Wei-na Cong1, Rong-ya Tao1, Jin-ying Tian1, Fei Ye1, Geng-tao Liu1
1 Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
Non-alcoholic steatohepatitis (NASH), a character of metabolic syndrome, may progress to liver cirrhosis. The major aims of this study were to establish a novel NASH mouse model accompanied with insulin resistance (IR) and obesity, further to explore its molecular mechanisms and investigate the treatment of NASH with PPARα agonist fenofibrate and PPARγ agonist rosiglitazone, respectively. The NASH model was induced by ad libitum feeding of the modified high-fat diet (mHFD) in C57BL/6 mice. As results, the models showed overt IR in insulin tolerant test. Compared with the controls, bodyweights of the models increased by 68%; plasma cholesterol, insulin and HOMA-IR index also elevated by 127% ,544% and 944%,respectively; The value of glucose infusion rate (GIR) in the hyperinsulinemic-euglycemic clamp was 7.2-fold lower. The models developed severe liver damages as indicated with serious steatosis, inflammation and fibrosis in morphological assessments, the hepatic triglyceride contents and serum ALT levels increased by 5 and 2 folds, respectively. The treatments of fenofibrate and rosiglitazone improved IR and dyslipidemia. The efficacy of fenofibrate was more effective in the treatment of NASH than rosiglitazone. In the mechanistic study, altered expressions of hepatic PPARα and PPARγ and their target genes led to enhanced lipogenesis and disturbed fatty acid β-oxidation. These results suggested that aberrant expressions of hepatic PPARα and PPARγ might play main roles in the pathogenesis of NASH via affecting lipogenesis and fatty acid oxidation in this novel NASH model.