Inhibition of stearoyl-coenzyme A desaturase 1 ameliorates hepatic steatosis by inducing AMPK-mediated lipophagy.

Youping Zhou,Shengjie Yu,Can Cai,Huihong Yu,Li Zhong,Wei Shen

doi:10.18632/aging.103082

Abstract

SCD1 is a key enzyme controlling lipid metabolism and a link between its activity and NAFLD has been proposed. Lipophagy is a novel regulatory approach to lipid metabolism regulation, which is involved in the development of NAFLD. However, the possible functional connection between SCD1 and lipophagy in NAFLD remains unknown. To investigate the molecular mechanisms through which SCD1 regulates lipophagy in hepatic steatosis, the model of hepatic steatosis was established by inducing mouse primary hepatocytes with sodium palmitate and feeding C57BL/6 mice with HFD. Our results indicated that sodium palmitate-treated hepatocytes exhibited increased SCD1 expression, AMPK inactivation and defective lipophagy. Inhibition of SCD1 expression in hepatocytes resulted in enhanced AMPK activity and lipophagy, and reduced lipid deposition. Although SCD1 overexpression led to decreased AMPK activity and lipophagy, lipid deposition was increased in hepatocytes. SCD1 regulated lipophagy through AMPK to affect lipid metabolism in mouse primary hepatocytes. Additionally, compared to HFD-fed mice, CAY10566(an SCD1-specific inhibitor)-treated mice exhibited significantly decreased hepatic steatosis and hepatic lipid droplet accumulation, as well as enhanced AMPK activity and lipophagy. This study elucidated that SCD1 inhibition ameliorates hepatic steatosis by inducing AMPK-mediated lipophagy, suggesting that the SCD1-AMPK-lipophagy pathway is a potential therapeutic target for NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is currently considered the most common cause of chronic liver disease worldwide with an estimated overall global prevalence of 25% [1]
Lipophagy is inhibited in the high-fat environment of NAFLD, which leads to reduced lipid mobilization and exacerbation of hepatic steatosis, while excessive lipid deposition further augments lipophagy and forms a “vicious circle” [11, 12]
These data suggested the upregulation of Stearoyl-coenzyme A desaturase 1 (SCD1), decreased AMPK activation and defective lipophagy in hepatic steatosis

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is currently considered the most common cause of chronic liver disease worldwide with an estimated overall global prevalence of 25% [1]. Stearoyl-coenzyme A desaturase 1 (SCD1), a key enzyme in lipid metabolism, involves the regulation of TG synthesis and fatty acid oxidation in hepatocytes [3, 4]. AMP-activated protein kinase (AMPK) is not just a sensor of balancing the cellular energy status, but it plays critical roles in regulating lipid metabolism: activated AMPK can inhibit lipogenesis, increase fatty acid oxidation, and affect cholesterol and total TG synthesis [12,13,14]. The change in AMPK activity is regulated by SCD1 activity: SCD1 inhibition increases AMPK phosphorylation and leads to changes in the expression of genes involved in lipogenesis [18]. Our previous study demonstrated that inhibition of SCD1 led to autophagy-induced apoptosis via AMPK signaling in human hepatocellular carcinoma (HCC) cells [19]

Methods

Results

Conclusion