A model of insulin resistance and nonalcoholic steatohepatitis in rats -: Role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury

Insulin resistance induces nonalcoholic fatty liver disease and nonalcoholic steatoliepatitis (NASH). We used a high-fat, high-calorie solid diet (HID) to create a model of insulin resistance and NASH in nongenetically modified rats and to study the relationship between visceral adipose tissue and liver. Obesity and insulin resistance occurred in HID rats, accompanied by a progressive increase in visceral adipose tissue tumor necrosis factor (TNF)-alpha mRNA and in circulating free fatty acids. HFD also decreased adiponectin mRNA and peroxisome proliferator-activated receptor (PPAR)-alpha expression in the visceral adipose tissue and the liver, respectively, and induced hepatic insulin resistance through TNF-alpha-mediated c-Jun N-terminal kinase (JNK)-dependent insulin receptor sub-strate-1(Ser307) phosphorylation. These modifications lead to hepatic steatosis accompanied by oxidative stress phenomena, necroinflammation, and hepatocyte apoptosis at 4 weeks and by pericentral fibrosis