Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation and fibrosis, which might progress to cirrhosis. Human NASH is associated with metabolic syndrome (MS). Currently, rodent NASH models either lack significant fibrosis or MS. ApoE(−/−) mice are a MS model used in cardiovascular research. The aim of this work was to establish and characterise a novel mouse NASH model with significant fibrosis and MS. ApoE(−/−) and wild-type mice (wt) were fed either a western-diet (WD), methionine-choline-deficient-diet (MCD) or normal chow. Liver histology, RT-PCR, hepatic hydroxyproline content, triglycerides and cholesterol levels, and fasting glucose levels assessed hepatic steatosis, inflammation and fibrosis. Further, portal pressure was measured invasively, and kidney pathology was assessed by histology. ApoE(−/−) mice receiving WD showed abnormal glucose tolerance, hepatomegaly, weight gain and full spectrum of NASH including hepatic steatosis, fibrosis and inflammation, with no sign of renal damage. MCD-animals showed less severe liver fibrosis, but detectable renal pathological changes, besides weight loss and unchanged glucose tolerance. This study describes a murine NASH model with distinct hepatic steatosis, inflammation and fibrosis, without renal pathology. ApoE(−/−) mice receiving WD represent a novel and fast model with all characteristic features of NASH and MS well suitable for NASH research.