MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4

• DOI: 10.1074/jbc.m114.633990
• Publication Date: 2015-02-06T06:24:40Z
• Authors: Kai Li; Jin Zhang; Junjie Yu; Bin Liu; Yajie Guo; Jiali Deng; Shanghai Chen; Chunxia Wang; Feifan Guo
• Keywords: Blood Glucose; Male; 0301 basic medicine; Gluconeogenesis; Mice, Obese; Mice, Transgenic; Diet, High-Fat; Activating Transcription Factor 4; Mice, Inbred C57BL; MicroRNAs; 03 medical and health sciences; Diabetes Mellitus, Type 2; Liver; Hyperglycemia; Animals; RNA Interference; Cells, Cultured

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.