MicroRNA-214 Suppresses Gluconeogenesis By Targeting Activating Transcriptional Factor 4 [Gene Regulation]

February 5th, 2015 by Li, K., Zhang, J., Yu, J., Liu, B., Guo, Y., Deng, J., Chen, S., Wang, C., Guo, F.

While 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 (PKA) signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high-fat diet (HFD)-induced diabetic and leptin receptor-mutated (db/db) mice. The over-expression 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 HFD-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 knockout mice (LV-ATF4 KO). ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, Liver-specific miR-214 transgenic mice (LV-miR-214 TG) exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase (G6P) in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis