Dihydromyricetin Alleviates Nonalcoholic Fatty Liver Disease and Its Associated Metabolic Syndrome by Inhibiting Endoplasmic Reticulum Stress in LDLR-/-Mice Fed with a High-Fat and High-Fructose Diet

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease. Previous studies have shown that dihydromyricetin (DHM) is beneficial for NAFLD. However, whether DHM alleviates NAFLD by inhibiting liver endoplasmic reticulum (ER) stress remains unknown. Thus, this study aimed to identify the potential roles and mechanisms of DHM. Twenty-four male low-density lipoprotein receptor (LDLR-/-) knockout mice aged 8 weeks were randomly divided into normal control, control, and DHM groups. Normal control mice were fed a normal diet (ND), and the last two groups of mice were fed a high-fat and high-fructose diet (HFD) for 12 weeks, treated with or without DHM. DHM alleviated diet-induced hyperlipidemia as early as 4 weeks after and until the end of HFD feeding. HFD increased insulin resistance, and the opposite was observed in the DHM group. Compared to the control group, the body weight of the mice and adipocyte size and weight of the retroperitoneal and epididymal fat were remarkably reduced in the DHM group. The expression of genes related to lipid metabolism, such as Acox1 and Cpt1α, was significantly upregulated. Moreover, Mttp was downregulated in the two fat sits in the DHM group. DHM alleviated diet-induced lipid deposition in the liver and decreased liver triglyceride and total cholesterol content. DHM improved liver function by inhibiting ER stress, alleviating atherogenesis, and promoting vascular remodeling. In conclusion, dihydromyricetin improved NAFLD and related insulin resistance, hyperlipidemia, and atherogenesis by inhibiting liver ER stress in HFD-fed LDLR-/- mice.