Signal-dependent Control of Gluconeogenic Key Enzyme Genes through Coactivator-associated Arginine Methyltransferase 1

Jens C. Brüning,Andrea Mesaros,Dagmar Metzger,Stephan Herzig,Ulrike Lemke,Anja Krones-Herzig,Anja Ziegler

doi:10.1074/jbc.m509770200

Abstract

Together with impaired glucose uptake in skeletal muscle, elevated hepatic gluconeogenesis is largely responsible for the hyperglycemic phenotype in type II diabetic patients. Intracellular glucocorticoid and cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent signaling pathways contribute to aberrant hepatic glucose production through the induction of gluconeogenic enzyme gene expression. Here we show that the coactivator-associated arginine methyltransferase 1 (CARM1) is required for cAMP-mediated activation of rate-limiting gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and glucose-6-phosphatase genes. Mutational analysis showed that CARM1 mediates its effect via the cAMP-responsive element within the PEPCK promoter, which is identified here as a CARM1 target in vivo. In hepatocytes, endogenous CARM1 physically interacts with cAMP-responsive element binding factor CREB and is recruited to the PEPCK and glucose-6-phosphatase promoters in a cAMP-dependent manner associated with increased promoter methylation. CARM1 might, therefore, represent a critical component of cAMP-dependent glucose metabolism in the liver.

Highlights

According to recent estimates, 200 –300 million people worldwide will be diagnosed with type II diabetes in 2010 [1, 2]
HepG2 hepatocytes co-transfected with phosphoenolpyruvate carboxykinase (PEPCK) or G6Pase luciferase reporter as in Fig. 1 and expression vectors for mutant protein kinase A, wild type protein kinase A, unspecific (RNAi control), or human coactivator-associated arginine methyltransferase 1 (CARM1)-specific RNA Interference (RNAi) vectors as indicated
CARM1 had no effect on glucocorticoid-induced PEPCK and G6Pase transcription, suggesting that CARM1 is involved in the cyclic AMP (cAMP)/protein kinase A (PKA)-dependent control of gluconeogenic gene expression

Summary

Introduction

200 –300 million people worldwide will be diagnosed with type II diabetes in 2010 [1, 2]. Chronic hyperglycemia as observed in type II diabetic patients represents the major cause for vascular complications and results from the development of a peripheral resistance against the action of the pancreatic ␤-cell hormone insulin [3]. Chronic activation of counter-regulatory hormones, in particular pancreatic glucagon acting via the intracellular cyclic AMP (cAMP)3/protein kinase A (PKA) pathway [5], aggravates hepatic glu-. We have identified CARM1 as a critical component of the cAMP-dependent regulatory complex involved in the control of hepatic gluconeogenic enzyme gene expression

Methods

Results

Conclusion