Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis

Background and Aim:  Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo .
Methods:  Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat.
Results:  The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-α and procollagen α (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P  = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n  = 1/8), whereas no tumor was detected in WT mice ( n  = 10).
Conclusions:  Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-α expression and liver fibrosis.     

Na+/H+ exchanger mediates TNF-α-induced hepatocyte apoptosis via the calpain-dependent degradation of Bcl-xL

Background and Aim:  It is well known that tumor necrosis factor-α (TNF-α) induces hepatocyte apoptosis and contributes to liver diseases. However, the exact mechanisms are not well understood.
Methods:  In the present study, we reported that Na⁺/H⁺ exchanger (NHE) is involved in TNF-α-induced hepatocyte apoptosis.
Results:  TNF-α time dependently induced an increase in NHE activity in hepatocytes, but cariporide, an NHE inhibitor, blocked the TNF-α-induced increase of NHE activity in a dose-dependent manner. Increased NHE activity induced by TNF-α was associated with increased intracellular calcium (Ca²⁺_i) concentration and calpain activity. Cariporide reversed these effects induced by TNF-α. In addition, TNF-α downregulated Bcl-xL, an anti-apoptotic protein, but not mRNA levels. The inhibition of either calpain or NHE blocked the TNF-α-induced decrease of the Bcl-xL protein. TNF-α did not change the pro-apoptotic Bax and Bak protein levels. Cariporide, calcium remover 1,2-bis (2-aminophenoxy) ethane-N,N,N0,N0–tetraacetic acid, or calpain inhibitor benzyloxycarbonyl-leucyl-leucinal attenuated TNF-α-induced hepatocyte apoptosis.
Conclusion:  TNF-α via NHE results in hepatocyte apoptosis through the calcium/calpain/Bcl-xL pathway.     

Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression

Background and Aims:  We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH).
Methods:  To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-α-receptor (TNF-R)1, TNF-R2, Fas, and TNFα-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.
Results:  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 ∼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.
Conclusions:  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.     

Decreasing levels of tumour necrosis factor alpha and interleukin 6 during lowering of body mass index with orlistat or placebo in obese subjects with cardiovascular risk factors

Aim:   Obesity is associated with increased levels of inflammatory mediators. The objective of this study was to evaluate changes in the leucocyte derived inflammatory mediators tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and the isoprostane 8-epi-prostaglandin (PG) F_2α during BMI lowering with orlistat (Xenical^®, Roche) or placebo.
Methods:   TNF-α, IL-6, and 8-epi PGF_2α evaluated in 376 subjects aged 18–75 years with BMI 28–38 kg/m² before and after 1 year of double-blind, randomized treatment with orlistat 120 mg or placebo three times daily.
Results:   Weight reduction was associated with decreasing (p < 0.001) levels of TNF-α and IL-6 in both orlistat and placebo groups. After 12 months, TNF-α was lower (p < 0.05) in the orlistat compared with the placebo group. In the orlistat group, the change in TNF-α correlated with change in s-glucose (r = 0.22; p = 0.01), and the change in 8-epi-PGF_2α correlated with changes in s-cholesterol (r = 0.27; p < 0.001) and s-LDL-cholesterol (r = 0.28; p < 0.001).
Conclusion:   Weight reduction was associated with decreasing levels of both TNF-α and IL-6. After 12 months of treatment, TNF-α levels were lower in orlistat than in placebo-treated subjects. Whether these results translate into reduced incidence of cardiovascular disease remains to be elucidated.     

Effects of probucol on hepatic tumor necrosis factor-α, interleukin-6 and adiponectin receptor-2 expression in diabetic rats

Background and Aims:  Probucol is a lipid-lowering agent with anti-oxidant effects. Oxidative stress and inflammation are important in the pathophysiology of insulin resistance. We aimed to evaluate the effects of probucol on liver histological changes, serum and hepatic levels of adipokines in rats with high fat-induced type 2 diabetes (T2D).
Methods:  Thirty-six rats were divided into a normal control group, a high fat-induced T2D group and a probucol treatment group. After six weeks of treatment with probucol, we evaluated liver histological changes and measured homeostasis model assessment index (HOMA-IR), serum superoxide dismutase (SOD), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor (TNF)-α, interleukin (IL)-6, adiponectin and hepatic TNF-α, IL-6 and adiponectin receptor-2 (adipoR2) mRNA.
Results:  The degree of hepatic steatosis and inflammation, HOMA-IR, serum ALT, TNF-α and IL-6 concentrations, and hepatic TNF-α and IL-6 mRNA expression in diabetic rats were significantly higher compared with normal controls. Serum SOD and adiponectin concentrations and hepatic adipoR2 mRNA expression in diabetic rats were significantly lower compared with normal controls. Probucol significantly reduced the degree of hepatic steatosis, HOMA-IR, serum ALT, TNF-α and IL-6 concentrations, and hepatic TNF-α and IL-6 mRNA expression. Probucol significantly raised serum SOD and adiponectin concentrations and hepatic adipoR2 mRNA expression.
Conclusions:  In rats with high fat-induced T2D, treatment with probucol improved insulin sensitivity, hepatic steatosis by raising circulating adiponectin and hepatic adipoR2 levels, in addition to reducing pro-inflammatory cytokines in the circulation and liver.     

Clinical significance of serum ornithine carbamoyltransferase in patients with non-alcoholic steatohepatitis

Aim:  Ornithine carbamoyltransferase (OCT) is reported to be a liver-specific marker for the evaluation of hapatocellular damage. In this study, we investigated its clinical significance in non-alcoholic steatohepatitis (NASH).
Methods:  Serum OCT levels were measured by the ELISA (enzyme-linked immunosorbent assay) method. One hundred and twenty patients with NASH (18 liver cirrhosis induced by NASH and 9 NASH combined with hepatocellular carcinoma) were measured.
Results:  The serum levels of OCT and the ratios of OCT : alanine amino transferase (ALT) and OCT : aspartate amino transferase (AST) were increased in parallel with the progression of NASH. Especially, OCT and both ratios were markedly increased in hepatocellular carcinoma. As for the relationship between fibrosis grade and OCT, the serum OCT levels and the ratio of OCT : ALT levels were increased in parallel with liver fibrosis. In NASH patients with ALT within normal range, about 30% showed elevation of OCT.
Conclusion:  Serum OCT levels and the ratios of OCT : ALT and OCT : AST increase in parallel with the progression of NASH. It was suggested that OCT is a useful marker in the progression of NASH.     

Genetic polymorphisms of adiponectin and tumor necrosis factor-alpha and nonalcoholic fatty liver disease in Chinese people

Background and Aim:  Hypoadiponectinemia and high tumor necrosis factor-alpha (TNF-α) levels are associated with the development of nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the genetic polymorphisms of adiponectin and TNF-α in Chinese NAFLD patients and their association with disease severity.
Methods:  Seventy-nine patients with histology-proven NAFLD (61 with simple steatosis and 18 with stage 2–4 fibrosis) and 40 controls were tested for the nucleotide polymorphisms at adiponectin −11 391, −11 377, +45, and +276 and TNF-α promoters −863, −308, and −238.
Results:  There was no significant deviation in the adiponectin and TNF-α gene polymorphisms between NAFLD patients and controls, or between patients with simple steatosis and those with stage 2–4 fibrosis. NAFLD patients with −11377G and +45G at the adiponectin gene were more likely to have hypertriglyceridemia. On multivariate analysis, older age, higher body mass index, and higher fasting glucose were independent factors associated with stage 2–4 fibrosis in NAFLD patients.
Conclusions:  Adiponectin and TNF-α gene polymorphisms were not shown to be associated with NAFLD or significant fibrosis in Chinese people. The adiponectin −11377G and +45G alleles were associated with hypertriglyceridemia in NAFLD patients. Since the current study is not adequately powered to detect smaller differences in allele frequencies, larger-sized studies in different ethnic groups are required.     

Hepatitis C virus F protein inhibits cell apoptosis by activation of intracellular NF-κB pathway

Aim:  To observe the influence of HCV F protein on apoptosis of HepG2 cells, and explore the association between F protein and NF-κB signal pathway.
Methods:  HCV 1b F gene containing HepG2-F cells and HCV 1b C gene containing HepG2-C cells were treated with 100 IU/mL TNF-α, and analyzed by flow cytometry, Western blotting, and dual luciferase reporter assay. Empty plasmid pcDNA3.1⁺ containing HepG2-3.1 cells were used as control.
Results:  (i) With the treatment of TNF-α for 18 h, the apoptosis rates (AR) of HepG2-F and HepG2-3.1 cells were 0.41% (± 0.11%) and 37.43% (± 2.03%) respectively, while that of HepG2-C was 4.07% (± 0.18%). At 36 h after TNF-α treatment, the AR of HepG2-F and HepG2-3.1 cells were 10.03% (± 0.41%) and 44.63% (± 3.37%), and that of HepG2-C was 14.95% (± 0.85%). (ii) After the treatment of TNF-α for 0.5–18 h, the p65 contents in the whole cells of HepG2-F and HepG2-3.1 showed no significant difference ( P  = 0.34, t  = 1.08), while the p65 contents in the nucleus of HepG2-F and HepG2-3.1 cells were 3.8–1.9 times and 1.8–1.0 times higher than that in the non-treated cells ( P  = 0.013, t  = 4.25). (iii) The relative luciferase unit (RLU) of the HepG2 cells, co-transfected with pcDNA3.1-F and pNF-κB-luc, and then treated with TNF-α (100 IU/mL) for 18 h, showed a pcDNA3.1-F dose-dependent increase.
Conclusion:  HCV F protein can over-activate NF-κB signal pathway, which makes HepG2-F cells able to resist TNF-α induced apoptosis.     

Serum neopterin levels in patients with non-alcoholic steatohepatitis

Aim:  Neopterin is a marker of cell-mediated immunity. It also has a fundamental role in host-defense reactions, including interactions with reactive oxygen intermediates and the promotion of local and systemic oxidative stress. The present study aimed to assess the importance of serum neopterin levels in patients with non-alcoholic steatohepatitis (NASH).
Methods:  Thirty-nine patients with NASH diagnosed by liver biopsy and 32 healthy adults (controls) were enrolled in the study. Serum neopterin levels were measured with an enzyme-linked immunosorbent assay in addition to other biochemical parameters, including liver enzymes. Histopathological examinations were graded as suggested by both the necroinflammatory activity grading system and the NASH scoring system.
Results:  The mean serum neopterin levels were higher in patients with NASH compared to the controls (24.1 ± 16.4 vs 16.2 ± 9.5, P  = 0.019). The histological examination of liver biopsies revealed that 34 of the patients with NASH had grade 1 steatohepatitis and only five patients had grade 2 steatohepatitis. A higher serum mean neopterin level was detected in grade 2 patients compared to grade 1 (40.6 ± 5.6 vs 21.7 ± 16.1, P  = 0.014). A gradual increase was also observed in serum neopterin levels with the increase of the NASH score.
Conclusion:  The serum neopterin levels were significantly higher in patients with NASH compared to the controls, and levels showed an association with the severity of liver damage.     

Marked elevation of serum mitochondrion-derived markers in mild models of non-alcoholic steatohepatitis in rats

Background and Aim:  In order to find sensitive serum markers in non-alcoholic steatohepatitis, liver-specific injury markers were thoroughly examined in mild models of NASH in rats.
Methods:  Wistar and Sprague–Dawley rats were fed a choline-deficient diet for 4 weeks, and serum activities of liver-specific enzyme markers were examined. In the drug-induced steatohepatitis model, tetracycline (0.4 mmol/kg) was given i.p. to rats and the course of hepatotoxicity was evaluated with serum markers, together with the accumulation of total lipid and thiobarbituric acid-reactive substances in the liver.
Results:  In Wistar rats, serum activities of most enzymes tested were significantly increased. In Sprague–Dawley rats, in contrast, the serum level of ornithine carbamyltransferase and glutamate dehydrogenase were markedly elevated in the choline-deficient diet group compared with the control diet groups, whereas other markers were not significantly increased. In the tetracycline-induced steatohepatitis model, the extent of the increase was much higher in mitochondrial markers and the peak of the increase in these markers corresponded with the increase of hepatic total lipid and thiobarbituric acid-reactive substance.
Conclusions:  These observations show that serum mitochondrial enzyme markers are potent markers for non-alcoholic steatohepatitis in rats and are possibly applicable to humans.     

Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats

Background and Aims:  Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model.
Methods:  Rats were treated with rolipram (0.5–5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred.
Result:  Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-α, IL-1β and GRO/CINC-1 levels. Rolipram, at doses of 0.5–5 mg/kg, suppressed serum transaminase and TNF-α production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg.
Conclusion:  In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.     

Reduction of fibrosis in a rat model of non-alcoholic steatohepatitis cirrhosis by human HGF gene transfection using electroporation

Background and Aim:  To study the histological changes caused by transfection of the hepatocyte growth factor ( HGF ) gene using electroporation (EP) in a non-alcoholic steatohepatitis (NASH) cirrhotic liver model.
Methods:  NASH cirrhotic livers were prepared by administering a choline-deficient diet to 5-week-old male Wister rats for 12 weeks. Three groups of rats were used: rats in the G(+) group were transfected with the GFP gene using EP, rats in the H(+) group were transfected with the HGF gene using EP, and rats in the H(–) group were only injected with the HGF gene. Rats were sacrificed 2 days after gene transfection, and the Azan positive rate (APR) and Sudan positive rate (SPR) were calculated to evaluate fibrosis and fatty changes.
Results:  The APR of the NASH cirrhotic livers was significantly higher than that in the normal livers. The APR did not decrease in the G(+) group and the H(–) group, but decreased significantly in the nonelectroporated as well as electroporated areas of the H(+) group. For SPR, there were no significant differences between the G(+), H(–), and H(+) groups.
Conclusion:  The improvement of fibrosis was not significant when a direct injection of the HGF gene was used alone, but it was enhanced by the concomitant use of EP. However, no efficacy was observed in fat components. These findings suggest that transfection of the HGF gene by EP may lead to an improvement of irreversible cirrhotic livers to reversible fatty livers.     

Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C

Background and Aim:  Ethnic differences in non-alcoholic steatohepatitis (NASH) are well-documented, but there has been no study on the prognosis of Japanese NASH patients with cirrhosis. Accordingly, we compared cirrhotic NASH with liver cirrhosis caused by chronic hepatitis C (LC-C) to clarify its clinical features and define the risk factors for death.
Methods:  A prospective evaluation of the outcomes of NASH patients with severe fibrosis was started in 1990. Data on age- and sex-matched patients with biopsy-proven LC-C were collected retrospectively and used as the control.
Results:  There were 68 patients with cirrhotic NASH and 69 with LC-C. The Child–Turcotte–Pugh (CTP) class was similar in these two groups. Although the outcome of the NASH group was better than that of the LC-C group, cirrhotic NASH followed a similar course to that of LC-C; that is, complications of cirrhosis developed, including hepatocellular carcinoma (HCC; the 5-year HCC rate was 11.3% for NASH and 30.5% for HCV) and death (the 5-year survival rates were 75.2% and 73.8%, respectively). HCC was the leading cause of death in both groups (NASH, 47%; HCV, 68%). The occurrence of HCC and the CTP class were significant risk factors for mortality in NASH patients according to a multivariate analysis (HCC: hazard ratio [HR] 7.96, 95% confidence interval [CI] 2.45–25.88, CTP class A: HR 0.17, 95% CI 0.06–0.50).
Conclusion:  In conclusion, the present study confirmed that cirrhotic NASH has a similar course to LC-C. The occurrence of HCC was the strongest predictor of mortality in the NASH groups. These findings may be helpful when deciding on therapeutic interventions for NASH and also for the daily management of these patients.     

Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis

Context  Nonalcoholic fatty liver disease represents the hepatic manifestation of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury. The pathophysiology that leads to NASH is not well understood.
Objective  We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor.
Design and patients  75 patients (28 men, 47 women) underwent liver biopsy for elevation in liver enzymes. Histological diagnosis identified normal liver in eight, fatty liver in 20, NASH grade 1 in 22, grade 2 in nine, grade 3 in three patients, and other forms of hepatitis or cirrhosis in 13 patients. We quantified hepatic 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) and hexose-6-phosphate-dehydrogenase (H6PDH) mRNA expression by real-time PCR. In addition, analysis of 24 h urinary excretion of cortisol metabolites using GCMS was performed and compared with healthy controls.
Results  11β-HSD1 mRNA expression correlated significantly ( R ²= 0·809; P  < 0·001) with H6PDH mRNA expression, negatively with waist-to-hip ratio in women ( R ²= 0·394; P = 0·005), but not with urinary (THF + 5α-THF)/THE ratio, total cortisol metabolite excretion, age, BMI, degree of fatty liver or NASH stages. Total cortisol metabolite excretion was increased in patients with fatty liver or NASH compared with healthy controls.
Conclusions  Our data suggest that expression of hepatic 11β-HSD1 and H6PDH are closely interlinked. 11β-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or NASH. However, those patients showed an increased 5α- and 5β-reduction of cortisol leading to an increased cortisol turnover rate and an activation of the HPA axis.     

Chronic Alcohol Ingestion Enhances Tumor Necrosis Factor-α Expression and Salivary Gland Apoptosis

We investigated the extent of induction in sublingual salivary gland cells apoptosis and tumor necrosis factor-α (TNF-α) expression with chronic ethanol ingestion. The experiments were conducted on rats pair-fed for 8 weeks with alcohol-containing and control liquid diet. The animals were killed, their sublingual glands dissected, and the glandular tissue used for quantitization of TNF-α expression and the assays of acinar cells apoptosis employing sandwich enzyme immunoassay for histone-associated DNA fragments. The mean value for TNF-α in sublingual gland of the control group was 22.3 pg/mg of protein and showed a 1.6-fold increase in the chronic ethanol diet group to 36.5 pg/mg of protein. In comparison with the controls, the sublingual gland of the chronic ethanol diet group also exhibited a 3.4-fold enhancement in acinar cell apoptosis. These findings suggest that chronic ethanol ingestion causes the enhancement in TNF-α expression and leads to the induction in salivary gland acinar cells apoptosis. Thus, the diminished secretion of saliva in alcoholics may be a direct result of increased salivary gland apoptosis.     

The Production of Tumor Necrosis Factor-α by Macrophages in Rats With Acute Alcohol Loading

Background: It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide-binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To study the pathophysiological roles of macrophages in alcoholic liver diseases, we examined the production of TNF-α by rat Kupffer cells, splenic macrophages, and alveolar macrophages with acute alcohol loading in the presence or absence of LBP.
Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from male Wistar rats given 5 mg/g body weight of ethanol intraperitoneally after an hour. The production of TNF-α by these cells incubated with endotoxin 100 ng/ml in the presence or absence of LBP (1% rat serum) was determined.
Results: Acute alcohol loading did not affect the production of TNF-α by Kupffer cells. With acute alcohol loading, splenic macrophages tended to produce more TNF-α. Alveolar macrophages produced more TNF-α than Kupffer cells, and although the production of TNF-α by alveolar macrophages tended to be suppressed by acute alcohol loading, the production of TNF-α by alveolar macrophages still remained high in the presence of rat serum.
Conclusions: Splenic macrophages and alveolar macrophages may be related to excessive production of TNF-α in acute alcoholics with endotoxemia.     

A novel and comprehensive mouse model of human non‐alcoholic steatohepatitis with the full range of dysmetabolic and histological abnormalities induced by gold thioglucose and a high‐fat diet

Background: The search for effective treatments of non‐alcoholic steatohepatitis (NASH), now the most common chronic liver disease in affluent countries, is hindered by a lack of animal models having the range of anthropometric and pathophysiological features as human NASH. Aims: To examine if mice treated with gold thioglucose (GTG) – known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity – and then fed a high‐fat diet (HF) had a comprehensive histological and dysmetabolic phenotype resembling human NASH. Methods: C57BL/6 mice were injected intraperitoneally with GTG and then fed HF for 12 weeks (GTG+HF). The extent of abdominal adiposity was assayed by CT scanning. A glucose tolerance test and an insulin tolerance test were performed to evaluate insulin resistance (IR). Histological, molecular and biochemical analyses were also performed. Results: Gold thioglucose+HF induced dysmetabolism, with hyperphagia, obesity with increased abdominal adiposity, IR and consequent steatohepatitis, with hepatocyte ballooning, Mallory–Denk bodies, perivenular and pericellular fibrosis as seen in adult NASH, paralleled by an increased expression of the profibrogenic factors, transforming growth factor‐β1 and TIMP‐1. Plasma adiponectin and the expression of adiponectin receptor 1 and receptor 2 were decreased, while PPAR‐γ and FAS were increased in the livers of GTG+HF mice. In addition, GTG+HF mice showed glucose intolerance and severe IR. Conclusions: Treatment with GTG and HF diet induce, in mice, a comprehensive model of human NASH, with the full range of dysmetabolic and histological abnormalities.