Hepatic p38α regulates gluconeogenesis by suppressing AMPK.

Abstract

BACKGROUND & AIMS:

It is proposed that p38 is involved in gluconeogenesis, however, the genetic evidence is lacking and precise mechanisms remain poorly understood. We sought to delineate the role of hepatic p38α in gluconeogenesis during fasting by applying a loss-of-function genetic approach.

METHODS:

We examined fasting glucose levels, performed pyruvate tolerance test, imaged G6Pase promoter activity, as well as determined the expression of gluconeogenic genes in mice with a targeted deletion of p38α in liver. Results were confirmed both in vivo and in vitro by using an adenoviral dominant-negative form of p38α (p38α-AF) and the constitutively active mitogen-activated protein kinase 6, respectively. Adenoviral dominant-negative form of AMP-activated protein kinase α (DN-AMPKα) was employed to test our proposed model.

RESULTS:

Mice lacking hepatic p38α exhibited reduced fasting glucose level and impaired gluconeogenesis. Interestingly, hepatic deficiency of p38α did not result in an alteration in CREB phosphorylation, but led to an increase in AMPKα phosphorylation. Adenoviral DN-AMPKα could abolish the effect of p38α-AF on gluconeogenesis. Knockdown of up-steam transforming growth factor β-activated kinase 1 decreased the AMPKα phosphorylation induced by p38α-AF, suggesting a negative feedback loop. Consistently, inverse correlations between p38 and AMPKα phosphorylation were observed during fasting and in diabetic mouse models. Importantly, adenoviral p38α-AF treatment ameliorated hyperglycemia in diabetic mice.

CONCLUSIONS:

Our study provides evidence that hepatic p38α functions as a negative regulator of AMPK signaling in maintaining gluconeogenesis, dysregulation of this regulatory network contributes to unrestrained gluconeogenesis in diabetes, and hepatic p38α could be a drug target for hyperglycemia.

• Authors: Yanyan Jing, Wei Liu, Hongchao Cao, Duo Zhang, Xuan Yao, Shengjie Zhang, Hongfeng Xia, Dan Li, Yu-cheng Wang, Jun Yan, Lijian Hui, Hao Ying
• Journal: Journal of hepatology (J Hepatol) Vol. 62 Issue 6 Pg. 1319-27 (Jun 2015) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 25595884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• RNA, Messenger
• Mitogen-Activated Protein Kinase 14
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Diabetes Mellitus, Experimental (genetics, metabolism)
• Fasting (metabolism)
• Gluconeogenesis (genetics, physiology)
• Glucose (metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 14 (deficiency, genetics, metabolism)
• Phosphorylation
• RNA, Messenger (genetics, metabolism)