CD68+ Kupffer cells/Mφs may play an essential role in steatohepatitis and fibrosis in FGF5 null mice fed with a HFD. Recruitment and activation of bone marrow derived Mφs is the key factor to develop steatohepatitis from simple steatosis. PMID:27708340

  8. Noninvasive predictors for liver fibrosis in patients with nonalcoholic steatohepatitis

    PubMed Central

    Uslusoy, Hüseyin Saadettin; Nak, Selim Giray; Gülten, Macit

    2011-01-01

    AIM: To evaluate certain anthropometric, clinical and laboratory features indicating liver fibrosis in nonalcoholic steatohepatitis and to establish the noninvasive markers for liver fibrosis. METHODS: Eighty-one patients (40 male, 41 female) who were diagnosed with fatty liver by ultrasonographic examination and fulfilled the inclusion criteria participated in the study. Anamnesis, anthropometric, clinical and laboratory features of all cases were recorded and then liver biopsy was performed after obtaining patient consent. Steatosis, necroinflammation and liver fibrosis were examined according to age ≥ 45, gender, body mass index, central obesity, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 1, γ-glutamyltransferase (GGT)/ALT > 1, platelet count, insulin, c-peptide levels and the presence of hypertension, diabetes, hypertriglyceridemia and insulin resistance. RESULTS: Eighty-one patients with non-alcoholic steatohepatitis (NASH) enrolled in the study. 69 of 81 patients were diagnosed with NASH, 11 were diagnosed with simple fatty liver and 1 was diagnosed with cirrhosis. AST/ALT > 1, GGT/ALT > 11, high serum ferritin and fasting insulin levels, the presence of diabetes, hypertension, hypertriglyceridemia and insulin resistance seemed to enhance the severity of steatosis, necroinflammation and fibrosis but these results were not statistically significant. CONCLUSION: Liver steatosis and fibrosis can occur in individuals with normal weight. There was no significant concordance between severity of liver histology and the presence of predictors for liver fibrosis including metabolic risk factors. PMID:21954411

  9. Noninvasive predictors for liver fibrosis in patients with nonalcoholic steatohepatitis.

    PubMed

    Uslusoy, Hüseyin Saadettin; Nak, Selim Giray; Gülten, Macit

    2011-08-27

    To evaluate certain anthropometric, clinical and laboratory features indicating liver fibrosis in nonalcoholic steatohepatitis and to establish the noninvasive markers for liver fibrosis. Eighty-one patients (40 male, 41 female) who were diagnosed with fatty liver by ultrasonographic examination and fulfilled the inclusion criteria participated in the study. Anamnesis, anthropometric, clinical and laboratory features of all cases were recorded and then liver biopsy was performed after obtaining patient consent. Steatosis, necroinflammation and liver fibrosis were examined according to age ≥ 45, gender, body mass index, central obesity, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 1, γ-glutamyltransferase (GGT)/ALT > 1, platelet count, insulin, c-peptide levels and the presence of hypertension, diabetes, hypertriglyceridemia and insulin resistance. Eighty-one patients with non-alcoholic steatohepatitis (NASH) enrolled in the study. 69 of 81 patients were diagnosed with NASH, 11 were diagnosed with simple fatty liver and 1 was diagnosed with cirrhosis. AST/ALT > 1, GGT/ALT > 11, high serum ferritin and fasting insulin levels, the presence of diabetes, hypertension, hypertriglyceridemia and insulin resistance seemed to enhance the severity of steatosis, necroinflammation and fibrosis but these results were not statistically significant. Liver steatosis and fibrosis can occur in individuals with normal weight. There was no significant concordance between severity of liver histology and the presence of predictors for liver fibrosis including metabolic risk factors.

  10. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease.

    PubMed

    Koo, Bo Kyung; Um, Sung Hee; Seo, Dong Soo; Joo, Sae Kyung; Bae, Jeong Mo; Park, Jeong Hwan; Chang, Mee Soo; Kim, Jung Ho; Lee, Jieun; Jeong, Won-Il; Kim, Won

    2017-09-12

    We explored whether growth differentiation factor 15 (GDF15) affects the histological severity of non-alcoholic fatty liver disease (NAFLD) independent of insulin resistance. In a biopsy-proven NAFLD cohort, we measured serum GDF15 levels using enzyme-linked immunosorbent assays. Among 190 subjects (mean age, 53±14 years; men, 52.1%), 72 (men, 65.3%) and 78 (men, 44.9%) were diagnosed with biopsy-proven non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), respectively. GDF15 levels were significantly higher in NASH patients than in controls (P = 0.010) or NAFL patients (P = 0.001). Subjects with advanced fibrosis (≥F3) also showed higher GDF15 levels compared to the others (F0-2; P <0.001). Among NAFLD patients, the highest quartile of GDF15 levels was significantly associated with a risk of advanced fibrosis even after adjustment for age, gender, body mass index, smoking status, hypertension, diabetes, aspartate aminotransferase, platelet, albumin, insulin resistance, and low skeletal muscle mass (odds ratio, 4.27; 95% confidence interval, 1.04-17.63), but not with NASH risk. GDF15 levels showed a significant positive correlation with liver stiffness (Spearman's ρ, 0.525; P < 0.001). Palmitate treatment increased the GDF15 mRNA expression level significantly in Kupffer cells, but not in hepatocytes. In LX-2 cells, GDF15 treatment resulted in enhanced expression of α-smooth muscle actin and collagen I, as well as phosphorylation of SMAD2 and SMAD3. Our findings suggest that GDF15 may serve as a novel biomarker of advanced fibrosis in NAFLD, thereby indicating the need for urgent anti-fibrotic pharmacotherapy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  11. Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress.

    PubMed

    Qiang, Xiaoyan; Xu, Lulu; Zhang, Miao; Zhang, Pengcheng; Wang, Yinhang; Wang, Yongchen; Zhao, Zheng; Chen, Huan; Liu, Xie; Zhang, Yubin

    2016-04-15

    Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid β-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation.

  12. Effect of Lipopolysaccharide on the Progression of Non-Alcoholic Fatty Liver Disease in High Caloric Diet-Fed Mice.

    PubMed

    Matsushita, N; Osaka, T; Haruta, I; Ueshiba, H; Yanagisawa, N; Omori-Miyake, M; Hashimoto, E; Shibata, N; Tokushige, K; Saito, K; Tsuneda, S; Yagi, J

    2016-02-01

    The incidence of non-alcoholic steatohepatitis (NASH) is increasing. Because gut microbiota have been highlighted as one of the key factors in the pathogenesis of metabolic syndrome, we investigated the involvement of the bacterial component in the progression of non-alcoholic fatty liver (NAFL) to NASH. C57BL/6 mice were fed with maintenance food (MF, groups A and B) or a high caloric diet (HCD, groups C and D) for 1 month. Mice were then divided into four groups: Groups A and C were inoculated with PBS, while groups B and D were inoculated with lipopolysaccharide (LPS) plus complete Freund's adjuvant (CFA). The inoculations were performed a total of 3 times over 3 months. At 6 months, while hepatic steatosis was observed in groups C and D, cellular infiltration and fibrosis were less evident in group C than in group D. Inflammatory cytokines were upregulated in groups B and D. 16S rRNA pyrosequencing of whole colon homogenates containing faeces showed that certain bacterial groups, such as Bacteroidaceae, Peptostreptococcaceae and Erysipelotrichaceae, were increased in groups C and D. Although loading of bacterial components (LPS) resulted in hepatic inflammation in both MF- and HCD-fed mice, HCD feeding was more crucial in the progression of NAFL during the triggering phase. © 2015 The Foundation for the Scandinavian Journal of Immunology.

  13. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: the liver disease of our age?

    PubMed

    Firneisz, Gábor

    2014-07-21

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

  14. Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

    PubMed Central

    Firneisz, Gábor

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients. PMID:25083080

  15. Non-alcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model.

    PubMed

    Müller, Peter; Messmer, Marie; Bayer, Monika; Pfeilschifter, Josef M; Hintermann, Edith; Christen, Urs

    2016-05-01

    Non-alcoholic fatty liver disease (NAFLD) and its more severe development non-alcoholic steatohepatitis (NASH) are increasing worldwide. In particular NASH, which is characterized by an active hepatic inflammation, has often severe consequences including progressive fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). Here we investigated how metabolic liver injury is influencing the pathogenesis of autoimmune hepatitis (AIH). We used the CYP2D6 mouse model in which wild type C57BL/6 mice are infected with an Adenovirus expressing the major liver autoantigen cytochrome P450 2D6 (CYP2D6). Such mice display several features of human AIH, including interface hepatitis, formation of LKM-1 antibodies and CYP2D6-specific T cells, as well as hepatic fibrosis. NAFLD was induced with a high-fat diet (HFD). We found that pre-existing NAFLD potentiates the severity of AIH. Mice fed for 12 weeks with a HFD displayed increased cellular infiltration of the liver, enhanced hepatic fibrosis and elevated numbers of liver autoantigen-specific T cells. Our data suggest that a pre-existing metabolic liver injury constitutes an additional risk for the severity of an autoimmune condition of the liver, such as AIH.

  16. PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

    PubMed

    Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2016-04-27

    Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis.

  17. Connection of Nicotine to Diet-Induced Obesity and Non-Alcoholic Fatty Liver Disease: Cellular and Mechanistic Insights

    PubMed Central

    Sinha-Hikim, Amiya P.; Sinha-Hikim, Indrani; Friedman, Theodore C.

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) poses a serious health hazard affecting 20–40% of adults in the general population in the USA and over 70% of the obese and extremely obese people. In addition to obesity, nicotine is recognized as a risk factor for NAFLD, and it has been reported that nicotine can exaggerate obesity-induced hepatic steatosis. The development of NAFLD has serious clinical complications because of its potential progression from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Multiple mechanisms can be involved in nicotine plus high-fat diet-induced (HFD) hepatic steatosis. Emerging evidence now suggests that nicotine exacerbates hepatic steatosis triggered by HFD, through increased oxidative stress and hepatocellular apoptosis, decreased phosphorylation (inactivation) of adenosine-5-monophosphate-activated protein kinase and, in turn, up-regulation of sterol response-element binding protein 1-c, fatty acid synthase, and activation of acetyl-coenzyme A-carboxylase, leading to increased hepatic lipogenesis. There is also growing evidence that chronic endoplasmic reticulum stress through regulation of several pathways leading to oxidative stress, inflammation, perturbed hepatic lipid homeostasis, apoptosis, and autophagy can induce hepatic steatosis and its progression to NASH. Evidence also suggests a central role of the gut microbiota in obesity and its related disorders, including NAFLD. This review explores the contribution of nicotine and obesity to the development of NAFLD and its molecular underpinning. PMID:28239368

  18. PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2016-01-01

    Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis. PMID:27128907

  19. Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Armengol, Sandra; Sabench, Fàtima; Ras, Rosa; Hernandez, Mercè; Aguilar, Carmen; Colom, Josep; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2016-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients. Materials and Methods We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD. Results We found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate) had the highest accuracy in diagnosing liver steatosis. Conclusion These findings suggest that alpha-ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH. PMID:27123846

  20. Altered Fatty Acid Metabolism-Related Gene Expression in Liver from Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Auguet, Teresa; Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Porras, José Antonio; Aragonès, Gemma; Sabench, Fátima; Hernandez, Mercé; Aguilar, Carmen; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2014-01-01

    Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis. PMID:25474087

  1. Altered fatty acid metabolism-related gene expression in liver from morbidly obese women with non-alcoholic fatty liver disease.

    PubMed

    Auguet, Teresa; Berlanga, Alba; Guiu-Jurado, Esther; Martinez, Salomé; Porras, José Antonio; Aragonès, Gemma; Sabench, Fátima; Hernandez, Mercé; Aguilar, Carmen; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

    2014-12-02

    Lipid accumulation in the human liver seems to be a crucial mechanism in the pathogenesis and the progression of non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate gene expression of different fatty acid (FA) metabolism-related genes in morbidly obese (MO) women with NAFLD. Liver expression of key genes related to de novo FA synthesis (LXRα, SREBP1c, ACC1, FAS), FA uptake and transport (PPARγ, CD36, FABP4), FA oxidation (PPARα), and inflammation (IL6, TNFα, CRP, PPARδ) were assessed by RT-qPCR in 127 MO women with normal liver histology (NL, n = 13), simple steatosis (SS, n = 47) and non-alcoholic steatohepatitis (NASH, n = 67). Liver FAS mRNA expression was significantly higher in MO NAFLD women with both SS and NASH compared to those with NL (p = 0.003, p = 0.010, respectively). Hepatic IL6 and TNFα mRNA expression was higher in NASH than in SS subjects (p = 0.033, p = 0.050, respectively). Interestingly, LXRα, ACC1 and FAS expression had an inverse relation with the grade of steatosis. These results were confirmed by western blot analysis. In conclusion, our results indicate that lipogenesis seems to be downregulated in advanced stages of SS, suggesting that, in this type of extreme obesity, the deregulation of the lipogenic pathway might be associated with the severity of steatosis.

  2. Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation

    PubMed Central

    Peverill, William; Powell, Lawrie W.; Skoien, Richard

    2014-01-01

    Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis and inflammation and, in some patients, progressive fibrosis leading to cirrhosis. An understanding of the pathogenesis of NASH is still evolving but current evidence suggests multiple metabolic factors critically disrupt homeostasis and induce an inflammatory cascade and ensuing fibrosis. The mechanisms underlying these changes and the complex inter-cellular interactions that mediate fibrogenesis are yet to be fully elucidated. Lipotoxicity, in the setting of excess free fatty acids, obesity, and insulin resistance, appears to be the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence contribute to activation of the inflammasome via a variety of intra- and inter-cellular signalling mechanisms leading to fibrosis. Current evidence suggests that periportal components, including the ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the Th17 response may mediate disease progression. This review aims to provide an overview of the pathogenesis of NASH and summarises the evidence pertaining to key mechanisms implicated in the transition from steatosis and inflammation to fibrosis. Currently there are limited treatments for NASH although an increasing understanding of its pathogenesis will likely improve the development and use of interventions in the future. PMID:24830559

  3.  The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women.

    PubMed

    Simental-Mendía, Luis E; Simental-Mendía, Esteban; Rodríguez-Hernández, Heriberto; Rodríguez-Morán, Martha; Guerrero-Romero, Fernando

    2016-01-01

     Introduction and aim. Given that early identification of non-alcoholic fatty liver disease (NAFLD) is an important issue for primary prevention of hepatic disease, the objectives of this study were to evaluate the efficacy of the product of triglyceride and glucose levels (TyG) for screening simple steatosis and non-alcoholic steatohepatitis (NASH) in asymptomatic women, and to compare its efficacy vs. other biomarkers for recognizing NAFLD. Asymptomatic women aged 20 to 65 years were enrolled into a cross-sectional study. The optimal values of TyG, for screening simple steatosis and NASH were established on a Receiver Operating Characteristic scatter plot; the sensitivity, specificity, and likelihood ratios of TyG index were estimated versus liver biopsy. According sensitivity and specificity, the efficacy of TyG was compared versus the well-known clinical biomarkers for recognizing NAFLD. A total of 50 asymptomatic women were enrolled. The best cutoff point of TyG for screening simple steatosis was 4.58 (sensitivity 0.94, specificity 0.69); in addition, the best cutoff point of TyG index for screening NASH was 4.59 (sensitivity 0.87, specificity 0.69). The positive and negative likelihood ratios were 3.03 and 0.08 for simple steatosis, and 2.80 and 0.18 for NASH. As compared versus SteatoTest, NashTest, Fatty liver index, and Algorithm, the TyG showed to be the best test for screening. TyG has high sensitivity and low negative likelihood ratio; as compared with other clinical biomarkers, the TyG showed to be the best test for screening simple steatosis and NASH.

  4. Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

    PubMed Central

    van Gorp, Patrick J.; Jeurissen, Mike L. J.; Houben, Tom; Walenbergh, Sofie M. A.; Debets, Jacques; Oligschlaeger, Yvonne; Gijbels, Marion J. J.; Neumann, Dietbert; Shiri-Sverdlov, Ronit

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)—a serum protein mainly secreted by liver—was shown to inhibit oxidized low-density lipoprotein (OxLDL)/lipopolysaccharides (LPS)-induced inflammation in mouse macrophages. Additionally, MSP could reduce palmitic acid (PA)-induced lipid accumulation and lipogenesis in the HepG2 cell line. Altogether, these data suggest MSP as a suppressor for metabolic inflammation. However, so far the potential of MSP to be used as a treatment for NASH was not investigated. We hypothesized that MSP reduces lipid accumulation and hepatic inflammation. To investigate the effects of MSP in the early stage of NASH, low-density lipoprotein receptor (Ldlr-/-) mice were fed either a regular chow or a high fat, high cholesterol (HFC) diet for 7 days. Recombinant MSP or saline (control) was administrated to the mice by utilizing subcutaneously-implanted osmotic mini-pumps for the last 4 days. As expected, mice fed an HFC diet showed increased plasma and hepatic lipid accumulation, as well as enhanced hepatic inflammation, compared with chow-fed controls. Upon MSP administration, the rise in cholesterol and triglyceride levels after an HFC diet remained unaltered. Surprisingly, while hepatic macrophage and neutrophil infiltration was similar between the groups, MSP-treated mice showed increased gene expression of pro-inflammatory and pro-apoptotic mediators in the liver, compared with saline-treated controls. Contrary to our expectations, MSP did not ameliorate NASH. Observed changes in inflammatory gene expression suggest that further research is needed to clarify the long-term effects of MSP. PMID:27685150

  5. Comprehensive Study of Multiple Stages Progressing to Nonalcoholic Steatohepatitis with Subsequent Fibrosis in SD Rats.

    PubMed

    Wang, Lulu; Wu, Susu; Cai, Minxuan; Ma, Ji; Li, Shengcun; Li, Maoru; Xu, Yan; Wei, Lixin; Shang, Jing

    2017-08-18

    Because of the absence of the time course of histological nonalcoholic fatty hepatitis with subsequent fibrotic progression, the effective approaches available for controlling the onset and progression of non-alcoholic steatohepatitis (NASH) remain limited. Therefore, we detected the serum and liver tissue related lipid metabolism disorder, liver pathology and relative molecular makers alteration dynamically in a high fat-sucrose diet during different time points. High fat-sucrose diet significantly increased the serum lipid level on day 10. The excess lipid accumulation in liver was referred to as simple steatosis after the feeding of a high fat-sucrose diet for 20 days. The high fat-sucrose diet induced a hepatic inflammation response on day 30. Similarly, hepatic fibrosis was also initiated on day 30 and gradually formed from the 30th to the 50th day. Oxidative stress may be related with the process from NASH to liver fibrosis. Insulin resistance was involved in the progression from hepatic steatosis to NASH with hepatic fibrosis from the 20th to the 50th day. In conclusion, we established a high fat-sucrose diet induced nonalcoholic fatty hepatitis with liver fibrosis rat model, which presented the time course of histological nonalcoholic steatohepatitis and the initiation and progression change of characteristic molecular makers in the process from steatosis to hepatic fibrosis.

  6. SFRP5 hepatic expression is associated with non-alcoholic liver disease in morbidly obese women.

    PubMed

    Gutiérrez-Vidal, Roxana; Vega-Badillo, Joel; Reyes-Fermín, Laura M; Hernández-Pérez, Hugo A; Sánchez-Muñoz, Fausto; López-Álvarez, Guadalupe S; Larrieta-Carrasco, Elena; Fernández-Silva, Itzel; Méndez-Sánchez, Nahum; Tovar, Armando R; Villamil-Ramírez, Hugo; Mejía-Domínguez, Ana M; Villarreal-Molina, Teresa; Hernández-Pando, Rogelio; Campos-Pérez, Francisco; Aguilar-Salinas, Carlos A; Canizales-Quinteros, Samuel

    2015-01-01

    Secreted frizzled-related protein 5 (SFRP5) was recently described as a new adipokine protective for hepatic steatosis and other obesity-related complications in the mouse model. To date, SFRP5 expression in non-alcoholic fatty liver disease (NAFLD) has not been fully assessed in humans. We measured circulating SFRP5 levels and its expression in liver and adipose tissue, and evaluated its association with NAFLD in morbidly obese women. Fifty-four morbidly obese women undergoing bariatric surgery were included in the study. Liver biopsies were used for histology and hepatic triglyceride content quantification. Circulating SFRP5 levels were measured through enzyme-linked immunoabsorbent assay, and SFRP5 expression was performed in hepatic and adipose tissue (subcutaneous and visceral). Although circulating SFRP5 levels showed a tendency to decrease with NAFLD progression, no significant differences were observed among non-alcoholic steatosis, steatohepatitis, and control subjects. Hepatic SFRP5 expression showed a negative correlation with hepatic triglyceride content (r = -0.349, P = 0.016 for mRNA and r = -0.291, P = 0.040 for SRFP5 protein) and ALT serum levels (r = -0.437, P = 0.001 for SRFP5 protein). In addition, hepatic SFRP5 protein levels were significantly lower in NASH than in control subjects (P = 0.006). This is the first study reporting an association of hepatic SFRP5 expression with NAFLD in humans.

  7. Gut–Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Poeta, Marco; Pierri, Luca; Vajro, Pietro

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A “multiple-hit” hypothesis has been invoked to explain its pathogenesis. The “first hit” is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as “second hits” implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis. In this regard, the gut–liver axis (GLA) seems to play a central role. Principal players are the gut microbiota, its bacterial products, and the intestinal barrier. A derangement of GLA (namely, dysbiosis and altered intestinal permeability) may promote bacteria/bacterial product translocation into portal circulation, activation of inflammation via toll-like receptors signaling in hepatocytes, and progression from simple steatosis to non-alcoholic steato-hepatitis (NASH). Among other factors a relevant role has been attributed to the farnesoid X receptor, a nuclear transcriptional factor activated from bile acids chemically modified by gut microbiota (GM) enzymes. The individuation and elucidation of GLA derangement in NAFLD pathomechanisms is of interest at all ages and especially in pediatrics to identify new therapeutic approaches in patients recalcitrant to lifestyle changes. Specific targeting of gut microbiota via pre-/probiotic supplementation, feces transplantation, and farnesoid X receptor modulation appear promising. PMID:28767077

  8. Increased expression of Zinc finger protein 267 in non-alcoholic fatty liver disease

    PubMed Central

    Schnabl, Bernd; Czech, Barbara; Valletta, Daniela; Weiss, Thomas S; Kirovski, Georgi; Hellerbrand, Claus

    2011-01-01

    Hepatocellular lipid accumulation is a hallmark of non-alcoholic fatty liver disease (NAFLD), which encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and ultimately cirrhosis. Zinc finger protein 267 (ZNF267) belongs to the family of Kruppel-like transcription factors, which regulate diverse biological processes that include development, proliferation, and differentiation. We have previously demonstrated that ZNF267 expression is up-regulated in liver cirrhosis and is further increased in hepatocellular carcinoma (HCC). Here, we analyzed the expression of ZNF267 in tissue specimens of NAFLD patients and found a significant up-regulation compared to normal liver tissue. Noteworthy, ZNF267 mRNA was already significantly increased in steatotic liver tissue without inflammation. In line with this, incubation of primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation and corresponding dose-dependent ZNF267 induction in vitro. Furthermore, hepatocellular lipid accumulation induced formation of reactive oxygen species (ROS), and also chemically induced ROS formation increased ZNF267 mRNA expression. In summary with previous findings, which revealed ZNF267 as pro-fibrogenic and pro-cancerogenic factor in chronic liver disease, the present study further suggests ZNF267 as promising therapeutic target particularly for NAFLD patients. In addition, it further indicates that hepatic steatosis per se has pathophysiological relevance and should not be considered as benign. PMID:22076166

  9. Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.

    PubMed

    Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

    2017-09-26

    We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.

  10. Betaine and nonalcoholic steatohepatitis: back to the future?

    PubMed

    Mukherjee, Sandeep

    2011-08-28

    Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries. Obesity and insulin resistance are the two most common risk factors for NASH, which can lead to recurrent NASH after liver transplantation. There is currently no approved therapy for NASH, and treatment is directed at risk factor modification and lifestyle changes. Betaine has been used for NASH, with mixed results, and may show promise in conjunction with other agents in clinical trials.

  11. Genome-Wide Analysis of Copy Number Variation Identifies Candidate Gene Loci Associated with the Progression of Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Zain, Shamsul Mohd; Mohamed, Rosmawati; Cooper, David N.; Razali, Rozaimi; Rampal, Sanjay; Mahadeva, Sanjiv; Chan, Wah-Kheong; Anwar, Arif; Rosli, Nurul Shielawati Mohamed; Mahfudz, Anis Shafina; Cheah, Phaik-Leng; Basu, Roma Choudhury; Mohamed, Zahurin

    2014-01-01

    Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in ‘second hit’ hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH. PMID:24743702

  12. Vitamin D Supplementation and Non-Alcoholic Fatty Liver Disease: Present and Future.

    PubMed

    Barchetta, Ilaria; Cimini, Flavia Agata; Cavallo, Maria Gisella

    2017-09-14

    Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease throughout the Western world and is recognized as the main cause of cryptogenic cirrhosis; however, the identification of an effective therapy for NAFLD is still a major challenge. Vitamin D deficiency is a wide-spread condition which reaches epidemic proportions in industrialized countries, mainly in relation to current lifestyle and limited dietary sources. Epidemiological studies point towards an association between hypovitaminosis D and the presence of NAFLD and steatohepatitis (NASH), independently of confounders such as obesity and insulin resistance. Furthermore, several pieces of experimental data have shown the anti-fibrotic, anti-inflammatory and insulin-sensitizing properties exerted by vitamin D on hepatic cells. However, results from trials evaluating the effects of oral vitamin D supplementation on liver damage in NAFLD and NASH are controversial. The aim of this review is to give an overview of the evidence currently available from clinical trials and to discuss possible shortcomings and new strategies to be considered in future investigations.

  13. MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH

    PubMed Central

    Zarfeshani, Aida; Ngo, Sherry; Sheppard, Allan M.

    2015-01-01

    Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern “epidemic” of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver’s limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of “extra-hepatic fat”, a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body’s attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis. PMID:26580662

  14. Novel Pharmacotherapy Options for NASH.

    PubMed

    Ratziu, Vlad

    2016-05-01

    While simple to recommend, diet and lifestyle measures as a first-line therapy for nonalcoholic steatohepatitis (NASH) are hardly a model of successful therapy, as most clinicians can testify. They can be complex to implement, hard to sustain, and of limited efficacy in advanced stages of the disease. The need for specific pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry, and regulators and is largely expected by patients. The result is a clear move away from products developed second hand for NASH (such as pioglitazone or metformin) or from generic, non-specific hepatoprotectors (such as pentoxifylline, ursodeoxycholic acid, or antioxidants) toward molecules developed and tested specifically for NASH that aim to correct one or several of the pathways of liver injury in this disease. The two most advanced molecules, obeticholic acid and elafibranor, have shown encouraging data on improving hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving liver fibrosis and elafibranor improving the glycemic and lipid profile. Much larger trials, currently ongoing, will need to confirm these preliminary data and better characterize the safety and tolerability profile. Meanwhile, other compounds are being tested, a few in phase 2b studies (cenicriviroc, aramchol for NASH, and simtuzumab for NASH fibrosis) and many more in earlier, smaller trials. Most of these drug candidates target different pathways, which speaks to the diversity and dynamism of the NASH pipeline.

  15. 6-gingerol protects against nutritional steatohepatitis by regulating key genes related to inflammation and lipid metabolism.

    PubMed

    Tzeng, Thing-Fong; Liou, Shorong-Shii; Chang, Chia Ju; Liu, I-Min

    2015-02-04

    Non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis (NASH), appears to be increasingly common worldwide. The aim of the study was to investigate the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone), a bioactive ingredient of plants belonging to the Zingiberaceae family, on experimental models of NASH. In HepG2 cells, 6-gingerol (100 μmol/L) treatment inhibited free fatty acids mixture (0.33 mmol/L palmitate and 0.66 mmol/L oleate)-induced triglyceride and inflammatory marker accumulations. Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After four weeks of MCD diet feeding, the mice were dosed orally with 6-gingerol (25, 50 or 100 mg/kg/day) once daily for another four weeks. 6-Gingerol (100 mg/kg/day) attenuated liver steatosis and necro-inflammation in MCD diet-fed mice. The expressions of inflammatory cytokine genes, including those for monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6, and nuclear transcription factor (NF-κB), which were increased in the livers of MCD diet-fed mice, were attenuated by 6-gingerol. 6-Gingerol possesses a repressive property on hepatic steatosis, which is associated with induction of peroxisome proliferator-activated receptor α. Our study demonstrated the protective role of 6-gingerol in ameliorating nutritional steatohepatitis. The effect was mediated through regulating key genes related to lipid metabolism and inflammation.

  16. Effect of dietary fat to produce non-alcoholic fatty liver in the rat.

    PubMed

    Ahmed, Umbreen; Redgrave, Trevor G; Oates, Phillip S

    2009-08-01

    Non-alcoholic steatohepatitis (NASH) belongs to a spectrum of non-alcoholic fatty liver disease (NAFLD). Oxidative stress is hypothesized to play an important role in the progression of the disease. We used the Lieber/DeCarli model for NASH to investigate the mechanisms involved in its progression. Male Sprague-Dawley rats were fed standard (35% of energy from fat) or high fat (71% of energy from fat) liquid diets, ad libitum or two-thirds of the amount consumed ad libitum initially for 3 weeks and then extended to 5 weeks. Steatosis was absent in rats at 3 weeks feeding, but by 5 weeks, the high fat/ad lib group showed microvesicular steatosis and foci of macrovesicular steatosis without inflammation. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were not different. By 5 weeks feeding, hepatic triglycerides were highest in the high fat ad lib group and the ad lib groups were higher compared with their restricted groups. The oxidative stress marker, hydroxyalkenal (HAE) was decreased in the standard ad lib compared with the high fat ad lib group. Liver mRNA of interleukin-6, haem oxygenase-1, and markers of endoplasmic stress: C/EBP homologous protein (CHOP), glucose responsive protein-78 (GRP78) and spliced X-box DNA binding protein (spliced XBP1) were similar in the ad lib groups. Extending the feeding period of the high fat/ad lib diet for 5 weeks placed our rats with Type I to II NAFLD compared to the more progressed Type III state previously obtained after 3 weeks feeding. The milder condition obtained raised the prospect of genetic modifiers present in our rats that resist disease progression.

  17. Reduced Lysosomal Acid Lipase Activity in Adult Patients With Non-alcoholic Fatty Liver Disease

    PubMed Central

    Baratta, Francesco; Pastori, Daniele; Del Ben, Maria; Polimeni, Licia; Labbadia, Giancarlo; Di Santo, Serena; Piemonte, Fiorella; Tozzi, Giulia; Violi, Francesco; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver. LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed. Median LAL activity was 1.15 (0.95–1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61–1.01), p < 0.001 vs. HS]. A further reduction was observed in the subgroup of NASH [0.67 (0.51–0.77), p < 0.001 vs. HS]. Patients with LAL activity below median had higher values of serum total cholesterol (p < 0.05) and LDL-c (p < 0.05), and increased serum liver enzymes (ALT, p < 0.001; AST, p < 0.01; GGT, p < 0.01). At multivariable logistic regression analysis, factors associated with LAL activity below median were ALT (OR: 1.018, 95% CI 1.004–1.032, p = 0.011) and metabolic syndrome (OR: 2.551, 95% CI 1.241–5.245, p = 0.011), whilst statin use predicted a better LAL function (OR: 0.464, 95% CI 0.248–0.866, p = 0.016). Our findings suggest a strong association between impaired LAL activity and NAFLD. A better knowledge of the role of LAL may provide new insights in NAFLD pathogenesis. PMID:26288848

  18. The role of nutraceuticals for the treatment of non-alcoholic fatty liver disease.

    PubMed

    Del Ben, Maria; Polimeni, Licia; Baratta, Francesco; Pastori, Daniele; Angelico, Francesco

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to liver fibrosis and to cirrhosis. NAFLD is considered as the hepatic component of the metabolic syndrome but mechanisms underlying the onset and progression of NAFLD are still under investigation. The traditional 'two hit hypothesis' has been developed within a more complex 'multiple parallel hit hypothesis' which comprises a wide spectrum of parallel hits. Many therapeutic approaches have been proposed so far and several types of nutraceuticals have been suggested for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH), the most promising of which are those with antioxidant effects. In particular, vitamin E appears to be effective for the treatment of nondiabetic subjects with more advanced NASH, although the high suggested daily dosages are a matter of concern. Moreover, polyphenols reduce liver fat accumulation, mainly by inhibiting lipogenesis. At present, there are insufficient data to support the use of vitamin C supplements in patients with NAFLD. Data on polyunsaturated fatty acid (PUFA) supplementation are heterogeneous, and no well-designed randomized controlled studies (RCTs) of adequate size, with histological assessment of steatosis, have been conducted. Based on the available data, silymarin supplementation for the treatment of NAFLD seems to have a favourable effect. The results with anti-inflammatory agents, such as vitamin D and carnitine are uncertain. In conclusion, there are insufficient data either to support or refute the use of nutraceuticals for subjects with NAFLD. Further RTCs, with histological changes as an outcome measure, are needed.

  19. Reduced Lysosomal Acid Lipase Activity in Adult Patients With Non-alcoholic Fatty Liver Disease.

    PubMed

    Baratta, Francesco; Pastori, Daniele; Del Ben, Maria; Polimeni, Licia; Labbadia, Giancarlo; Di Santo, Serena; Piemonte, Fiorella; Tozzi, Giulia; Violi, Francesco; Angelico, Francesco

    2015-07-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by intra-hepatic fat accumulation and mechanisms involved in its pathogenesis are not fully explained. Lysosomal Acid Lipase (LAL) is a key enzyme in lipid metabolism. We investigated its activity in patients with fatty liver. LAL activity (nmol/spot/h) was measured in 100 adult healthy subjects (HS) and in 240 NAFLD patients. A sub-analysis on 35 patients with biopsy-proven non-alcoholic steatohepatitis (NASH) was performed. Median LAL activity was 1.15 (0.95-1.72) in HS. It was significantly reduced in NAFLD [0.78 (0.61-1.01), p < 0.001 vs. HS]. A further reduction was observed in the subgroup of NASH [0.67 (0.51-0.77), p < 0.001 vs. HS]. Patients with LAL activity below median had higher values of serum total cholesterol (p < 0.05) and LDL-c (p < 0.05), and increased serum liver enzymes (ALT, p < 0.001; AST, p < 0.01; GGT, p < 0.01). At multivariable logistic regression analysis, factors associated with LAL activity below median were ALT (OR: 1.018, 95% CI 1.004-1.032, p = 0.011) and metabolic syndrome (OR: 2.551, 95% CI 1.241-5.245, p = 0.011), whilst statin use predicted a better LAL function (OR: 0.464, 95% CI 0.248-0.866, p = 0.016). Our findings suggest a strong association between impaired LAL activity and NAFLD. A better knowledge of the role of LAL may provide new insights in NAFLD pathogenesis.

  20. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.

    PubMed

    Milić, Sandra; Lulić, Davorka; Štimac, Davor

    2014-07-28

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m(2). However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m(2)) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.

  1. Non-alcoholic fatty liver disease: need for a balanced nutritional source.

    PubMed

    Veena, Jayagopalan; Muragundla, Anjaneyulu; Sidgiddi, Srinivas; Subramaniam, Swaminathan

    2014-12-14

    Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are an increasingly common chronic liver disease closely associated with diabetes and obesity that have reached epidemic proportions. Reports on the prevalence of NAFLD have suggested that 27-34% of the general population in the USA and 40-90% of the obese population worldwide have this disease. Increasing urbanisation rate and associated inappropriate lifestyle changes are not only the risk factors of diabetes, but also unmask genetic predisposition in various populations for the metabolic syndrome and its manifestations including NAFLD and NASH. Lifestyle modifications and balanced nutrition are among the foremost management strategies along with ursodeoxycholic acid, metformin, vitamin E and pentoxifylline. Although weight reduction associated with current therapeutic strategies has shown some promise, maintaining it in the long run is largely unsuccessful. With the safety of pharmacotherapy still being uncertain and can be started only after confirmation, other reasonable interventions such as nutrition hold promise in preventing disease progression. The role of dietary components including branched-chain amino acids, methionine, choline and folic acid is currently being evaluated in various clinical trials. Nutritional approaches sought to overcome the limitations of pharmacotherapy also include evaluating the effects of natural ingredients, such as silymarin and spirulina, on liver disease. Understanding the specific interaction between nutrients and dietary needs in NAFLD and maintaining this balance through either a diet or a nutritional product thus becomes extremely important in providing a more realistic and feasible alternative to treat NAFLD. A planned complete nutritional combination addressing specific needs and helping to prevent the progression of NAFLD is the need of the hour to avert people from ending up with complications.

  2. Review article: Drug therapy for non-alcoholic fatty liver disease.

    PubMed

    Comar, K M; Sterling, R K

    2006-01-15

    Non-alcoholic fatty liver disease represents a spectrum of liver diseases, characterized mainly by macrovesicular steatosis in the absence of significant alcohol ingestion. Non-alcoholic fatty liver disease includes both non-alcoholic fatty liver and non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis once considered a benign process is now known to lead to progressive fibrosis and cirrhosis. Histologically indistinguishable from alcoholic liver disease, the exact aetiology of non-alcoholic fatty liver disease remains unknown, but the fundamental pathophysiological process appears to be insulin resistance and oxidative stress related to the metabolic syndrome. Therapy has focused on risk factors, weight reduction and pharmacological intervention. Promising pharmacological treatments have been demonstrated with antioxidants, insulin sensitizers, hepatoprotectants and lipid-lowering agents. However, without larger randomized studies, no pharmacological treatments can be recommended at this time.

  3. [Non-alcoholic fatty liver: 10 years' experience at the Insituto Nacional de la Nutrición Salvador Zubirán].

    PubMed

    de la Mora, G; Olivera, M; de la Cerda, R; Arista, J; Kershenobich, D; Uribe, M

    1994-01-01

    To describe the characteristics of non-alcoholic steatohepatitis (NASH) at the Instituto Nacional de la Nutricion Salvador Zubiran. We reviewed all liver biopsy reports from January 1982 to December 1991. From patient records we obtained the following data: clinical, biochemical, imaging studies and we reviewed the histological material. We correlated clinical, biochemical and histological data. From 2963 biopsies reviewed we obtained 16 cases of NASH. We found a 7:1 female/male ratio. Median age was 30 years and six patients were obese. Eleven patients had concomitant disease (diabetes in seven) and nine were using drugs. All had been studied for biochemical abnormalities and were asymptomatic. Ten patients had hepatomegaly and six splenomegaly. Ultrasound suggested the diagnosis in 50% of the cases. All had steatosis, inflammatory infiltrate, necrosis, fibrosis and Mallory bodies at different stages. One case had cirrhosis on initial biopsy and two developed cirrhosis on follow-up (one and eight years later). We did not find any correlation between clinical, biochemical or imaging characteristics and histological findings. When we compared these findings between obese and non obese patients and primary and secondary NASH we did not find any differences between groups. NASH is infrequent in our institution. The underlying pathogenesis seems to be multifactorial. There is no biochemical-histological correlation. Cirrhosis can develop in some cases.

  4. PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model.

    PubMed

    Lee, Su Jin; Kang, Jeong Han; Choi, Soo Young; Suk, Ki Tae; Kim, Dong Joon; Kwon, Oh-Shin

    2013-01-01

    The precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH) has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 mediated α-SMA expression was investigated using NASH model mice. In preparation of the NASH model, male C57BL6/J mice were fed a methionine-choline-deficient (MCD) diet for 3 weeks, after which time they were intraperitoneally injected with lipopolysaccharide (LPS). In addition, Tlr4(Lps-d) (CH3/HeJ) mice were used to demonstrate the TGFβ1 signaling's dependency on TLR4 induction. Liver histology and hepatic hepatitis markers were investigated, and hepatic gene expression levels were determined by real-time PCR. Acute liver injury by LPS injection specifically elevated not only α-SMA expression but also phospho-PKCδ in this model. In contrast, Tlr4(Lps-d) (CH3/HeJ) and blockade of TGFβ1 receptor by SB431542 resulted in a significant reduction of PKCδ activation and α-SMA expression. Moreover, the TGFβ1-induced α-SMA production was significantly reduced by a specific PKCδ inhibitor. These findings suggested that PKCδ plays a critical role in TGFβ1-induced α-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCδ in the regulation of α-SMA expression in NASH liver tissues, and the impaired induction of PKCδ phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCδ inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCδ represents a promising target for treating NASH.

  5. Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet.

    PubMed

    Bison, Anaïs; Marchal-Bressenot, Aude; Li, Zhen; Elamouri, Ilef; Feigerlova, Eva; Peng, Lu; Houlgatte, Remi; Beck, Bernard; Pourié, Gregory; Alberto, Jean-Marc; Umoret, Remy; Conroy, Guillaume; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Guéant-Rodriguez, Rosa-Maria

    2016-11-17

    Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet.

  6. Foetal programming by methyl donor deficiency produces steato-hepatitis in rats exposed to high fat diet

    PubMed Central

    Bison, Anaïs; Marchal-Bressenot, Aude; Li, Zhen; Elamouri, Ilef; Feigerlova, Eva; Peng, Lu; Houlgatte, Remi; Beck, Bernard; Pourié, Gregory; Alberto, Jean-Marc; Umoret, Remy; Conroy, Guillaume; Bronowicki, Jean-Pierre; Guéant, Jean-Louis; Guéant-Rodriguez, Rosa-Maria

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome, which emerges as a major public health problem. Deficiency in methyl donors (folate and vitamin B12) during gestation and lactation is frequent in humans and produces foetal programming effects of metabolic syndrome, with small birth weight and liver steatosis at day 21 (d21), in rat pups. We investigated the effects of fetal programming on liver of rats born from deficient mothers (iMDD) and subsequently subjected to normal diet after d21 and high fat diet (HF) after d50. We observed increased abdominal fat, ASAT/ALAT ratio and angiotensin blood level, but no histological liver abnormality in d50 iMDD rats. In contrast, d185 iMDD/HF animals had hallmarks of steato-hepatitis, with increased markers of inflammation and fibrosis (caspase1, cleaved IL-1β, α1(I) and α2(I) collagens and α-SMA), insulin resistance (HOMA-IR and Glut 2) and expression of genes involved in stellate cell stimulation and remodelling and key genes triggering NASH pathomechanisms (transforming growth factor beta super family, angiotensin and angiotensin receptor type 1). Our data showed a foetal programming effect of MDD on liver inflammation and fibrosis, which suggests investigating whether MDD during pregnancy is a risk factor of NASH in populations subsequently exposed to HF diet. PMID:27853271

  7. Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects.

    PubMed

    Vega-Badillo, Joel; Gutiérrez-Vidal, Roxana; Hernández-Pérez, Hugo A; Villamil-Ramírez, Hugo; León-Mimila, Paola; Sánchez-Muñoz, Fausto; Morán-Ramos, Sofía; Larrieta-Carrasco, Elena; Fernández-Silva, Itzel; Méndez-Sánchez, Nahúm; Tovar, Armando R; Campos-Pérez, Francisco; Villarreal-Molina, Teresa; Hernández-Pando, Rogelio; Aguilar-Salinas, Carlos A; Canizales-Quinteros, Samuel

    2016-09-01

    Abnormal cholesterol metabolism may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH) and fibrosis. miR-33 and miR-144 regulate adenosine triphosphate binding cassette transporter (ABCA1) and other target genes involved in cholesterol efflux, fatty acid oxidation and inflammation. We explored relationships between non-alcoholic fatty liver disease (NAFLD) and the hepatic expression of ABCA1/ABCG1, as well as other target genes regulated by miR-33 (carnitine O-octanoyltransferase, CROT and hydroxyacyl-CoA-dehydrogenase β-subunit, HADHB) and miR-144 (toll-like receptor-2, TLR2). Moreover, we evaluated whether the expression of these genes is correlated with miR-33a/b and miR-144 expression in Mexican individuals with morbid obesity. Eighty-four morbidly obese subjects undergoing bariatric surgery were included in this study. Liver biopsies were obtained to measure hepatic triglyceride and free cholesterol contents, as well as ABCA1, ABCG1, CROT, HADHB, TLR2, miR-33a/b and miR-144 expression. Hepatic free cholesterol content was significantly increased in NASH as compared to non-NASH subjects, while ABCA1 and ABCG1 protein levels significantly decreased with NASH and fibrosis progression. The relative expression of miR-33a and miR-144 correlated inversely with ABCA1 but not with ABCG1 protein levels. Moreover, both miRNAs increased significantly in NASH individuals. miR-33 target genes CROT and HADHB correlated inversely with miR-33a. However, the expression of these genes was not associated with NASH. miR-33a/144 and their target gene ABCA1 may contribute to the pathogenesis of NASH in morbidly obese subjects. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Obstructive sleep apnea and non-alcoholic Fatty liver disease: is the liver another target?

    PubMed

    Mirrakhimov, Aibek E; Polotsky, Vsevolod Y

    2012-01-01

    Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

  9. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.

    PubMed

    Ceccarelli, Sara; Panera, Nadia; Mina, Marco; Gnani, Daniela; De Stefanis, Cristiano; Crudele, Annalisa; Rychlicki, Chiara; Petrini, Stefania; Bruscalupi, Giovannella; Agostinelli, Laura; Stronati, Laura; Cucchiara, Salvatore; Musso, Giovanni; Furlanello, Cesare; Svegliati-Baroni, Gianluca; Nobili, Valerio; Alisi, Anna

    2015-12-08

    Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.

  10. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis.

    PubMed

    Musso, G; Cassader, M; Olivetti, C; Rosina, F; Carbone, G; Gambino, R

    2013-05-01

    Obstructive sleep apnoea syndrome (OSAS) and non-alcoholic fatty liver disease (NAFLD) are common in clinical practice. NAFLD encompasses simple steatosis and non-alcoholic steatohepatitis (NASH): both confer an increased risk of cardiovascular disease and diabetes; NASH increases also liver-related risk. Growing experimental evidence connects chronic intermittent hypoxia of OSAS to NAFLD. We reviewed English and non-English articles and international meeting abstracts through December 2012. Observational studies were included if they assessed OSAS by polysomnography and NAFLD by histological, radiological or biochemical criteria. Two reviewers evaluated retrieved articles by appropriate quality scores. Main outcomes were pooled using random- or fixed-effects models. The effect of age, sex and body mass index (BMI) on effect estimates was assessed by meta-regression. Eighteen cross-sectional studies (2,183 participants) were included. Pooled odds ratios (ORs) of OSAS for the presence of NAFLD, as defined by histology, radiology, and AST or ALT elevation, were 2.01(95% CI: 1.36-2.97), 2.99(1.79-4.99), 2.36(1.46-3.82) and 2.60(1.88-3.61), respectively. Pooled ORs of OSAS for NASH, fibrosis-any stage, or advanced fibrosis in biopsy-proven NAFLD patients were 2.37(1.59-3.51), 2.16(1.45-3.20) and 2.30(1.21-4.38). The magnitude and direction of effects were unaffected by age, sex and BMI. In conclusion, OSAS is associated with an increased risk of NAFLD, NASH and fibrosis. OSAS patients should be screened for the presence and severity of NAFLD. © 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.

  11. Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

    PubMed Central

    Kristiansen, Maria Nicoline Baandrup; Veidal, Sanne Skovgård; Rigbolt, Kristoffer Tobias Gustav; Tølbøl, Kirstine Sloth; Roth, Jonathan David; Jelsing, Jacob; Vrang, Niels; Feigh, Michael

    2016-01-01

    AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS: Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lepob/Lepob (ob/ob) mice (ob/ob-NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob/ob mice (ob/ob chow). After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob/ob-NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation. Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice (0 vs 4.7 ± 0.4, P < 0.001 compared to lean chow

  12. Liver steatosis and nonalcoholic steatohepatitis: from pathogenesis to therapy.

    PubMed

    Hernández-Pérez, Elizabeth; León García, Plácido Enrique; López-Díazguerrero, Norma Edith; Rivera-Cabrera, Fernando; Del Ángel Benítez, Elizabeth

    2016-09-13

    Non-alcoholic fatty liver disease refers to a disease spectrum that ranges from steatosis to non-alcoholic steatohepatitis, which leads to fibrosis, cirrhosis and hepatocellular carcinoma. Given the increasing prevalence of obesity worldwide, the incidence of non-alcoholic fatty liver disease has become a world health problem. Non-alcoholic fatty liver disease is considered to be the hepatic manifestation of metabolic syndrome associated with insulin resistance, central obesity, and type 2 diabetes mellitus. Allegedly, insulin resistance plays a pivotal role in its pathogenesis. Here we highlight non-alcoholic fatty liver disease epidemiology and pathophysiology, its progression towards steatohepatitis with particular emphasis in liver fibrosis and participation of advanced glycation end products. The different treatments reported are described here as well. We conducted a search in PubMed with the terms steatohepatitis, steatosis advanced glycation end products, liver fibrosis and adipocytokines. Articles were selected according to their relevance.

  13. Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials

    PubMed Central

    He, Lingling; Liu, Xiaoli; Wang, Lijia; Yang, Zhiyun

    2016-01-01

    Abstract The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: “nonalcoholic steatohepatitis,” “non-alcoholic steatohepatitis,” “thiazolidinedione,” “pioglitazone,” “rosiglitazone,” “randomized,” and “clinical trial.” Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the

  14. Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

    PubMed Central

    de Campos Mazo, Daniel Ferraz; Mattar, Rejane; Stefano, José Tadeu; da Silva-Etto, Joyce Matie Kinoshita; Diniz, Márcio Augusto; Duarte, Sebastião Mauro Bezerra; Rabelo, Fabíola; Lima, Rodrigo Vieira Costa; de Campos, Priscila Brizolla; Carrilho, Flair José; Oliveira, Claudia P

    2016-01-01

    AIM To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher’s exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0

  15. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment.

    PubMed

    Dongiovanni, Paola; Anstee, Quentin M; Valenti, Luca

    2013-01-01

    Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.

  16. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein in non-alcoholic fatty liver disease

    PubMed Central

    Lai, Lee-Lee; Sthaneshwar, Pavai; Nik Mustapha, Nik Raihan; Goh, Khean-Lee; Mahadeva, Sanjiv

    2017-01-01

    Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has been suggested to be useful for the assessment of disease severity in non-alcoholic fatty liver disease (NAFLD). Consecutive adult NAFLD patients who had a liver biopsy were included. Serum WFA+-M2BP level was measured using a lectin-antibody sandwich immunoassay using a chemiluminescence enzyme immunoassay machine (HISCL-5000, Sysmex, Kobe, Japan). The measured levels were indexed using the following equation: Cut-off index (COI) = ([WFA+-M2BP]sample−[WFA+-M2BP]NC) / ([WFA+-M2BP]PC−[WFA+-M2BP]NC), where PC = positive control and NC = negative control. Histopathological examination of liver biopsy specimen was reported according to Non-Alcoholic Steatohepatitis (NASH) Clinical Research Network Scoring System. Data for 220 cases were analyzed. The AUROC of the COI for the diagnosis of NASH was 0.65. The AUROC of the COI for the diagnosis of steatosis grade ≥2 and 3 was 0.64 and 0.53, respectively. The AUROC of the COI for the diagnosis of lobular inflammation grade ≥1, ≥2 and 3 was 0.57, 0.68 and 0.59, respectively. The AUROC of the COI for the diagnosis of hepatocyte ballooning grade ≥1 and 2 was 0.64 and 0.65, respectively. The AUROC of the COI for the diagnosis of fibrosis stage ≥1, ≥2, ≥3 and 4 was 0.61, 0.71, 0.74 and 0.84, respectively. Out of the 220 cases, 152 cases were the same 76 patients who had a repeat liver biopsy after 48 weeks of intervention. The AUROC of the change in the COI to detect improvement in steatosis, lobular inflammation, hepatocyte ballooning and fibrosis was 0.57, 0.54, 0.59 and 0.52, respectively. In conclusion, serum WFA+-M2BP was most useful for the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis in NAFLD patients. However, it was less useful for differentiating NASH from non-NASH, and for diagnosis and follow-up of the individual histopathological components of NASH. PMID:28369100

  17. Predictors of non-alcoholic fatty liver disease in obese and overweight Egyptian children: single center study.

    PubMed

    el-Karaksy, Hanaa M; el-Koofy, Nehal M; Anwar, Ghada M; el-Mougy, Fatma M; el-Hennawy, Ahmed; Fahmy, Mona E

    2011-01-01

    Pediatric non-alcoholic fatty liver disease (NAFLD) is a global problem which has been increasingly recognized with the dramatic rise in pediatric obesity. The aim of the present study was to identify the clinical, sonographic, and biochemical predictors for NAFLD in obese children. Seventy-six children (2-15 years) were included after an informed consent. All were subjected to full anthropometric assessment (including height, weight, body mass index, subscapular skin fold thickness, waist and hip circumference and calculation of waist: hip ratio), biochemical assessment of liver function tests, lipid profile and insulin resistance and sonographic assessment of hepatic echogenicity. Liver biopsy when indicated, was done in 33 patients. Sixteen patients (21%) had elevated ALT and 6 (7.9%) had elevated AST. Significant dyslipidemia (low HDL-c, high total cholesterol, high LDL-c and triglycerides) and higher insulin resistance were found in obese patients (P<0.01). The main sonographic findings were hepatomegaly in 20 patients (26.3%) and echogenic liver in 41 patients (53.9%). Liver biopsy showed simple steatosis in eight cases (24.2%) and non-alcoholic steatohepatitis (NASH) in seven cases (21.2%). Anthropometric measurements, increased hepatic echogenicty by ultrasound, insulin resistance and lipid profile were good predictors of NAFLD in obese children if assessed together. However, LDL-c was the only sensitive predictor (independent variable) for NAFLD in both uni- and multivariate logistic regression analyses. Dyslipidemia per se is a strong predictor of NAFLD among obese Egyptian children.

  18. Non-invasive imaging techniques in assessing non-alcoholic fatty liver disease: a current status of available methods

    PubMed Central

    Lăpădat, AM; Jianu, IR; Ungureanu, BS; Florescu, LM; Gheonea, DI; Sovaila, S; Gheonea, IA

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an ailment affecting and increasing a number of people worldwide diagnosed via non-invasive imaging techniques, at a time when a minimum harm caused by medical procedures is rightfully emphasized, more sought after, than ever before. Liver steatosis should not be taken lightly even if its evolution is largely benign as it has the potential to develop into non-alcoholic steatohepatitis (NASH) or even more concerning, hepatic cirrhosis, and hepatocellular carcinoma (HCC). Traditionally, liver biopsy has been the standard for diagnosing this particular liver disease, but nowadays, a consistent number of imagistic methods are available for diagnosing hepatosteatosis and choosing the one appropriate to the clinical context is the key. Although different in sensitivity and specificity when it comes to determining the hepatic fat fraction (FF), these imaging techniques possessing a diverse availability, operating difficulty, cost, and reproducibility are invaluable to any modern physician. Ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), elastography, and spectroscopy will be discussed in order to lay out the advantages and disadvantages of their diagnostic potential and application. Although imagistics has given physicians a valuable insight into the means of managing NAFLD, the current methods are far from perfect, but given the time, they will surely be improved and the use of liver biopsy will be completely removed. PMID:28255371

  19. Non-invasive imaging techniques in assessing non-alcoholic fatty liver disease: a current status of available methods.

    PubMed

    Lăpădat, A M; Jianu, I R; Ungureanu, B S; Florescu, L M; Gheonea, D I; Sovaila, S; Gheonea, I A

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is an ailment affecting and increasing a number of people worldwide diagnosed via non-invasive imaging techniques, at a time when a minimum harm caused by medical procedures is rightfully emphasized, more sought after, than ever before. Liver steatosis should not be taken lightly even if its evolution is largely benign as it has the potential to develop into non-alcoholic steatohepatitis (NASH) or even more concerning, hepatic cirrhosis, and hepatocellular carcinoma (HCC). Traditionally, liver biopsy has been the standard for diagnosing this particular liver disease, but nowadays, a consistent number of imagistic methods are available for diagnosing hepatosteatosis and choosing the one appropriate to the clinical context is the key. Although different in sensitivity and specificity when it comes to determining the hepatic fat fraction (FF), these imaging techniques possessing a diverse availability, operating difficulty, cost, and reproducibility are invaluable to any modern physician. Ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), elastography, and spectroscopy will be discussed in order to lay out the advantages and disadvantages of their diagnostic potential and application. Although imagistics has given physicians a valuable insight into the means of managing NAFLD, the current methods are far from perfect, but given the time, they will surely be improved and the use of liver biopsy will be completely removed.

  20. Evaluation of Non-alcoholic Fatty Liver Disease Using Acoustic Radiation Force Impulse Imaging Elastography in Rat Models.

    PubMed

    Guo, Yanrong; Dong, Changfeng; Lin, Haoming; Zhang, Xinyu; Wen, Huiying; Shen, Yuanyuan; Wang, Tianfu; Chen, Siping; Liu, Yingxia; Chen, Xin

    2017-08-12

    The aim of this study is to evaluate the utility of acoustic radiation force impulse (ARFI) elastography for assessing hepatic fibrosis stage and non-alcoholic fatty liver disease (NAFLD) severity, as well as the relationship among hepatic histologic changes using shear wave velocity (SWV). Animal models with various degrees of NAFLD were established in 110 rats. The right liver lobe was processed and embedded in a fabricated gelatin solution (porcine skin). Liver mechanics were measured using SWV induced by acoustic radiation force. Among the histologic findings, liver elasticity could be used to differentiate normal rats from rats with simple steatosis (SS) as well as distinguish SS from non-alcoholic steatohepatitis (NASH), with areas under the receiver operating characteristic curves (AUROC) of 0.963 (95% confidence interval = 0.871-0.973) and 0.882 (95% confidence interval = 0.807-0.956), respectively. For NAFLD rats, the diagnostic performance of ARFI elastography in predicting significant fibrosis (F ≥ 2) had an AUROC of 0.963. For evaluating steatosis severity, we found a progressive increase in ARFI velocity proportional to steatotic severity in NAFLD rat models, but we observed no significant differences for steatotic severity after excluding the rats with fibrosis. ARFI elastography may be used to differentiate among degrees of severity of NAFLD and hepatic fibrotic stages in NAFLD rat models. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  1. The Nutraceutic Silybin Counteracts Excess Lipid Accumulation and Ongoing Oxidative Stress in an In Vitro Model of Non-Alcoholic Fatty Liver Disease Progression

    PubMed Central

    Vecchione, Giulia; Grasselli, Elena; Cioffi, Federica; Baldini, Francesca; Oliveira, Paulo J.; Sardão, Vilma A.; Cortese, Katia; Lanni, Antonia; Voci, Adriana; Portincasa, Piero; Vergani, Laura

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity and mortality. Oxidative stress and release of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), are major consequences of hepatic lipid overload, which can contribute to progression of NAFLD to non-alcoholic steatohepatitis (NASH). Also, mitochondria are involved in the NAFLD pathogenesis for their role in hepatic lipid metabolism. Definitive treatments for NAFLD/NASH are lacking so far. Silybin, the extract of the milk thistle seeds, has previously shown beneficial effects in NAFLD. Sequential exposure of hepatocytes to high concentrations of fatty acids (FAs) and TNFα resulted in fat overload and oxidative stress, which mimic in vitro the progression of NAFLD from simple steatosis (SS) to steatohepatitis (SH). The exposure to 50 µM silybin for 24 h reduced fat accumulation in the model of NAFLD progression. The in vitro progression of NAFLD from SS to SH resulted in reduced hepatocyte viability, increased apoptosis and oxidative stress, reduction in lipid droplet size, and up-regulation of IκB kinase β-interacting protein and adipose triglyceride lipase expressions. The direct action of silybin on SS or SH cells and the underlying mechanisms were assessed. Beneficial action of silybin was sustained by changes in expression/activity of peroxisome proliferator-activated receptors and enzymes for FA oxidation. Moreover, silybin counteracted the FA-induced mitochondrial damage by acting on complementary pathways: (i) increased the mitochondrial size and improved the mitochondrial cristae organization; (ii) stimulated mitochondrial FA oxidation; (iii) reduced basal and maximal respiration and ATP production in SH cells; (iv) stimulated ATP production in SS cells; and (v) rescued the FA-induced apoptotic signals and oxidative stress in SH cells. We provide new insights about the direct protective effects of the nutraceutic silybin on hepatocytes mimicking

  2. Nonalcoholic steatohepatitis and insulin resistance in children

    PubMed Central

    Arata, Mikage; Nakajima, Junya; Nishimata, Shigeo; Nagata, Tomomi; Kawashima, Hisashi

    2014-01-01

    Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a “two-hit” model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH. PMID:25512797

  3. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease.

    PubMed

    Sahebkar, Amirhossein; Chew, Gerard T; Watts, Gerald F

    2014-03-01

    Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects. This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD). ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

  4. Cannabinoid receptor type 2 functional variant influences liver damage in children with non-alcoholic fatty liver disease.

    PubMed

    Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco; Miraglia del Giudice, Emanuele; Nobili, Valerio

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD.CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02).Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.

  5. Cannabinoid Receptor Type 2 Functional Variant Influences Liver Damage in Children with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Rossi, Francesca; Bellini, Giulia; Alisi, Anna; Alterio, Arianna; Maione, Sabatino; Perrone, Laura; Locatelli, Franco

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis. Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD. CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage. We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02). Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage. PMID:22927922

  6. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

    PubMed

    Suzuki-Kemuriyama, Noriko; Matsuzaka, Takashi; Kuba, Motoko; Ohno, Hiroshi; Han, Song-Iee; Takeuchi, Yoshinori; Isaka, Masaaki; Kobayashi, Kazuto; Iwasaki, Hitoshi; Yatoh, Shigeru; Suzuki, Hiroaki; Miyajima, Katsuhiro; Nakae, Dai; Yahagi, Naoya; Nakagawa, Yoshimi; Sone, Hirohito; Yamada, Nobuhiro; Shimano, Hitoshi

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

  7. A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model

    PubMed Central

    Hara, Yuichi; Hino, Keisuke

    2016-01-01

    Background & Aims Simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) are subtypes of non-alcoholic fatty liver disease (NAFLD), and the pathogenic differences between SS and NASH remain unclear. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that regulate gene expression. The aim of this study was to use animal models and human samples to examine the relationship between miRNA expression profiles and each type of NAFLD (SS and NASH). Methods DD Shionogi, Fatty Liver Shionogi (FLS) and FLS ob/ob mice were used as models for normal control, SS and NASH, respectively. Microarray analysis and real-time PCR were used to identify candidate NAFLD-related miRNAs. Human serum samples were used to examine the expression profiles of these candidate miRNAs in control subjects and patients with SS or NASH. Results Fourteen miRNAs showed clear expression differences among liver tissues from SS, NASH, and control mice with good reproducibility. Among these NAFLD candidate miRNAs, seven showed similar expression patterns and were upregulated in both SS and NASH tissues; these seven candidate miRNAs mapped to an miRNA cluster in the 14q32.2 maternally imprinted region delineated by delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3 mat). Software-based predictions indicated that the transforming growth factor-β pathway, insulin like growth factor-1 and 5' adenosine monophosphate activated protein kinase were potential targets of theses Dlk1-Dio3 mat NAFLD candidate miRNAs. In addition, serum samples from patients with SS or NASH differed markedly with regard to expression of the putative Dlk1-Dio3 mat miRNAs, and these differences accurately corresponded with NAFLD diagnosis. Conclusion The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH. PMID:27135827

  8. Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp27 and fenofibrate.

    PubMed

    Rajamoorthi, Ananthi; Arias, Noemi; Basta, Jeannine; Lee, Richard G; Baldán, Ángel

    2017-09-05

    Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD progresses from benign steatosis to steatohepatitis (NASH) to cirrhosis, and is linked to hepatocellular carcinoma. No targeted treatment is currently approved for NAFLD/NASH. We showed that fat-specific protein 27 (FSP27), a lipid droplet-associated protein that controls triglyceride turnover in the hepatocyte, is required for fasting- and diet-induced triglyceride accumulation in the liver. However, silencing Fsp27 with antisense oligonucleotides (ASOs) did not improve hepatosteatosis in genetic nor nutritional mouse models of obesity. Herein, we tested the therapeutic potential of ASO-Fsp27 when used in combination with the PPARα agonist fenofibrate. C57BL/6 mice were fed a high-trans-fat, high-cholesterol, high-fructose diet for 8 weeks to establish NASH, then kept on diet for 6 additional weeks while dosed with ASOs and fenofibrate, alone or in combination. Data show that ASO-Fsp27 and fenofibrate synergize to promote resistance to diet-induced obesity and hypertriglyceridemia, and to reverse hepatic steatosis, inflammation, oxidative stress, and fibrosis. This multifactorial improvement of liver disease noted when combining both drugs suggests that a course of treatment that includes both reduced FSP27 activity and activation of PPARα could provide therapeutic benefit to patients with NAFLD/NASH. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

  9. A Longitudinal Study of Whole Body, Tissue and Cellular Physiology in a Mouse Model of Fibrosing NASH with High Fidelity to the Human Condition.

    PubMed

    Krishnan, Anuradha; Abdullah, Tasduq Sheikh; Mounajjed, Taofic; Hartono, Stella P; McConico, Andrea; White, Thomas A; LeBrasseur, Nathan K; Lanza, Ian R; Nair, Sreekumaran; Gores, Gregory J; Charlton, Michael

    2017-02-23

    The sequence of events that lead to inflammation and fibrosing nonalcoholic steatohepatitis (NASH) are incompletely understood. We investigated the chronology of whole body, tissue and cellular events that occur during the evolution of diet-induced NASH.

  10. IL-17 Axis Driven Inflammation in Non-Alcoholic Fatty Liver Disease Progression

    PubMed Central

    Giles, Daniel A.; Moreno-Fernandez, Maria E; Divanovic, Senad

    2016-01-01

    Obesity is a primary risk factor for the development of non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common chronic liver disease in the world, represents a spectrum of disorders that range from steatosis (NAFL) to steatohepatitis (NASH) to cirrhosis. It is anticipated that NAFLD will soon surpass chronic hepatitis C infection as the leading cause for needing liver transplantation. Despite its clinical and public health significance no specific therapies are available. Although the etiology of NAFLD is multifactorial and remains largely enigmatic, it is well accepted that inflammation is a central component of NAFLD pathogenesis. Despite the significance, critical immune mediators, loci of immune activation, the immune signaling pathways and the mechanism(s) underlying disease progression remain incompletely understood. Recent findings have focused on the role of Interleukin 17 (IL-17) family of proinflammatory cytokines in obesity and pathogenesis of obesity-associated sequelae. Notably, obesity favors a Th17 bias and is associated with increased IL-17A expression in both humans and mice. Further, in mice, IL-17 axis has been implicated in regulation of both obesity and NAFLD pathogenesis. However, despite these recent advances several important questions require further evaluation including: the relevant cellular source of IL-17A production; the critical IL-17RA-expressing cell type; the critical liver infiltrating immune cells; and the underlying cellular effector mechanisms. Addressing these questions may aid in the identification and development of novel therapeutic targets for prevention of inflammation-driven NAFLD progression. PMID:26028039

  11. Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD).

    PubMed

    Alwahsh, Salamah Mohammad; Gebhardt, Rolf

    2017-04-01

    Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.

  12. The central role of the non alcoholic fatty liver disease in metabolic syndrome.

    PubMed

    Hurjui, Daniela Maria; Niţă, Otilia; Graur, Lidia Iuliana; Mihalache, Laura; Popescu, Dana Stefana; Graur, Mariana

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Most NAFLD patients are hyperinsulinaemic and more insulin resistant compared with nonsteatotic healthy subjects, and there is a near universal association between NAFLD and insulinresistance (IR) irrespective of obesity. The metabolic syndrome (MS) is highly prevalent in the general adult population (approximatively 22%) and it carries an increased cardiovascular morbidity and mortality. Pathophysiologic considerations, clinical associations, and laboratory investigations support that IR and hyperinsulinaemia have a central role in pathogenesis of both MS and NAFLD. The fatty liver is resistant to the action of insulin to suppress hepatic glucose production, which results in hyperglycaemia and, further, in hyperinsulinemia. The MS is associated with maldistribution of body fat, increased free fatty acids (FFAs) and IR, leading to type 2 diabetes, hypertension, dyslipidemia. Visceral fat is an important clinical marker of metabolic cardiovascular risk and a marker of IR in multiple tissues, independent of body mass index (BMI). NAFLD and atherosclerosis share common molecular mediators and NAFLD itself might play an early role in the development and progression of atherosclerosis. These data suggest that NAFLD should be considered part of a multi-organ system derangement in insulin sensitivity, and help explain why NAFLD is so closely linked with diabetes, MS and is an important risk factor for coronary heart disease. NAFLD may be the hepatic manifestation of the MS and raises the possibility that it may play an early role in the etiology of MS.

  13. The value of different insulin resistance indices in assessment of non-alcoholic fatty liver disease in overweight/obese children.

    PubMed

    El-Karaksy, Hanaa M; El-Raziky, Mona S; Fouad, Hanan M; Anwar, Ghada M; El-Mougy, Fatma M; El-Koofy, Nehal M; El-Hennawy, Ahmad M

    2015-01-01

    The aim of the present study was to determine the association between insulin resistance (IR) and both non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in a group of Egyptian overweight/obese children and adolescents and to evaluate different IR indices in detection of NAFLD. The study included 76 overweight/obese children aged 2-15 years; 52.6% were males. Laboratory analysis included fasting blood glucose, serum insulin, lipid profile, liver biochemical profile, and liver ultrasound. IR was calculated using the following indices; the homeostasis model assessment method (HOMA-IR), the quantitative insulin-sensitivity check index (QUICKI) and hepatic insulin sensitivity. The National Cholesterol Education Program Adult Treatment Panel III criteria were used to estimate prevalence of MetS. Liver biopsy was done when medically indicated and accepted by parents. IR was detected in 43.4% and 34.2% by using QUICKI and HOMA, respectively. MetS was detected in 36.8% and NAFLD was detected in 45.5% among those performing liver biopsy. Cases with NAFLD had more frequent IR than children with normal histology. QUICKI showed significant difference between normal subjects and both steatosis and non-alcoholic steatohepatitis; while HOMA-IR was sensitive in cases with NASH only. MetS was present in 100% of patients with NASH and in 75% of those with steatosis and they were all obese. Patients with NASH had significantly higher ALT than those with normal histology. IR was significantly associated with NAFLD. QUICKI is considered more sensitive than HOMA-IR in differentiating simple steatosis from normal liver histology. Copyright © 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  14. Copy number variation in exportin-4 (XPO4) gene and its association with histological severity of non-alcoholic fatty liver disease

    PubMed Central

    Zain, Shamsul Mohd; Mohamed, Zahurin; Pirmohamed, Munir; Tan, Hwa Li; Alshawsh, Mohammed Abdullah; Mahadeva, Sanjiv; Chan, Wah-Kheong; Mustapha, Nik Raihan Nik; Mohamed, Rosmawati

    2015-01-01

    A recent genome-wide copy number (CNV) scan identified a 13q12.11 duplication in the exportin-4 (XPO4) gene to be associated with non-alcoholic steatohepatitis (NASH). We sought to confirm the finding in a larger cohort and to assess the serum XPO4 pattern in a broad spectrum of non-alcoholic fatty liver disease (NAFLD) cases. We analysed 249 NAFLD patients and 232 matched controls using TaqMan assay and serum XPO4 was measured. Copy number distribution was as follows: copy number neutral (NAFLD: 53.8%, controls: 68.6%), copy number losses (NAFLD: 13.3%, controls: 12.9%), copy number gains (NAFLD: 32.9%, controls: 18.5%). CNV gain was significantly associated with a greater risk of NAFLD (adjusted OR 2.22, 95% CI 1.42–3.46, P = 0.0004) and NASH (adjusted OR 2.33, 95% CI 1.47–3.68, P = 0.0003). Interestingly, subjects carrying extra copy number showed significantly higher serum ALT and triglyceride (P < 0.05). Serum XPO4 levels progressively declined (P = 0.043) from controls (24.6 ng/mL) to simple steatosis (20.8 ng/mL) to NASH (13.8 ng/mL). In conclusion, XPO4 CNV duplication was associated with histological severity of NAFLD, and accompanied by changes in serum XPO4 levels providing insights into NAFLD pathogenesis, and has the potential for biomarker development. PMID:26293807

  15. Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Arias-Loste, María Teresa; Iruzubieta, Paula; Puente, Ángela; Ramos, David; Santa Cruz, Carolina; Estébanez, Ángel; Llerena, Susana; Alonso-Martín, Carmen; San Segundo, David; Álvarez, Lorena; López Useros, Antonio; Fábrega, Emilio; López-Hoyos, Marcos; Crespo, Javier

    2016-01-01

    Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH. PMID:27834919

  16. Pathological Findings of NASH and NAFLD: for Guidebook of NASH and NAFLD, 2015: The Japan Society of Hepatology.

    PubMed

    2017-01-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasingly common chronic liver disease worldwide. NAFLD comprises a variety of clinical and histopathological changes that can be broadly divided into nonalcoholic fatty liver (NAFL, simple steatosis) and nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFL and NASH is important because NASH is a more advanced form. This diagnosis therefore determines the prognosis and therapeutic management. At present the interpretation of NASH is made based on the histopathological features of steatohepatitis, i.e. 'steatosis', 'lobular inflammation', hepatocyte 'ballooning, 'Mallory-Denk bodies' and 'fibrosis'. Here, we summarize the pathological findings guidelines for NASH as it was already published in 2015 in Japanese in the clinical guidebook organized by the Japan Society of Hepatology.

  17. Non-invasive Testing for NASH and NASH with Advanced Fibrosis: Are We There Yet?

    PubMed Central

    Arulanandan, Ahilan; Loomba, Rohit

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most prevalent etiology of chronic liver disease in America. NAFLD can be broadly classified in two subtypes: nonalcoholic fatty liver (NAFL), which is generally considered a benign condition with negligible risk of progression to cirrhosis, and nonalcoholic steatohepatitis (NASH), which is generally considered to be progressive with substantial risk of progression to cirrhosis. Additionally, recent studies suggest the odds of liver mortality increases amongst NASH patients with advanced fibrosis (bridging fibrosis ± cirrhosis). Liver biopsy examination is the current gold standard to accurately discriminate between NAFL vs. NASH as well as diagnose advanced fibrosis. However, due to its invasive nature, risk of bleeding (and even rarely death), prohibitive cost, and sampling error, liver biopsies are imperfect for diagnosis and monitoring of NAFLD. As a result, noninvasive biomarkers that can accurately detect NASH and advanced fibrosis without biopsy are needed. This article will discuss the most novel noninvasive biomarkers in diagnosing NASH and advanced fibrosis. PMID:26500833

  18. [Non-alcoholic fatty liver disease and hepatocellular carcinoma - 2016].

    PubMed

    Pár, Alajos; Pár, Gabriella

    2016-06-19

    In the past decade non-alcoholic liver disease became the most frequently diagnosed liver disease in developed countries. At the same time, the dramatic rise in the incidence of hepatocellular carcinoma is attributed to this common metabolic disorder, and mainly to its severe form, non-alcoholic steatohepatitis. The risk factors of these associated diseases are genetic predisposition, obesity and diabetes as well as chronic low grade necro-infammation, which often leads to liver fibrosis. Free fatty acids, cytokines, lipotoxicity, insulin resistance, microRNS dysregulation and alteration in intestinal microbiota play a pivotal role in the pathogenesis. Treatment of non-alcoholic fatty liver disease - weight reduction and physical exercise in obesity, metformin in diabetes, statins in dyslipidemia and, as a new option, obeticholic acid - may diminish the risk of the hepatocellular carcinoma related to this metabolic disease.

  19. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    PubMed

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  20. Gene expression profiling reveals key genes and pathways related to the development of non-alcoholic fatty liver disease.

    PubMed

    Wang, Ruifeng; Wang, Xiaobing; Zhuang, Liwei

    2016-01-01

     Background. This study aims to identify key genes and pathways involved in non-alcoholic fatty liver disease (NAFLD). The dataset GSE48452 was downloaded from Gene Expression Omnibus, including 14 control liver samples, 27 healthy obese samples, 14 steatosis samples and 18 nonalcoholic steatohepatitis (NASH) samples. Differentially expressed genes (DEGs) between controls and other samples were screened through LIMMA package. Then pathway enrichment analysis for DEGs was performed by using DAVID, and alterations of enriched pathways were determined. Furthermore, protein-protein interaction (PPI) networks were constructed based on the PPI information from HPRD database, and then, networks were visualized through Cytoscape. Additionally, interactions between microRNAs (miRNAs) and pathways were analyzed via Fisher's exact test. A total of 505, 814 and 783 DEGs were identified for healthy obese, steatosis and NASH samples in comparison with controls, respectively. DEGs were enriched in ribosome (RPL36A, RPL14, etc.), ubiquitin mediated proteolysis (UBE2A, UBA7, etc.), focal adhesion (PRKCA, EGFR, CDC42, VEGFA, etc.), Fc?R-mediated phagocytosis (PRKCA, CDC42, etc.), and so on. The 27 enriched pathways gradually deviated from baseline (namely, controls) along with the changes of obese-steatosis-NASH. In PPI networks, PRKCA interacted with EGFR and CDC42. Besides, hsa-miR-330-3p and hsa-miR-126 modulated focal adhesion through targeting VEGFA and CDC42. The identified DEGs (PRKCA, EGFR, CDC42, VEGFA), disturbed pathways (ribosome, ubiquitin mediated proteolysis, focal adhesion, Fc?R-mediated phagocytosis, etc.) and miRNAs (hsa-miR-330-3p, hsa-miR-126, etc.) might be closely related to NAFLD progression. These results might contribute to understanding NAFLD mechanism, conducting experimental researches, and designing clinical practices.

  1. The Metabolic Syndrome and Its Influence on Nonalcoholic Steatohepatitis.

    PubMed

    Kanwar, Pushpjeet; Kowdley, Kris V

    2016-05-01

    Nonalcoholic steatohepatitis (NASH) and the metabolic syndrome (MetS) are highly prevalent in the Western population. Their pathogenesis is closely linked to insulin resistance, which serves as a therapeutic target for the management of these conditions. This review article reviews the research supporting the influence of MetS on NASH and includes studies supporting their similar epidemiology, pathogenesis, and treatment.

  2. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression.

    PubMed

    Farrell, Geoffrey C; Larter, Claire Z; Hou, Jing Yun; Zhang, Rena H; Yeh, Matthew M; Williams, Jacqueline; dela Pena, Aileen; Francisco, Rona; Osvath, Sarah R; Brooling, John; Teoh, Narcissus; Sedger, Lisa M

    2009-03-01

    We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-alpha-receptor (TNF-R)1, TNF-R2, Fas, and TNFalpha-related apoptosis-inducing ligand-receptor (TRAIL-R) mRNA, TUNEL, caspase 3 activation, liver injury and liver pathology in mice fed a methionine and choline deficient (MCD) diet. For endogenous stress pathways, we determined serum insulin-like growth factor-1 (IGF-1), hepatic p53, Bcl-XL, tBid and p21 expression. Methionine and choline deficient feeding increased alanine aminotransferase (ALT) and apoptosis from day 10, without increases in TNF-R1, TNF-R2, and Fas. However, murine TRAIL receptors, particularly decoyTRAIL-R1/TNFRSFH23 and Killer/DR5 mRNA increased. MCD feeding enhanced hepatic p53 expression, corresponding to approximately 50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21. Nutritional restitution experiments showed that correcting either methionine or choline deficiency suppressed liver inflammation (extrinsic pathway), but failed to correct apoptosis, IGF-1 or p53. Methionine and choline deficiency lower IGF-1 to de-repress p53 during induction of steatohepatitis. The p53 induced by nutritional stress is biologically active in mediating mitochondrial cell death pathways, but may also be responsible for TRAIL receptor expression, thereby linking intrinsic and exogenous apoptosis pathways in NASH.

  3. NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations.

    PubMed

    Adinolfi, Luigi Elio; Rinaldi, Luca; Guerrera, Barbara; Restivo, Luciano; Marrone, Aldo; Giordano, Mauro; Zampino, Rosa

    2016-05-25

    The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%-10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely "viral steatosis" and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host's genetic background predisposes him or her to the development of steatosis. HCV's impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related "metabolic steatosis" impairs the response rate to interferon-based treatment, whereas it seems that "viral steatosis" may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.

  4. NAFLD and NASH in HCV Infection: Prevalence and Significance in Hepatic and Extrahepatic Manifestations

    PubMed Central

    Adinolfi, Luigi Elio; Rinaldi, Luca; Guerrera, Barbara; Restivo, Luciano; Marrone, Aldo; Giordano, Mauro; Zampino, Rosa

    2016-01-01

    The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases. PMID:27231906

  5. Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains

    PubMed Central

    Pandey, Vikash; Sultan, Marc; Kashofer, Karl; Ralser, Meryem; Amstislavskiy, Vyacheslav; Starmann, Julia; Osprian, Ingrid; Grimm, Christina; Hache, Hendrik; Yaspo, Marie-Laure; Sültmann, Holger; Trauner, Michael; Denk, Helmut; Zatloukal, Kurt; Lehrach, Hans; Wierling, Christoph

    2014-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. Methodology and Results In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. Conclusions We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J

  6. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.

    PubMed

    Shen, Feng; Zheng, Rui-Dan; Sun, Xing-Qiang; Ding, Wen-Jin; Wang, Xiao-Ying; Fan, Jian-Gao

    2017-08-15

    Gut microbiota plays a significant role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study aimed to assess the contribution of gut microbiota dysbiosis to the pathogenesis of NAFLD. Forty-seven human feces samples (25 NAFLD patients and 22 healthy subjects) were collected and 16S rDNA amplicon sequencing was conducted on Hiseq 2000 platform. Discrepancy of species composition between controls and NAFLD group was defined by Metastats analysis under P value <0.01. NAFLD patients harbored lower gut microbiota diversity than healthy subjects did. In comparison to the control group, the Proteobacteria (13.50%) and Fusobacteria (2.76%) phyla were more abundant in NAFLD patients. Additionally, the Lachnospiraceae (21.90%), Enterobacteriaceae (12.02%), Erysipelotrichaceae (3.83%), and Streptococcaceae (1.39%) families, as well as the Escherichia_Shigella (10.84%), Lachnospiraceae_Incertae_Sedis (7.79%), and Blautia (4.95%) genera were enriched in the NAFLD group. However, there was a lower abundance of Prevotella in the NAFLD group than that in the control group (5.83% vs 27.56%, P<0.01). The phylum Bacteroidetes (44.63%) also tended to be more abundant in healthy subjects, and the families Prevotellaceae (28.66%) and Ruminococcaceae (26.44%) followed the same trend. Compared to those without non-alcoholic steatohepatitis (NASH), patients with NASH had higher abundance of genus Blautia (5.82% vs 2.25%; P=0.01) and the corresponding Lachnospiraceae family (24.33% vs 14.21%; P<0.01). Patients with significant fibrosis had a higher abundance of genus Escherichia_Shigella (12.53% vs 1.97%; P<0.01) and the corresponding Enterobacteriaceae family (13.92% vs 2.07%; P<0.01) compared to those with F0/F1 fibrosis. NAFLD patients and healthy subjects harbor varying gut microbiota. In contrast to the results of previous research on children, decreased levels of Prevotella might be detrimental for adults with NAFLD. The increased level of the genus Blautia

  7. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis

    PubMed Central

    Pirola, Carlos J; Gianotti, Tomas Fernández; Castaño, Gustavo O; Mallardi, Pablo; Martino, Julio San; Ledesma, María Mora Gonzalez Lopez; Flichman, Diego; Mirshahi, Faridodin; Sanyal, Arun J; Sookoian, Silvia

    2014-01-01

    Objectives We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome. Methods The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls. Results Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity. Conclusions miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk. PMID:24973316

  8. Prognostic value of high sensitivity C-reaction protein in non-insulin dependent diabetes mellitus patients with non-alcoholic fatty liver disease.

    PubMed

    Bi, Yiliang; Min, Min; Shen, Wei; Deng, Pei; Du, Qiupeng; Dong, Mingjie; Liu, Yan

    2015-01-01

    High sensitivity C-reaction protein (hsCRP) has been used as a significant predictive factor of cardiovascular events in patients with non-insulin dependent diabetes mellitus (NIDDM). However, existing reports in regards to the significance of hsCRP in predicting the progression of hepatic complications in NIDDM patients are too sparse to deliver clear results. This study is aimed at investigating the prognostic value of hsCRP in NIDDM patients with non-alcoholic fatty liver disease (NAFLD). 1128 NIDDM patients with a definite diagnosis of NAFLD were enrolled and followed for one year. The baseline body mass index (BMI), waist-hip circumference ratio (WHR), serum aspartate aminotransferase (AST), presence of hypertension, alanine aminotransferase (ALT), serum hsCRP, total cholesterol (Tch), fasting blood glucose (FBG), triglycerine (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and hepatitis B surface antigen (HBsAg) were recorded to analyze the significance of hsCRP in predicting the short-term progression from NAFLD to non-alcoholic steatohepatitis (NASH). One year after baseline, 32% of the NAFLD patients suffered progression to NASH and the percentages of NASH were respectively 8.2%, 12.5%, 33.8% and 72.6% in 4 groups with quartered baseline serum level of hsCRP; there was significant difference among the 4 groups in percentage of NASH (P<0.001). With sex, age, WHR, BMI, hypertension, TG, TCH, HDL-C, LDL-C, FBG and HBsAg included, the calibrated regression model gave the OR values of 1.000, 1.669, 6.635 and 32.131 in in 4 quartered baseline serum levels of hsCRP. High serum level of hsCRP is an independent risk factor of short-term progression to NASH in patients with NIDDM and NAFLD. Those NIDDM patients with NAFLD that present with high serum level of hsCRP should be subjected to regular monitoring, lifestyle intervention and medication.

  9. [Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

    PubMed

    Miranda Manrique, Gonzalo

    2016-01-01

    Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research.

  10. [An Overview of NAFLD/NASH in Japan].

    PubMed

    Kim, Soo Ryang; Kim, Ke Ih

    2016-01-01

    Clinical identity of nonalcoholic steatohepatitis (NASH) has established it as a chronic liver disease since the 1990s in the USA and in the 21st century in Japan, although its significance is not well recognized in Japanese society. It is characterized as a chronic liver disease, differentiated from viral liver disease and alcoholic liver disease. Nonalcoholic fatty liver disease (NAFLD) comprises nonalcoholic fatty liver (NAFL) and NASH. NASH is considered to be the hepatic manifestation of a metabolic syndrome. It is understood that among individuals with NAFLD, NAFL is a benign condition, whereas NASH can progress to cirrhosis and ultimately to hepatocellular carcinoma. The precise mechanism of NASH is poorly understood, although insulin resistance, oxidative stress and multiple parallel hits theory have been reported. Computed tomography and ultrasonography are performed to detect NAFLD, but these are not sufficient to distinguish between NAFL and NASH. The distinct diagnosis of NAFL and NASH is currently made by liver biopsy, requiring hospitalization. Therefore, there is an urgent need to develop simple, non-invasive markers that can accurately distinguish between NASH and NAFL. In Japan, the number of NASH patients is estimated to be about 1 million. The treatment of NASH comprises changes in life style, including eating habits and exercise that will lead to weight loss, and drug intake, including vitamin E. Based on the global increase in obese people, NASH as a chronic liver disease will become the most important chronic liver disease in the 21st century, not only in Japan but also worldwide.

  11. The Phytocomplex from Fucus vesiculosus and Ascophyllum nodosum Controls Postprandial Plasma Glucose Levels: An In Vitro and In Vivo Study in a Mouse Model of NASH.

    PubMed

    Gabbia, Daniela; Dall'Acqua, Stefano; Di Gangi, Iole Maria; Bogialli, Sara; Caputi, Valentina; Albertoni, Laura; Marsilio, Ilaria; Paccagnella, Nicola; Carrara, Maria; Giron, Maria Cecilia; De Martin, Sara

    2017-02-15

    Edible seaweeds have been consumed by Asian coastal communities since ancient times. Fucus vesiculosus and Ascophyllum nodosum extracts have been traditionally used for the treatment of obesity and several gastrointestinal diseases. We evaluated the ability of extracts obtained from these algae to inhibit the digestive enzymes α-amylase and α-glucosidase in vitro, and control postprandial plasma glucose levels in a mouse model of non-alcoholic steatohepatitis (NASH); a liver disease often preceding the development of Type 2 diabetes (T2DM). This model was obtained by the administration of a high-fat diet. Our results demonstrate that these algae only delayed and reduced the peak of blood glucose (p < 0.05) in mice fed with normal diet, without changing the area under the blood glucose curve (AUC). In the model of NASH, the phytocomplex was able to reduce both the postprandial glycaemic peak, and the AUC. The administration of the extract in a diet particularly rich in fat is associated with a delay in carbohydrate digestion, but also with a decrease in its assimilation. In conclusion, our results indicate that this algal extract may be useful in the control of carbohydrate digestion and absorption. This effect may be therapeutically exploited to prevent the transition of NASH to T2DM.

  12. The Phytocomplex from Fucus vesiculosus and Ascophyllum nodosum Controls Postprandial Plasma Glucose Levels: An In Vitro and In Vivo Study in a Mouse Model of NASH

    PubMed Central

    Gabbia, Daniela; Dall’Acqua, Stefano; Di Gangi, Iole Maria; Bogialli, Sara; Caputi, Valentina; Albertoni, Laura; Marsilio, Ilaria; Paccagnella, Nicola; Carrara, Maria; Giron, Maria Cecilia; De Martin, Sara

    2017-01-01

    Edible seaweeds have been consumed by Asian coastal communities since ancient times. Fucus vesiculosus and Ascophyllum nodosum extracts have been traditionally used for the treatment of obesity and several gastrointestinal diseases. We evaluated the ability of extracts obtained from these algae to inhibit the digestive enzymes α-amylase and α-glucosidase in vitro, and control postprandial plasma glucose levels in a mouse model of non-alcoholic steatohepatitis (NASH); a liver disease often preceding the development of Type 2 diabetes (T2DM). This model was obtained by the administration of a high-fat diet. Our results demonstrate that these algae only delayed and reduced the peak of blood glucose (p < 0.05) in mice fed with normal diet, without changing the area under the blood glucose curve (AUC). In the model of NASH, the phytocomplex was able to reduce both the postprandial glycaemic peak, and the AUC. The administration of the extract in a diet particularly rich in fat is associated with a delay in carbohydrate digestion, but also with a decrease in its assimilation. In conclusion, our results indicate that this algal extract may be useful in the control of carbohydrate digestion and absorption. This effect may be therapeutically exploited to prevent the transition of NASH to T2DM. PMID:28212301

  13. Niacin inhibits fat accumulation, oxidative stress, and inflammatory cytokine IL-8 in cultured hepatocytes: Impact on non-alcoholic fatty liver disease.

    PubMed

    Ganji, Shobha H; Kashyap, Moti L; Kamanna, Vaijinath S

    2015-09-01

    Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that niacin significantly prevented hepatic steatosis and regressed pre-existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with niacin or control for 24 h. The data indicated that niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid-induced fat accumulation in human hepatocytes by 45-62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. These findings suggest that niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro-inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of niacin and niacin-related compounds for the treatment of NAFLD/NASH and its complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis.

    PubMed

    Ucar, Fatma; Sezer, Sevilay; Erdogan, Serpil; Akyol, Sumeyya; Armutcu, Ferah; Akyol, Omer

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common underlying causes of chronic liver injury. They are associated with a wide spectrum of hepatic disorders including basic steatosis, steatohepatitis, and cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD and NASH are still unknown. This review describes the roles of oxidative stress and inflammatory responses in the pathogenesis of NAFLD and its progression to NASH.

  15. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease.

    PubMed

    Ronis, Martin J J; Baumgardner, January N; Sharma, Neha; Vantrease, Jamie; Ferguson, Matthew; Tong, Yudong; Wu, Xianli; Cleves, Mario A; Badger, Thomas M

    2013-02-01

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by non-alcoholic fatty liver disease (NAFLD) leading to non-alcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been shown to protect against steatosis and alcoholic liver injury. The current study was designed to determine if a similar beneficial effect of MCT occurs in a rat model of NAFLD. Groups of male rats were isocalorically overfed diets containing 10%, 35% or 70% total energy as corn oil or a 70% fat diet in which corn oil was replaced with increasing concentrations of saturated fat (18:82, beef tallow:MCT oil) from 20% to 65% for 21 days using total enteral nutrition (TEN). As dietary content of corn oil increased, hepatic steatosis and serum alanine amino transferases were elevated (P < 0.05). This was accompanied by greater expression of cytochrome P450 enzyme CYP2E1 (P < 0.05) and higher concentrations of polyunsaturated 18:2 and 20:4 fatty acids (FA) in the hepatic lipid fractions (P < 0.05). Keeping the total dietary fat at 70%, but increasing the proportion of MCT-enriched saturated fat resulted in a dose-dependent reduction in steatosis and necrosis without affecting CYP2E1 induction. There was no incorporation of C8-C10 FAs into liver lipids, but increasing the ratio of MCT to corn oil: reduced liver lipid 18:2 and 20:4 concentrations; reduced membrane susceptibility to radical attack; stimulated FA β- and ω-oxidation as a result of activation of peroxisomal proliferator activated receptor (PPAR)α, and appeared to increase mitochondrial respiration through complex III. These data suggest that replacing unsaturated fats like corn oil with MCT oil in the diet could be utilized as a potential treatment for NAFLD.

  16. Predictors of Non-alcoholic Fatty Liver Disease in Obese and Overweight Egyptian Children: Single Center Study

    PubMed Central

    El-Karaksy, Hanaa M.; El-Koofy, Nehal M.; Anwar, Ghada M.; El-Mougy, Fatma M.; El-Hennawy, Ahmed; Fahmy, Mona E.

    2011-01-01

    Background/Aim: Pediatric non-alcoholic fatty liver disease (NAFLD) is a global problem which has been increasingly recognized with the dramatic rise in pediatric obesity. The aim of the present study was to identify the clinical, sonographic, and biochemical predictors for NAFLD in obese children. Materials and Methods: Seventy-six children (2-15 years) were included after an informed consent. All were subjected to full anthropometric assessment (including height, weight, body mass index, subscapular skin fold thickness, waist and hip circumference and calculation of waist: hip ratio), biochemical assessment of liver function tests, lipid profile and insulin resistance and sonographic assessment of hepatic echogenicity. Liver biopsy when indicated, was done in 33 patients. Results: Sixteen patients (21%) had elevated ALT and 6 (7.9%) had elevated AST. Significant dyslipidemia (low HDL-c, high total cholesterol, high LDL-c and triglycerides) and higher insulin resistance were found in obese patients (P<0.01). The main sonographic findings were hepatomegaly in 20 patients (26.3%) and echogenic liver in 41 patients (53.9%). Liver biopsy showed simple steatosis in eight cases (24.2%) and non-alcoholic steatohepatitis (NASH) in seven cases (21.2%). Anthropometric measurements, increased hepatic echogenicty by ultrasound, insulin resistance and lipid profile were good predictors of NAFLD in obese children if assessed together. However, LDL-c was the only sensitive predictor (independent variable) for NAFLD in both uni- and multivariate logistic regression analyses. Conclusion: Dyslipidemia per se is a strong predictor of NAFLD among obese Egyptian children. PMID:21196652

  17. Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression.

    PubMed

    Abd El-Haleim, Enas A; Bahgat, Ashraf K; Saleh, Samira

    2016-02-15

    Peroxisome proliferator-activated receptors (PPARs) gamma and alpha have been shown to play key roles in maintaining glucose and lipid homeostasis by acting as insulin sensitizers and lipid-lowering agents respectively, which would make them potential candidates for the treatment of non-alcoholic steatohepatitis (NASH) characterized by insulin resistance, hyperglycemia, and hypertriglyceridemia. The effects of pioglitazone, a PPAR-γ agonist, and fenofibrate, a PPAR-α agonist, as monotherapy and in combination on the expressions of key genes linked to the development of NASH were studied in rats with fructose-induced NASH. Fructose-enriched diet was given to rats for 12 weeks. Fenofibrate (100mg/kg), pioglitazone (4 mg/kg) and combined treatment with both in half doses were given. Body weight, liver index, insulin resistance indices, triglycerides, oxidative stress markers, AST/ALT ratio and TNF-α were measured. Additionally, hepatic genes expressions of SOCS-3, sterol regulatory element binding protein-1c, fatty acid synthase, malonyl CoA decarboxylase, TGF-β1, and adipose tissue genes expressions of leptin and adiponectin were investigated. The combination of both drugs, in half doses, improved NASH-related disturbances similar to, or even better than, a full dose of fenofibrate alone possibly due to attenuating effects of pioglitazone on expression of genes responsible for insulin resistance, fatty acid synthesis and fibrosis in addition to correcting the balance between leptin and adiponectin. Histopathology confirmed the ability of this combination to decrease steatosis area and to normalize hepatic tissue structure. In Conclusion, dual activation of PPAR-γ and PPAR-α has remarkable effect in ameliorating NASH by modulation of some hepatic and adipose tissue genes expressions.

  18. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages. PMID:22654421

  19. Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Takahashi, Yoshihisa; Soejima, Yurie; Fukusato, Toshio

    2012-05-21

    Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

  20. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease

    PubMed Central

    Wood, Kayleigh L; Miller, Michael H; Dillon, John F

    2015-01-01

    Non-alcoholic fatty liver disease has an increasing prevalence in Western countries, affecting up to 20% of the population. Objective The aim of this project was to systematically review and summarise the genetic association studies that investigate possible genetic influences that confer susceptibility to non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Design The MEDLINE and SCOPUS databases were searched to identify candidate gene studies on histologically diagnosed non-alcoholic fatty liver disease. Results A total of 85 articles have been summarised and categorised on the basis of the general pathway each candidate gene is involved in, including lipid metabolism, lipoprotein processing, cholesterol synthesis, glucose homoeostasis, inflammatory response, protection against oxidative stress and whole body metabolism. Conclusions The main findings demonstrate a small but consistent association of PNPLA3 with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Genetic association studies have investigated general disease susceptibility, histological characteristics, severity and progression. However, further study is required to better elucidate the genetic factors influencing fatty liver disease. PMID:26462272

  1. Nonalcoholic steatohepatitis (NASH) in ob/ob mice treated with yo jyo hen shi ko (YHK): effects on peroxisome proliferator-activated receptors (PPARs) and microsomal triglyceride transfer protein (MTP).

    PubMed

    Stefano, José Tadeu; de Oliveira, Claudia Pinto Marques Souza; Corrêa-Giannella, Maria Lúcia; de Lima, Vicência Mara Rodrigues; de Sá, Sandra Valéria; de Oliveira, Ellen Pierre; de Mello, Evandro Sobroza; Giannella-Neto, Daniel; Alves, Venâncio Avancini Ferreira; Carrilho, Flair José

    2007-12-01

    YHK has antioxidant properties, has a hypoglycemic effect, and may reduce plasma lipid levels. In this study, we examined the hepatic expression of PPAR-alpha and -gamma and MTP in ob/ob mice receiving or not receiving YHK. Ob/ob mice were assigned to receive oral YHK (20 mg/kg/day) fed solution (methionine/choline-deficient [MCD] diet+YHK group) or vehicle (MCD group) by gavage for 4 weeks. Liver fragments were collected for histologic examination and mRNA isolation. PPAR-alpha and -gamma and MTP gene expression was examined by RT-qPCR. YHK treatment was associated with NASH prevention, weight loss, and reduction of visceral fat and of serum concentrations of aminotransferases in comparison to the MCD group. YHK promoted an increment in PPAR-alpha and MTP and a decrement in PPAR-gamma mRNA contents. These findings suggest that modulation of PPAR-alpha and -gamma and MTP RNA expression may be implicated in the protective effect of YHK in experimental NASH, limiting hepatocyte lipid accumulation.

  2. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

    PubMed Central

    Leung, Christopher; Herath, Chandana B; Jia, Zhiyuan; Andrikopoulos, Sof; Brown, Bronwyn E; Davies, Michael J; Rivera, Leni R; Furness, John B; Forbes, Josephine M; Angus, Peter W

    2016-01-01

    AIM To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. METHODS Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. RESULTS Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE-/- animals developed NASH of similar severity to RAGE+/+ animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. CONCLUSION In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD. PMID:27672297

  3. Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease.

    PubMed

    Leung, Christopher; Herath, Chandana B; Jia, Zhiyuan; Andrikopoulos, Sof; Brown, Bronwyn E; Davies, Michael J; Rivera, Leni R; Furness, John B; Forbes, Josephine M; Angus, Peter W

    2016-09-21

    To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE. Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined. Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury. In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD.

  4. Non-alcoholic fatty liver disease and insulin resistance: importance of risk factors and histological spectrum.

    PubMed

    Guidorizzi de Siqueira, Ana Cristina; Cotrim, Helma P; Rocha, Raquel; Carvalho, Fernando M; de Freitas, Luiz A R; Barreto, Danyella; Gouveia, Leandro; Landeiro, Luciana

    2005-08-01

    Non-alcoholic fatty liver disease (NAFLD) has been associated with several metabolic conditions (MC) and secondary causes, but the relationship between insulin resistance (IR) and the underlying aetiology of NAFLD has not been extensively explored. To determine the frequency of IR among NAFLD patients and to describe IR according to risk factors and histological findings of the disease. A case-series study of 64 patients with clinical and histological diagnosis of NAFLD. IR was calculated by homeostasis model assessment (HOMA) and IR was considered when HOMA > or = 3. Histological grades of NAFLD were: stage 1, steatosis isolated; stage 2, steatosis and inflammation; stage 3, steatosis and ballooning degeneration; stage 4, steatosis and fibrosis and/or Mallory bodies. Fibrosis was graded 0-4 (cirrhosis). IR was found in 21 (33%) patients. Among those with IR, 16 patients (76%) had associated MC and five patients (24%) had exposure to petrochemicals. The mean value of HOMA varied from 3.5 in NAFLD associated with MC to 1.6 in patients with exposure to petrochemicals (P < 0.03). Waist circumference was the metabolic factor most strongly associated with IR (P < 0.005). Steatohepatitis (NASH) was observed in 54 (84.3%) cases. The HOMA mean value was significantly higher in patients with advanced fibrosis. IR occurred in 33% of the NAFLD patients, being more frequent among those with MC than among those with exposure to petrochemicals. The presence of IR in cases with advanced fibrosis suggests that it may influence the prognosis of NAFLD.

  5. Standardized Salvia miltiorrhiza extract suppresses hepatic stellate cell activation and attenuates steatohepatitis induced by a methionine-choline deficient diet in mice.

    PubMed

    Lee, Hak Sung; Son, Woo-Chan; Ryu, Jae-Eun; Koo, Bon Am; Kim, Yeong Shik

    2014-06-17

    The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME) on gene and protein expression of non-alcoholic steatohepatitis (NASH)-related factors in activated human hepatic stellate cells (HSC), and in mice with steatohepatitis induced by a methionine-choline deficient (MCD) diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight) was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor β-1 (TGF-β1) or TGF-β1 plus SME (0.1-10 μg/mL). To investigate the effect of SME on reactive oxygen species (ROS)-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2) or H2O2 plus SME (0.1-100 μg/mL). MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-α), TGF-β1, interleukin-1β (IL-1β), C-reactive protein (CRP), α-smooth muscle actin (α-SMA), type I collagen, matrix metalloproteinase-2 (MMP-2) and MMP-9. TGF-β1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD) activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.

  6. The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice.

    PubMed

    Rolla, Simona; Alchera, Elisa; Imarisio, Chiara; Bardina, Valentina; Valente, Guido; Cappello, Paola; Mombello, Cristina; Follenzi, Antonia; Novelli, Francesco; Carini, Rita

    2016-02-01

    The mechanisms responsible for the evolution of steatosis towards NASH (non-alcoholic steatohepatitis) and fibrosis are not completely defined. In the present study we evaluated the role of CD4(+) T-helper (Th) cells in this process. We analysed the infiltration of different subsets of CD4(+) Th cells in C57BL/6 mice fed on a MCD (methionine choline-deficient) diet, which is a model reproducing all phases of human NASH progression. There was an increase in Th17 cells at the beginning of NASH development and at the NASH-fibrosis transition, whereas levels of Th22 cells peaked between the first and the second expansion of Th17 cells. An increase in the production of IL (interleukin)-6, TNFα (tumour necrosis factor α), TGFβ (transforming growth factor β) and CCL20 (CC chemokine ligand 20) accompanied the changes in Th17/Th22 cells. Livers of IL-17(-/-) mice were protected from NASH development and characterized by an extensive infiltration of Th22 cells. In vitro, IL-17 exacerbated the JNK (c-Jun N-terminal kinase)-dependent mouse hepatocyte lipotoxicity induced by palmitate. IL-22 prevented lipotoxicity through PI3K (phosphoinositide 3-kinase)-mediated inhibition of JNK, but did not play a protective role in the presence of IL-17, which up-regulated the PI3K/Akt inhibitor PTEN (phosphatase and tensin homologue deleted on chromosome 10). Consistently, livers of IL-17(-/-) mice fed on the MCD diet displayed decreased activation of JNK, reduced expression of PTEN and increased phosphorylation of Akt compared with livers of wild-type mice. Hepatic infiltration of Th17 cells is critical for NASH initiation and development of fibrosis in mice, and reflects an infiltration of Th22 cells. Th22 cells are protective in NASH, but only in the absence of IL-17. These data strongly support the potentiality of clinical applications of IL-17 inhibitors that can prevent NASH by both abolishing the lipotoxic action of IL-17 and allowing IL-22-mediated protection.

  7. Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage.

    PubMed

    Neuman, Manuela G; French, Samuel W; Zakhari, Samir; Malnick, Stephen; Seitz, Helmut K; Cohen, Lawrence B; Salaspuro, Mikko; Voinea-Griffin, Andreea; Barasch, Andrei; Kirpich, Irina A; Thomes, Paul G; Schrum, Laura W; Donohue, Terrence M; Kharbanda, Kusum K; Cruz, Marcus; Opris, Mihai

    2017-02-01

    This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed

  8. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome.

    PubMed

    Stättermayer, Albert Friedrich; Traussnigg, Stefan; Aigner, Elmar; Kienbacher, Christian; Huber-Schönauer, Ursula; Steindl-Munda, Petra; Stadlmayr, Andreas; Wrba, Friedrich; Trauner, Michael; Datz, Christian; Ferenci, Peter

    2017-01-01

    The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial including metabolic, genetic (e.g. PNPLA3 [patatin-like phospholipase domain-containing 3 gene]), viral factors and drugs. Besides, there is evidence for a role of copper deficiency. Aim of the study was to evaluate the role of hepatic copper content, PNPLA3 in NAFLD patients with and without metabolic syndrome (MetS). One-hundred seventy-four NAFLD patients, who underwent liver biopsy for diagnostic work-up, were studied. Diagnosis of MetS was based on the WHO Clinical Criteria. Steatosis was semiquantified as percentage of fat containing hepatocytes and was graded according to Brunt. Histological features of non-alcoholic steatohepatitis (NASH) were assessed using the Bedossa classification. Hepatic copper content (in μg/g dry weight) was measured by flame atomic absorption spectroscopy. SNP rs738409 in PNPLA3 was investigated by RT-PCR. Mean hepatic copper content was 22.3 (19.6-25.1) μg/g. The mean percentage of histologically lipid containing hepatocytes was 42.2% (38.3-46.0) and correlated inversely with hepatic copper content (ρ=-0.358, P<0.001). By subgroup analysis this inverse correlation remained significant only in patients without MetS (OR: 0.959 [CI95%: 0.926-0.944], P=0.020). Presence of minor allele (G) of PNPLA3 was also associated with moderate/severe steatosis (≥33%) both in patients with (OR: 2.405 [CI95%: 1.220-4.744], P=0.011) and without MetS (OR: 2.481 [CI95%: 1.172-5.250], P=0.018), but was only associated with NASH (OR: 2.002 [CI95%: 1.062-3.772], P=0.032) and liver fibrosis (OR: 2.646 [CI95%: 1.299-5.389], P=0.007) in patients without MetS. Hepatic copper content and PNPLA3 mutations are associated with disease activity in NAFLD patients without MetS. Presence of MetS appears to mask the effects of hepatic copper and PNPLA3. Copyright © 2016 Elsevier GmbH. All rights reserved.

  9. Macrophage activation marker soluble CD163 and non-alcoholic fatty liver disease in morbidly obese patients undergoing bariatric surgery.

    PubMed

    Kazankov, Konstantin; Tordjman, Joan; Møller, Holger Jon; Vilstrup, Hendrik; Poitou, Christine; Bedossa, Pierre; Bouillot, Jean-Luc; Clement, Karine; Grønbaek, Henning

    2015-08-01

    Macrophages play an important role in non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163) is a specific marker of macrophage activation. We aimed to measure sCD163 in morbidly obese patients with varying degrees of NAFLD before and after bariatric surgery (BS). Demographic, clinical, and biochemical data, and plasma sCD163 measured by enzyme-linked immunosorbent assay, of 196 patients were collected preoperatively and 3, 6, and 12 months after BS leading to significant weight loss. Peroperative liver biopsies were assessed for the NAFLD Activity Score (NAS), Kleiner fibrosis score, and the fatty liver inhibition of progression (FLIP) algorithm. In a subset, CD163 immunohistochemistry and real-time quantitative polymerase chain reaction for CD163 mRNA were performed. sCD163 was higher in patients with NAS ≥ 5 compared with those with NAS < 5 (2.4(2.0-3.1) vs 1.9(1.5-2.3) mg/L, P < 0.001) and in patients with bridging fibrosis (F ≥ 3) compared with lower fibrosis stages (2.6(2.0-4.9) vs 2.0(1.5-2.4) mg/L, P = 0.001). Preoperative sCD163 was independently associated with both the NAS (P = 0.002) and the fibrosis score (P = 0.024). sCD163 decreased after BS and was greatly reduced after 12 months, more rapidly so in patients with NAS ≥ 5 (P < 0.001) and non-alcoholic steatohepatitis (NASH) according to the FLIP algorithm (P = 0.03). Immunohistochemistry showed CD163-positive macrophages aligning fat-laden hepatocytes and forming microgranulomas in patients with NASH. CD163 mRNA expression did not vary with NAS. sCD163 increased in parallel with the severity of NAFLD in morbid obesity, indicating macrophage activation. BS reduced sCD163 even in patients with severe liver injury and fibrosis, suggesting full reversibility of macrophage activation associated with improved insulin sensitivity. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  10. Curcumin prevents the non-alcoholic fatty hepatitis via mitochondria protection and apoptosis reduction

    PubMed Central

    Wang, Long; lv, Yisong; Yao, Huixiang; Yin, Li; Shang, Jianhui

    2015-01-01

    Background: Non-alcoholic fatty hepatitis (NASH) is highly prevalent, mitochondria damage is the main pathophysiological characteristic of NASH. However, treatment for mitochondria damage is rarely reported. Methods: NASH model was established in rats, the protective effects of curcumin were evaluated by histological observation; structure and function assessments of mitochondria; and apoptotic genes expression. Results: NASH rats treated with curcumin displayed relatively slight liver damage when compared with NASH livers. The average mitochondrial length and width of NASH (12.0 ± 3.2 and 5.1 ± 1.1 micrometers) were significantly longer than that of normal (6.2 ± 2.1 and 2.1 ± 1.5 micrometers) and NASH treated with curcumin (7.4 ± 1.2 and 3.2 ± 1.5 micrometers) rats. The average malondialdehyde (MDA) and 4-hydroxy nonyl alcohol (HNE) levels in liver homogenates of NASH rats (4.23 ± 0.22 and 19.23 ± 2.3 nmol/Ml) were significantly higher than these in normal (1.32 ± 0.12 and 3.52 ± 0.43 nmol/mL) and NASH treated with curcumin (1.74 ± 0.11 and 4.66 ± 0.99 nmol/mL) rats. The expression levels of CytC, Casp3 and Casp8 of the NASH livers were significantly higher than normal and NASH treated with curcumin rats livers. Conclusion: Our data demonstrated that curcumin prevents the NASH by mitochondria protection and apoptosis reduction and provided a possible novel treatment for NASH. PMID:26617882

  11. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis

    PubMed Central

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-01-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated. PMID:25411525

  12. Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis.

    PubMed

    Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

    2014-11-01

    Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated.

  13. The benefits of exercise for patients with non-alcoholic fatty liver disease.

    PubMed

    Keating, Shelley E; George, Jacob; Johnson, Nathan A

    2015-01-01

    As exercise is now an established therapy for the management of non-alcoholic fatty liver disease (NAFLD), recent investigations have sought to identify the optimal dose (type, intensity and amount) of exercise for hepatic benefit. Here, the authors discuss the following: the role of aerobic exercise for the modulation of hepatic steatosis; the limited evidence for the role of resistance training in reducing liver fat; the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis; and the benefits of exercise for patients with NAFLD, beyond steatosis. Based on current evidence, the authors provide recommendations for exercise prescription for patients with NAFLD.

  14. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

    PubMed Central

    Takahashi, Yoshihisa; Fukusato, Toshio

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH. PMID:25400438

  15. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

    PubMed

    Takahashi, Yoshihisa; Fukusato, Toshio

    2014-11-14

    Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.

  16. Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats

    USDA-ARS?s Scientific Manuscript database

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes chemical carcinogen-initiated hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low d...

  17. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine initiated early hepatocarcinogenesis in rats

    USDA-ARS?s Scientific Manuscript database

    It has been suggested that patients with nonalcoholic steatohepatitis (NASH) are at a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes hepatocarcinogenesis. In the present study, Sprague-Dawley rats were injected with a low dose of hepatic carcinogen die...

  18. Moderate alcohol consumption aggravates high fat-diet induced steatohepatitis in rats

    USDA-ARS?s Scientific Manuscript database

    Background: Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Methods: Sprague-Dawley rats were first fed ad libitum...

  19. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation

    PubMed Central

    Ganz, Michal; Csak, Timea; Szabo, Gyongyi

    2014-01-01

    AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge. METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o staining; biochemical studies to look at ALT and triglyceride levels; RNA analysis using quantitative polymerase chain reaction; and cytokine analysis, which included the enzyme-linked immunosorbent assay method to look at interleukin (IL)-1β and tumor necrosis factor-α (TNFα) levels. Furthermore, at each length of feeding we also looked at insulin resistance and glucose tolerance using insulin tolerance tests (ITT) and glucose tolerance tests. RESULTS: There was no insulin resistance, steatosis, or inflammasome activation at 6 wk. In contrast, at 16 wk we found significant insulin resistance demonstrated by impaired glucose and ITT in male, but not female mice. In males, elevated alanine aminotransferase and triglyceride levels, indicated liver damage and steatosis, respectively. Increased liver TNFα and monocyte chemoattractant protein-1 mRNA and protein, correlated with steatohepatitis. The inflammasome components, adaptor molecule, Aim2, and NOD-like receptor 4, increased at the mRNA level, and functional inflammasome activation was indicated by increased caspase-1 activity and IL-1β protein levels in male mice fed a long-term HFD. Male mice on HFD had increased α-smooth muscle actin and pro-collagen-1 mRNA indicating evolving fibrosis. In contrast, female mice displayed only elevated triglyceride levels, steatosis, and no

  20. Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E.

    PubMed

    Kobori, Masuko; Takahashi, Yumiko; Sakurai, Mutsumi; Ni, Yinhua; Chen, Guanliang; Nagashimada, Mayumi; Kaneko, Shuichi; Ota, Tsuguhito

    2017-03-08

    Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH) [...].

  1. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers

    PubMed Central

    Kwan, Hiu Yee; Niu, Xuyan; Dai, Wenlin; Tong, Tiejun; Chao, Xiaojuan; Su, Tao; Chan, Chi Leung; Lee, Kim Chung; Fu, Xiuqiong; Yi, Hua; Yu, Hua; Li, Ting; Tse, Anfernee Kai Wing; Fong, Wang Fun; Pan, Si-Yuan; Lu, Aiping; Yu, Zhi-Ling

    2015-01-01

    Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism. PMID:25766252

  2. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers.

    PubMed

    Kwan, Hiu Yee; Niu, Xuyan; Dai, Wenlin; Tong, Tiejun; Chao, Xiaojuan; Su, Tao; Chan, Chi Leung; Lee, Kim Chung; Fu, Xiuqiong; Yi, Hua; Yu, Hua; Li, Ting; Tse, Anfernee Kai Wing; Fong, Wang Fun; Pan, Si-Yuan; Lu, Aiping; Yu, Zhi-Ling

    2015-03-13

    Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism.

  3. Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.

    PubMed

    Alonso, Cristina; Fernández-Ramos, David; Varela-Rey, Marta; Martínez-Arranz, Ibon; Navasa, Nicolás; Van Liempd, Sebastiaan M; Lavín Trueba, José L; Mayo, Rebeca; Ilisso, Concetta P; de Juan, Virginia G; Iruarrizaga-Lejarreta, Marta; delaCruz-Villar, Laura; Mincholé, Itziar; Robinson, Aaron; Crespo, Javier; Martín-Duce, Antonio; Romero-Gómez, Manuel; Sann, Holger; Platon, Julian; Van Eyk, Jennifer; Aspichueta, Patricia; Noureddin, Mazen; Falcón-Pérez, Juan M; Anguita, Juan; Aransay, Ana M; Martínez-Chantar, María Luz; Lu, Shelly C; Mato, José M

    2017-05-01

    Nonalcoholic fatty liver disease (NAFLD) is a consequence of defects in diverse metabolic pathways that involve hepatic accumulation of triglycerides. Features of these aberrations might determine whether NAFLD progresses to nonalcoholic steatohepatitis (NASH). We investigated whether the diverse defects observed in patients with NAFLD are caused by different NAFLD subtypes with specific serum metabolomic profiles, and whether these can distinguish patients with NASH from patients with simple steatosis. We collected liver and serum from methionine adenosyltransferase 1a knockout (MAT1A-KO) mice, which have chronically low levels of hepatic S-adenosylmethionine (SAMe) and spontaneously develop steatohepatitis, as well as C57Bl/6 mice (controls); the metabolomes of all samples were determined. We also analyzed serum metabolomes of 535 patients with biopsy-proven NAFLD (353 with simple steatosis and 182 with NASH) and compared them with serum metabolomes of mice. MAT1A-KO mice were also given SAMe (30 mg/kg/day for 8 weeks); liver samples were collected and analyzed histologically for steatohepatitis. Livers of MAT1A-KO mice were characterized by high levels of triglycerides, diglycerides, fatty acids, ceramides, and oxidized fatty acids, as well as low levels of SAMe and downstream metabolites. There was a correlation between liver and serum metabolomes. We identified a serum metabolomic signature associated with MAT1A-KO mice that also was present in 49% of the patients; based on this signature, we identified 2 NAFLD subtypes. We identified specific panels of markers that could distinguish patients with NASH from patients with simple steatosis for each subtype of NAFLD. Administration of SAMe reduced features of steatohepatitis in MAT1A-KO mice. In an analysis of serum metabolomes of patients with NAFLD and MAT1A-KO mice with steatohepatitis, we identified 2 major subtypes of NAFLD and markers that differentiate steatosis from NASH in each subtype. These might be

  4. Diagnosis and treatment of pediatric nonalcoholic steatohepatitis and the implications for bariatric surgery.

    PubMed

    Pardee, Perrie E; Lavine, Joel E; Schwimmer, Jeffrey B

    2009-08-01

    This review focuses on the diagnosis, risk factors, prevalence, pathogenesis and treatment of pediatric nonalcoholic steatohepatitis (NASH). NASH is a progressive form of nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in children. The factors that account for differences between children with NASH and children with milder forms of NAFLD are unclear. The diagnosis of NASH requires interpretation of liver histology because no noninvasive markers predict the presence or severity of NASH. There is no proven treatment for NASH. Several clinical trials for NAFLD are in progress; however, clinical trials focusing on NASH are needed. Heightened physician awareness of NAFLD, NASH, and associated risk factors is important to identify and treat affected children.

  5. Diagnosis and Treatment of Pediatric Nonalcoholic Steatohepatitis and the Implications for Bariatric Surgery

    PubMed Central

    Pardee, Perrie E.; Lavine, Joel E.; Schwimmer, Jeffrey B.

    2009-01-01

    This review focuses on the diagnosis, risk factors, prevalence, pathogenesis and treatment of pediatric nonalcoholic steatohepatitis (NASH). NASH is a progressive form of nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in children. The factors that account for differences between children with NASH versus children with milder forms of NAFLD are unclear. The diagnosis of NASH requires interpretation of liver histology because no noninvasive markers predict the presence or severity of NASH. There is no proven treatment for NASH. Several clinical trials for NAFLD are in progress, however, clinical trials focusing on NASH are needed. Heightened physician awareness of NAFLD, NASH, and associated risk factors is important to identify and treat affected children. PMID:19573756

  6. Wrestling J. B. Nash.

    ERIC Educational Resources Information Center

    Ellis, Gary D.

    This paper focuses on how between 1965 and the present, the field of recreation has and has not accomplished the goals of author and educator J. B. Nash's in regard to recreation, physical education, and health, focusing on public recreation sponsored by city governments, county governments, and special tax districts. The paper looks at Nash's…

  7. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease.

    PubMed

    Pastori, Daniele; Polimeni, Licia; Baratta, Francesco; Pani, Arianna; Del Ben, Maria; Angelico, Francesco

    2015-01-01

    Non-alcoholic fatty liver disease is an emerging liver disease in Western countries and the most frequent cause of incidental elevation of serum liver enzymes. Dyslipidaemia is frequently observed in patients with non-alcoholic fatty liver disease, and treatment of dyslipidaemia plays a critical role in the overall management of these patients. Moreover, coronary artery disease remains the most common cause of death. Statins are effective lipid-lowering agents, associated with a lowering the risk of cardiovascular events in several interventional randomized clinical trials. However, statins are often underused in patients with non-alcoholic fatty liver disease and many physicians are concerned about the prescription of statins to patients with unexplained persistent elevation of liver enzymes or active liver disease. Based on currently available data, statin therapy, at low-to-moderate doses, seems to be safe and has low liver toxicity. Treatment of dyslipidaemia in patients with non-alcoholic fatty liver disease is recommended and may also improve liver function tests. In these patients, the risks of not taking statins could outweigh the risks of taking the drug. Conversely, the usefulness of statins for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis is still a matter of debate and randomized clinical trials of adequate size and duration are required.

  8. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research.

    PubMed

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Crespo Yanguas, Sara; Colle, Isabelle; Van Den Bossche, Bert; Da Silva, Tereza Cristina; de Oliveira, Cláudia Pinto Marques Souza; Andraus, Wellington; Alves, Venâncio Avancini; Cogliati, Bruno; Vinken, Mathieu

    2015-07-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and '-omics'-based read-outs are still in their infancy, but show great promise. In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed.

  9. Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

    PubMed Central

    Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

    2015-01-01

    Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

  10. [Pediatric nonalcoholic fatty liver disease/nonalcoholic steatohepatitis].

    PubMed

    Takahashi, Yoshihisa; Fukusato, Toshio; Inui, Ayano; Fujisawa, Tomoo

    2012-10-01

    Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is a hepatic disease associated with metabolic syndrome. In recent years, pediatric NAFLD has increased in line with the increased prevalence of pediatric obesity. The estimated prevalence of pediatric NAFLD is 2.6-9.6%. With regard to the pathogenesis of NAFLD/ NASH, the "two-hit" or "multiple-hit" hypothesis is widely accepted, and many genetic and environmental factors are associated with the development of NAFLD/NASH. Liver biopsy is regarded as the gold standard for the diagnosis of NAFLD/NASH. Pediatric NAFLD has different histopathological characteristics from those of adult NAFLD. Although pharmacotherapy has been studied in clinical trials, lifestyle modification by diet and exercise remains the mainstay of treatment for NAFLD/NASH.

  11. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    USDA-ARS?s Scientific Manuscript database

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

  12. Effects of polyphenol compounds melanin on NAFLD/NASH prevention.

    PubMed

    Belemets, Natalia; Kobyliak, Nazarii; Virchenko, Oleksandr; Falalyeyeva, Tetyana; Olena, Tsyryuk; Bodnar, Petro; Savchuk, Oleksiy; Galenova, Tetyana; Caprnda, Martin; Rodrigo, Luis; Skladany, Lubomir; Delev, Delian; Opatrilova, Radka; Kruzliak, Peter; Beregova, Tetyana; Ostapchenko, Lyudmyla

    2017-04-01

    One of the pathogenic mechanisms of the progression non-alcoholic liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is the accumulation of reactive oxygen species (ROS). So, antioxidant therapy is necessary for successful treatment of the liver injury. We have paid attention to melanin produced by yeast Nadsoniella nigra strain X-1 as novel antioxidant and anti-inflammatory agents with low toxicity. In current study we aimed to investigate the preventive effect of melanin on the monosodium glutamate (MSG) induced NAFLD model in rats. The study was carried out on 45 Wistar rats that were divided into 3 groups: intact, MSG- and MSG+melanin groups (n=15 in each group). Newborn rats of MSG- and MSG+melanin groups were administered with MSG (4mg/g, 8μl/g, subcutaneously) at 2nd-10th days of life. Since the age of 1 month, rats of MSG-group were treated with water (0.25ml/100g), rats of MSG+melanin groups-with melanin (1mg/kg) dissolved in water (0.25ml/100g). had been performed intermittently (two-week courses alternated with two-week breaks) for 3 months. In 4-month rats anthropometrical parameters and visceral adipose tissue (VAT) mass were estimated. To assess morphological changes in liver we used NAS (NAFLD activity score). The content of pro-inflammatory cytokines (interleukin (IL)-1β, IL-12Bp40, interferon (INF)-γ) and anti-inflammatory cytokines (IL-4, IL-10, tumor growth factor (TGF)-β) were measured by ELISA. We found significantly lower total score (1.0±0.19 vs 3.33±0.36, p<0.001), degree of steatosis (0.73±0.18 vs 1.80±0.17, p<0.001) and manifestation of lobular inflammation (0.27±0.11 vs 1.20±0.17, p<0.001) due to NAFLD activity score in MSG+melanin group compared to MSG-obesity. NASH we confirmed only in 33.3% of rats with MSG-obesity that was significantly higher than after melanin (6.7%) administration (p=0.033). Melanin administration reduce amount of visceral fat on 44.5% (p<0.001) as compared to MSG-obesity group. Melanin reduced

  13. Enhanced A-FABP expression in visceral fat: potential contributor to the progression of NASH

    PubMed Central

    Yoon, Min Yong; Sung, Jun Mo; Song, Chang Seok; Lee, Won Young; Rhee, Eun Jung; Shin, Jun Ho; Yoo, Chang Hak; Chae, Seoung Wan; Kim, Ja Yeon; Jin, Wook

    2012-01-01

    Background/Aims Adipose tissue is an active endocrine organ that secretes various metabolically important substances including adipokines, which represent a link between insulin resistance and nonalcoholic steatohepatitis (NASH). The factors responsible for the progression from simple steatosis to steatohepatitis remain elusive, but adipokine imbalance may play a pivotal role. We evaluated the expressions of adipokines such as visfatin, adipocyte-fatty-acid-binding protein (A-FABP), and retinol-binding protein-4 (RBP-4) in serum and tissue. The aim was to discover whether these adipokines are potential predictors of NASH. Methods Polymerase chain reaction, quantification of mRNA, and Western blots encoding A-FABP, RBP-4, and visfatin were used to study tissue samples from the liver, and visceral and subcutaneous adipose tissue. The tissue samples were from biopsy specimens obtained from patients with proven NASH who were undergoing laparoscopic cholecystectomy due to gallbladder polyps. Results Patients were classified into two groups: NASH, n=10 and non-NASH, n=20 according to their nonalcoholic fatty liver disease Activity Score. Although serum A-FABP levels did not differ between the two groups, the expressions of A-FABP mRNA and protein in the visceral adipose tissue were significantly higher in NASH group than in non-NASH group (104.34 vs. 97.05, P<0.05, and 190.01 vs. 95.15, P<0.01, respectively). Furthermore, the A-FABP protein expression ratio between visceral adipose tissue and liver was higher in NASH group than in non-NASH group (4.38 vs. 1.64, P<0.05). Conclusions NASH patients had higher levels of A-FABP expression in their visceral fat compared to non-NASH patients. This differential A-FABP expression may predispose patients to the progressive form of NASH. PMID:23091808