title: Liver MicroRNA-291b-3p Promotes Hepatic Lipogenesis through Negative Regulation of Adenosine 5'-Monophosphate (AMP)-activated Protein Kinase α1.
abstract: In a microarray study, we found that hepatic miR-291b-3p was significantly increased in leptin-receptor-deficient type 2 mice (db/db), a mouse model of diabetes. The function of miR-291b-3p is unknown. The potential role of miR-291b-3p in regulating hepatic lipid metabolism was explored in this study. High-fat diet (HFD)- and chow-fed mice were injected with an adenovirus expressing a miR-291b-3p inhibitor and a miR-291b-3p mimic through the tail vein. Hepatic lipids and lipogenic gene expression were analyzed. Additionally, gain- and loss-of-function studies were performed in vitro to identify direct targets of miR-291b-3p. MiR-291b-3p expression and the protein levels of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) were increased in the steatotic liver of db/db mice and HFD-fed mice versus their respective controls. Inhibition of hepatic miR-291b-3p expression prevented increases in hepatic lipogenesis and steatosis in HFD-fed mice. The opposite was observed when miR-291b-3p was overexpressed in the livers of chow-fed C57BL/6J wild-type mice. In vitro studies revealed that silencing of miR-291b-3p in NCTC1469 hepatic cells ameliorated oleic acid/palmitic acid mixture-induced elevation of cellular triglycerides. Importantly, we identified AMP-activated protein kinase (AMPK)-α1 as a direct target of miR-291b-3p. Using metformin, an activator of AMPK, we showed that AMPK activation-induced inhibition of hepatic lipid accumulation was accompanied by reduced expression of miR-291b-3p in the liver. Liver miR-291b-3p promoted hepatic lipogenesis and lipid accumulation in mice. AMPKα1 is a direct target of miR-291b-3p. In conclusion, our findings indicate that miR-291b-3p promotes hepatic lipogenesis by suppressing AMPKα1 expression and activity, indicating the therapeutic potential of miR-291b-3p inhibitors in fatty liver disease.
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Meng
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fang
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Dou
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Huang
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Shutong
authors.initials: S
authors.lastname: Zhou
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Man
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China, Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742 lyu123@umd.edu.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: From The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China, lijian@bjhmoh.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004041:Dietary Fats; C000611398:MIRN-291 microRNA, mouse; D035683:MicroRNAs; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D008687:Metformin; D054890:Fatty Acid Synthase, Type I; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated kinase (AMPK); AMPKα liver disease; fatty acid; fatty acid synthase (FAS); lipid accumulation liver disease; lipid metabolism; microRNA (miRNA); nonalcoholic fatty liver disease