A cholesterol-containing modified western diet inducing steatohepatitis (NASH) with insulin resistance in wildtype B6 mice

Obesity is associated with insulin resistance and type II diabetes but also with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) that are hepatic manifestations of the metabolic syndrome. One of the most relevant factors contributing to obesity is diet. Feeding studies with rodents using diets like high-fat-, methionine-choline-deficient- or paigen-diet often did not induce the same phenotype like in human metabolic syndrome. Here we designed a new high-fat-containing western-diet that caused obesity, insulin resistance and NASH in mice.

C57BL/6-mice fed a western-diet with cholesterol (WD-C, 25 g/100 g fat) or high-fat-diet (HFD, 25 g/100 g fat) for 20 weeks significantly gained weight, increased their body fat mass and were glucose intolerant and slightly hyperinsulinaemic compared to chow-fed mice. Serum parameters for liver inflammation were elevated after feeding a WD-C but not after feeding a western-diet (WD, 25 g/100 g fat) or HFD. Histological scoring of the liver revealed steatohepatitis with fibrosis (NASH) in WD-C-fed mice and only simple steatosis without inflammation in WD- and HFD-fed mice. Gene expression analysis detected an up-regulation of chemokines, pro-inflammatory cytokines, immune cell infiltration and induction of markers for fibrosis and apoptosis only in livers of WD-C-fed mice. Serum level of triglycerides and cholesterol were slightly elevated, but liver triglycerides and cholesterol were highly increased in WD-C-fed mice compared to chow-fed mice. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered cultured hepatocytes more susceptible to TNFα/actinomycinD-induced apoptosis.

Mice fed a WD-C therefore are a potential better model for human metabolic syndrome and NASH than mice fed a HFD.