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 1, 3, * , Weiwei Fang 1, 2, * , Libo Sun 4 , Yonggang Lu 1 , Lin Dou 1 , Xiuqing Huang 1 , Mingxiao Sun 1 , Cheng Pang 1, 2 , Jing Qu 5, 6 , Guanghui Liu 3, 6 , Jian Li 1, 2 1 The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China 2 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China 3 National Laboratory of Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China 4 Department of Hepatobiliay Surgery and You-An Liver Transplantation Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China 5 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 6 University of Chinese Academy of Sciences, Beijing 100049, China * These authors contributed equally to this work Correspondence to: Jian Li, email: lijian@bjhmoh.cn Guanghui Liu, email: ghliu@ibp.ac.cn Jing Qu, email: qujing@ioz.ac.cn 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 .