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.
Highlights
MiR-214 targets activating transcription factor 4 (ATF4) involved in glucose metabolism; the role of miR-214 and ATF4 in hepatic gluconeogenesis is unknown
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
Expression of miR-214 Is Suppressed in the Livers of Fasted and Diabetic Mice—In an effort to explore the function of miR214 in gluconeogenesis, we first examined miR-214 expression in primary hepatocytes treated with glucagon
Summary
T2D, type 2 diabetes; miRNA, microRNA; Dex, dexamethasone; Glc-6-P, glucose-6-phosphatase; GTT, glucose tolerance test; HFD, high fat diet; H89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide; ITT, insulin tolerance test; LV-ATF4 KO, liver-specific ATF4 knockout mice; LV-miR-214 TG, liver-specific miR-214 transgenic mice; PCK, phosphoenolpyruvate carboxykinase; PTT, pyruvate tolerance test; SNK, Student-Newman-Keuls; ANOVA, analysis of variance; CREB, cAMP-response element-binding protein 1. MiR-214 can directly target phosphatase and tensin homolog deleted on chromosome 10 and fibroblast growth factor-21 receptor 1 (FGFR1) [21, 22]. FGFR1 is involved in the effect of fibroblast growth factor-21 (FGF21) on gluconeogenesis [26]. All these implied that miR-214 could be involved in the regulation of gluconeogenesis. Previous studies suggest that cooperative interaction between ATF4 and FOXO1 affects glucose metabolism [30]. Given that CREB and FOXO1 are key regulators of hepatic gluconeogenesis [25], we postulated that miR-214 might be involved in the regulation of hepatic gluconeogenesis via targeting ATF4
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