Effect of genistein supplementation on methionine-choline deficient diet-induced nonalcoholic fatty liver disease development in db/db mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) occurs in a wide spectrum from simple steatosis to steatohepatitis, fibrosis and rarely, progression to cirrhosis. When db/db mice are fed a methionine-choline deficient (MCD) diet, significant liver fibrosis is observed as compared to other animal models. Previous studies reported that genistein has been shown to attenuate non-alcoholic steatohepatitis (NASH) induced in obese and type 2 diabetic animal models. However, there have been no studies of effect of genistein on NASH using animal model which has weight loss, anti-NASH effect of genistein is unclear. Therefore, we investigated the effect of genistein on the development of NASH induced by an MCD diet in db/db mice. Male C57BL/KsJdb/db mice were fed a control diet or MCD diet for 6 weeks. To investigate the effect of genistein, the additional group fed an MCD diet with 0.05% genistein. MCD diet-fed mice exhibited a significantly lower body and liver weight. And serum glucose, insulin, cholesterol and alanine aminotransferase levels were also decreased by MCD diet. MCD diet develops a higher degree of steatohepatitis corresponding with an increased oxidative stress, endoplasmic reticulum stress, hepatic steatosis, inflammation, stellate cell activation and mild fibrosis. Genistein reduced serum insulin levels, but we did not observe any inhibitory effect against hepatic steatosis by genistein supplementation. In contrast, hepatic oxidative stress and endoplasmic reticulum stress, and AMP-dependent kinase inactivation were alleviated by genistein. Genistein also down-regulated the augmented mRNA expression of genes associated with inflammatory cytokines or chemokines (tumor necrosis factor α, monocyte chemoattractant protein 1, toll-like receptor 4 and interleukin 1β) and fibrosis (transforming growth factor β1, procollagen type Ⅰ and tissue inhibitors of metalloproteinase 1). In conclusion, these results suggest the genistein alleviated MCD diet-mediated NASH development by suppressing lipid peroxidation, inflammation and even liver fibrosis in db/db mice.