Alleviation of nonalcoholic fatty liver disease development by genistein in ApoE-/- mice fed a high-fat diet

Abstract

Nonalcoholic fatty liver disease (NAFLD) occurs in a wide variety of clinical presentations, ranging from asymptomatic hepatic steatosis to severe nonalcoholic steatohepatitis (NASH). Recent studies reported that ApoE-/- mice fed a high-fat diet (HFD) can be used as a model of NASH as well as arteriosclerosis. Because genistein has been shown to alleviate hepatic steatosis, we investigated the effects of genistein on the development of NASH in ApoE-/- mice fed an HFD. Both wild-type (WT) mice and ApoE-/- mice were fed either an HFD (45% of the calories from fat) or an HFD supplemented with genistein (0.5g/kg diet). After 24 weeks on an HFD, serum triglyceride, total cholesterol, thiobarbituric acid reactive substances, monocyte chemoattractant protein 1 (MCP-1), and alanine aminotransferase (ALT) levels were more exacerbated in ApoE-/- mice compared to WT mice. In addition, ApoE-/- mice exhibited more severe hepatic fat accumulation and hepatic inflammation. These findings confirmed that ApoE-/- mice fed an HFD are a promising NASH model. Cholesterol levels in both sera and livers were alleviated by genistein in ApoE-/- mice. Furthermore, ApoE-/- mice exhibited a reduced serum MCP-1 and ALT levels as well as hepatic triglyceride and hepatic pro-inflammatory gene expressions such as MCP-1, tumor necrosis factor α, and cyclooxygenase 2 in response to genistein. Hepatic gene expressions related to lipid metabolism including peroxisome proliferator activated receptor gamma (PPARγ), CD36 and monoacylglycerol O-acyltransferase 1 were reduced by genistein in ApoE-/- mice. In particular, serum cholesterol levels were significantly correlated with liver injury and the expression of various hepatic inflammatory genes, indicating that hypercholesterolemia plays an important role in accelerating NASH progression. In summary, genistein acts as an antioxidant resulting in reduced serum lipid peroxidation products and inflammation. Genistein also reduces the expressions of PPARγ and its target genes, resulting in both the influx of the oxidized lipid products into liver and the lipid formation. In conclusion, genistein alleviated metabolic abnormalities including hypercholesterolemia, obesity, and NASH in ApoE-/- mice fed an HFD.