title: Reduced miR-200b and miR-200c expression contributes to abnormal hepatic lipid accumulation by stimulating JUN expression and activating the transcription of srebp1.
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.
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.|National Laboratory of Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.|Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Hepatobiliay Surgery and You-An Liver Transplantation Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Dou
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.|Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.|Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008055:Lipids / Q000032:analysis*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D007004:Hypoglycemic Agents; D008055:Lipids; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D016755:Proto-Oncogene Proteins c-jun; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000068900:Sitagliptin Phosphate
keywords: JUN; SREBP1; lipogenesis; miR-200b; miR-200c