The establishment of a novel non-alcoholic steatohepatitis model accompanied with obesity and insulin resistance in mice

Non-alcoholic steatohepatitis (NASH) is a hepatic manifestation of the metabolic syndrome that can progress to liver cirrhosis. The major aim of this study was to establish a novel NASH mouse model accompanied by obesity and insulin resistance, then explore the molecular mechanisms of NASH and evaluate the effects of both the peroxisome proliferator-activated receptor alpha. (PPAR alpha) agonist fenofibrate and the PPAR-gamma agonist rosiglitazone in this established NASH model. The novel model was induced in C5713L/6 mice by 23 weeks of ad libitum feeding of a modified high-fat diet (mHFD), with lower methinione and choline and higher fat content. In comparison to the controls, the model animals developed pronounced obesity, dyslipidemia and insulin resistance. Marked liver lesions characterized by severe steatosis, inflammation, fibrosis, increased hepatic triglyceride content, and elevated serum alanine aminotransferase (ALT) levels were observed in the models. In this novel model, treatment with fenofibrate or rosiglitazone significantly improved insulin sensitivity and corrected dyslipidemia; however, fenofibrate was more effective than rosiglitazone in improving hepatic morphology and ALT levels. Further study showed that long-term feeding of mHFD significantly increased expression of mRNA for hepatic PPAR-gamma, adipose fatty acid binding protein (ap2) and CD36 and suppressed expression of mRNA for hepatic PPAR alpha and carnitine palmitoyl transferase-1a (CPT-1a). These results showed the successful establishment of the combined NASH and obese-insulin resistance mouse model. Additionally, aberrant expressions of hepatic PPAR alpha and PPAR-gamma may play a major role in the pathogenesis of NASH by affecting hepatic lipogenesis and fatty acid oxidation in this novel model. (C) 2008 Elsevier Inc. All rights reserved.