title: Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling.
abstract: Understanding the regulation of insulin signalling in tissues provides insights into carbohydrate and lipid metabolism in physiology and disease. Here we show that hepatic miR-378/378* expression changes in response to fasting and refeeding in mice. Mice overexpressing hepatic miR-378/378* exhibit pure hepatic insulin resistance. miR-378 inhibits hepatic insulin signalling through targeting p110α, a subunit of PI3K and hence a critical component of insulin signalling. Knockdown of hepatic p110α mimics the effect of miR-378, while restoration of p110α expression abolishes the action of miR-378 on insulin signalling as well as its systemic effects on glucose and lipid homeostasis. miR-378/378* knockout mice display hypoglycemia and increased hepatic triglyceride level with enhanced insulin sensitivity. Inhibition of hepatic p110α in miR-378/378* knockout mice corrects the abnormal glucose tolerance. Finally, we show that overexpression of hepatic miR-378/378* ameliorates hepatic steatosis in ob/ob mice without exacerbating hyperglycemia. Our findings establish fasting-responsive miR-378 as a critical regulator of hepatic insulin signalling.
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Hongchao
authors.initials: H
authors.lastname: Cao
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ye
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, Jiangsu China.
authors.forename: Cunjie
authors.initials: C
authors.lastname: Chang
authors.affiliation: 1] Center for RNA Research, State Key Laboratory of Molecular Biology, University of Chinese Academy of Sciences, Shanghai 200031, China [2] Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Lu
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jing
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yao
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Zhengjun
authors.initials: Z
authors.lastname: Duan
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Nutrition, Shanghai Xuhui Central Hospital, Shanghai 200031, China.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: 1] Center for RNA Research, State Key Laboratory of Molecular Biology, University of Chinese Academy of Sciences, Shanghai 200031, China [2] Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Mo-Fang
authors.initials: MF
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing 210061, Jiangsu China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: 1] Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2] Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D005215:Fasting / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D058534:Class I Phosphatidylinositol 3-Kinases; D005947:Glucose; D007328:Insulin; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; C546119:MIRN378 microRNA, mouse; C546639:Pik3ca protein, mouse