title: MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.
abstract: Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis.
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Kai
authors: K
authors: Li
authors: the Key Laboratory of Molecular Medicine, Ministry of Education, Institute of Medical Sciences, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, 130 Dongan Road, Shanghai 200032, China.
authors: Jin
authors: J
authors: Zhang
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Junjie
authors: J
authors: Yu
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Bin
authors: B
authors: Liu
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Yajie
authors: Y
authors: Guo
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Jiali
authors: J
authors: Deng
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and.
authors: Shanghai
authors: S
authors: Chen
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and wangcx@sibs.ac.cn.
authors: Chunxia
authors: C
authors: Wang
authors: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031 and ffguo@sibs.ac.cn.
authors: Feifan
authors: F
authors: Guo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001786:Blood Glucose; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005943:Gluconeogenesis; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D034622:RNA Interference
chemical_list: C081452:Atf4 protein, mouse; D001786:Blood Glucose; D035683:MicroRNAs; C534781:Mirn214 microRNA, mouse; D051701:Activating Transcription Factor 4
keywords: ATF4; Fasting; Glucagon; Glucogenesis; Glucose Metabolism; Hyperglycemia; MicroRNA-214; Transgenic Mice; Type 2 Diabetes
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