Genistein alleviates the development of nonalcoholic steatohepatitis in <i><scp>A</scp>po<scp>E</scp>^―/―</i> mice fed a high‐fat diet

Abstract

SCOPE: Genistein (GEN) is a compound that has been shown to alleviate hepatic steatosis. Here, we investigated its protective effects against non-alcoholic steatohepatitis (NASH) development in apolipoprotein E-deficient (ApoE(-/-) ) mice fed a high-fat diet (HFD). METHODS AND RESULTS: Wild-type and ApoE(-/-) mice were fed an HFD with or without GEN (0.5 g/kg diet) for 24 weeks. Body weights were reduced and fecal cholesterol excretion was increased by GEN. GEN supplementation lowered serum and hepatic cholesterol and lipid peroxidation levels, and hepatic heme oxygenase 1 protein levels in ApoE(-/-) mice. Hepatic expressions of scavenger receptors involved in oxidized LDL uptake, CD36 and scavenger receptor A, were downregulated by GEN. GEN reduced serum alanine aminotransferase and monocyte chemoattractant protein 1 levels, and hepatic nuclear factor-κB-mediated inflammatory gene expressions in ApoE(-/-) mice. These levels were higher in ApoE(-/-) mice fed an HFD than their corresponding wild-type mice. GEN also alleviated hepatic steatosis by reducing mRNA levels of monoacylglycerol O-acyltransferase 1, a target gene of peroxisome proliferator-activated receptor γ. CONCLUSION: GEN alleviated NASH as well as hypercholesterolemia and obesity in ApoE(-/-) mice fed an HFD. Restoration of altered cholesterol metabolism and oxidative stress may be involved in the protective effect of GEN against NASH development.