Research Papers:
Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1
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Abstract
Jun Guo1,3,*, Weiwei Fang1,2,*, Libo Sun4, Yonggang Lu1, Lin Dou1, Xiuqing Huang1, Mingxiao Sun1, Cheng Pang1,2, Jing Qu5,6, Guanghui Liu3,6, Jian Li1,2
1The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China
2Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
3National Laboratory of Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
4Department of Hepatobiliay Surgery and You-An Liver Transplantation Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
5State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
6University of Chinese Academy of Sciences, Beijing 100049, China
*These authors contributed equally to this work
Correspondence to:
Jian Li, email: [email protected]
Guanghui Liu, email: [email protected]
Jing Qu, email: [email protected]
Keywords: miR-200b, miR-200c, lipogenesis, JUN, SREBP1
Received: September 22, 2015 Accepted: April 22, 2016 Published: May 05, 2016
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.
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