MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase-Mediated Gluconeogenesis.

Abstract

MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes.

• Authors: Shu Zhuo, Mengmei Yang, Yanan Zhao, Xiaofang Chen, Feifei Zhang, Na Li, Pengle Yao, Tengfei Zhu, Hong Mei, Shanshan Wang, Yu Li, Shiting Chen, Yingying Le
• Journal: Diabetes (Diabetes) Vol. 65 Issue 11 Pg. 3276-3288 (Nov 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 27495223 (Publication Type: Journal Article)
• Copyright: © 2016 by the American Diabetes Association.

Chemical References

• Forkhead Box Protein O1
• MicroRNAs
• Mirn451 microRNA, mouse
• Glycerol Kinase
• Oncogene Protein v-akt
• Glucose-6-Phosphatase
• Phosphoenolpyruvate Carboxykinase (ATP)
• Glucose

Topics

• Animals
• Diabetes Mellitus, Experimental (genetics, metabolism)
• Forkhead Box Protein O1 (genetics, metabolism)
• Gluconeogenesis (genetics, physiology)
• Glucose (metabolism)
• Glucose-6-Phosphatase (genetics, metabolism)
• Glycerol Kinase (genetics, metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Oncogene Protein v-akt (genetics, metabolism)
• Phosphoenolpyruvate Carboxykinase (ATP) (genetics, metabolism)
• Rats
• Signal Transduction (genetics, physiology)