Abstract
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 α (LXRα), 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/LXRα 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 LXRα 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 LXRα in ob/ob mice. Similarly, metformin decreased apoA5 expression and TG level in mouse hepatocytes, with increased phosphorylation of cellular AMPK and LXRα. Addition of AMPK inhibitor or siRNA knockdown of LXRα significantly attenuated metformin-induced down-regulation of cellular apoA5 expression and TG level. AMPK inhibitor also significantly inhibited metformin-induced LXRα 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/LXRα signaling pathway.
Highlights
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disorder, and is strongly linked to obesity with a reported prevalence as high as 80% in obese population [1, 2]
Recent evidence demonstrated that liver X receptor α (LXRα), 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
APOA5 mRNA expression is regulated by several factors including liver X receptor α (LXRα), a ligand-activated nuclear transcription factor that has been demonstrated to downregulate hepatic APOA5 mRNA expression [12]
Summary
Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disorder, and is strongly linked to obesity with a reported prevalence as high as 80% in obese population [1, 2]. Recent evidence demonstrated that metformin, a first-line antihyperglycemic drug for type 2 diabetes mellitus, effectively improved liver dysfunction in obese patients with NAFLD [4], which indicates that this agent could be enlisted as a promising medicine for obesity-related NAFLD. Earlier studies implicated apoA5 as a key regulator of plasma TG homeostasis [5, 6], while recent data identified its role in the biogenesis of hepatocyte lipid droplets [79], a histological hallmark of NAFLD. Two studies observed overexpression of hepatic APOA5 mRNA in NAFLD patients, which implicated apoA5 as a potential therapeutic target for NAFLD [10, 11]. We investigated whether metformin could improve obesity-related NAFLD through inhibition of hepatic apoA5 synthesis regulated via the AMPK/LXRα signaling pathway
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