Metformin improves nonalcoholic fatty liver disease in obese mice via down-regulation of apolipoprotein A5 as part of the AMPK/LXRα signaling pathway

Apolipoprotein A5 (apoA5) has been implicated in the formation of hepatocyte lipid droplets, a histological hallmark of non-alcoholic fatty liver disease (NAFLD). Recent evidence demonstrated that liver X receptor alpha (LXR alpha), a transcription factor involved in down-regulation of APOA5 mRNA, is activated by AMP-activated protein kinase (AMPK) that contributes to metformin-related antihyperglycemic effects. In this study we investigated the role of apoA5 and AMPK/LXR alpha signaling pathway in metformin-related improvement of NAFLD. Leptin-deficient (ob/ob) obese mice with NAFLD were treated with metformin, and signaling pathways were compared with non-metformin treated mice. Additionally, we determined cellular apoA5 and triglyceride (TG) levels in mouse hepatocytes in vitro and the effects of metformin, with or without an AMPK inhibitor or LXR alpha siRNA, on these levels. We found that metformin dose-dependently ameliorated hepatosteatosis and liver dysfunction in ob/ob mice, with a significant reduction in hepatic apoA5 expression and TG level. Metformin also dose-dependently increased phosphorylation of hepatic AMPK and LXR alpha in ob/ob mice. Similarly, metformin decreased apoA5 expression and TG level in mouse hepatocytes, with increased phosphorylation of cellular AMPK and LXR alpha. Addition of AMPK inhibitor or siRNA knockdown of LXR alpha significantly attenuated metformin-induced down-regulation of cellular apoA5 expression and TG level. AMPK inhibitor also significantly inhibited metformin-induced LXR alpha phosphorylation in these hepatocytes. Therefore, our findings indicate that metformin improves obesity-related NAFLD via inhibition of hepatic apoA5 synthesis as part of the AMPK/LXR alpha signaling pathway.