Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1.

Jun Guo,Weiwei Fang,Jing Qu,Libo Sun,Xiuqing Huang,Cheng Pang,Guanghui Liu,Yonggang Lu,Lin Dou,Mingxiao Sun,Jian Li

doi:10.18632/oncotarget.9183

Abstract

Previous studies indicated that miR-200s participated in IL-6-induced hepatic insulin resistance. However, the role of miR-200s in hepatic lipid accumulation has not been elucidated. Here we found that miR-200b and miR-200c were reduced in the steatotic livers of mice fed a high-fat diet (HFD) and patients with nonalcoholic fatty liver disease. This down-regulation was accompanied by an increase in the expression of lipogenic proteins such as sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS). The suppression of miR-200b and miR-200c in Hep1-6 and NCTC1469 hepatocytes enhanced intracellular triglyceride levels, which were associated with increased SREBP-1 and FAS protein levels. In contrast, the over-expression of miR-200b and miR-200c suppressed lipid accumulation and reduced the expression of SREBP1 and FAS in Hep1-6 and NCTC1469 cells transfected with miR-200b or miR-200c mimics. Importantly, the up-regulation of miR-200b and miR-200c could reverse oleic acid/palmitic acid-induced lipid accumulation in hepatocytes. A luciferase reporter assay identified that miR-200b and miR-200c could directly bind the 3′UTR of jun. JUN activated the transcription of srebp1 to increase lipid accumulation. The data also demonstrated that increased miR-200b and miR-200c expression might be associated with sitagliptin-reduced hepatic lipid accumulation in mice fed a HFD. These findings suggest, for the first time, that reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1.

Highlights

Obesity is a global health problem that causes a series of pathological disorders including nonalcoholic fatty liver disease (NAFLD), type 2 diabetes and cardiovascular disease [1,2,3]
The expression of miR-200b and miR-200c was suppressed in the livers of NAFLD patients (Figure 1F), and the levels of lipogenic proteins such as sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) were elevated compared with the healthy controls (Figure 1G)
We examined miRNA expression in the livers of db/db mice and found that the expression of the miR-200 family members miR-200a, miR-200b and miR-200c was reduced in response to hepatic insulin resistance [23]

Summary

Introduction

Obesity is a global health problem that causes a series of pathological disorders including nonalcoholic fatty liver disease (NAFLD), type 2 diabetes and cardiovascular disease [1,2,3]. Abnormal lipid accumulation in the liver may result in hepatic steatosis and nonalcoholic steatohepatitis (NASH) [4, 5]. Liver lipid homeostasis is correlated with different processes including the uptake, synthesis, storage and secretion of lipids [6]. Www.impactjournals.com/oncotarget sterol regulatory element-binding proteins (SREBPs) have been reported to widely regulate lipogenic gene expression [7]. Srebp-1a and srebp1c, are expressed from various promoters [8]. SREBP1c mainly stimulates proteins involved in fatty acid metabolism such as fatty acid synthase (FAS) [9, 10]. SREBP-2 and SREBP-1a mainly participate in cholesterol metabolism [11]

Objectives

Methods

Results

Conclusion