P38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

Yan Xiong,Qu Fan Collins,Jie An,Edgar Lupo,Hui-Yu Liu,Delong Liu,Jacques Robidoux,Zhenqi Liu,Wenhong Cao

doi:10.1074/jbc.m606742200

Abstract

Hepatic lipogenesis is the principal route to convert excess carbohydrates into fatty acids and is mainly regulated by two opposing hormones, insulin and glucagon. Although insulin stimulates hepatic lipogenesis, glucagon inhibits it. However, the mechanism by which glucagon suppresses lipogenesis remains poorly understood. In this study, we have observed that p38 mitogen-activated protein kinase plays an inhibitory role in hepatic lipogenesis. Levels of plasma triglyceride and triglyceride accumulation in the liver were both elevated when p38 activation was blocked. Expression levels of central lipogenic genes, including sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase, hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl pyrophosphate synthase, and cytochrome P-450-51, were decreased in liver by fasting and in primary hepatocytes by glucagon but increased by the inhibition of p38. In addition, we have shown that p38 can inhibit insulin-induced expression of key lipogenic genes in isolated hepatocytes. Our results in hepatoma cells demonstrate that p38 plays an inhibitory role in the activation of the SREBP-1c promoter. Finally, we have shown that transcription of the PGC-1beta gene, a key coactivator of SREBP-1c, was reduced in liver by fasting and in isolated hepatocytes by glucagon. This reduction was significantly reversed by the blockade of p38. Insulin-induced expression of the PGC-1beta gene was enhanced by the inhibition of p38 but suppressed by the activation of p38. Together, we have identified an inhibitory role for p38 in the transcription of central lipogenic genes, SREBPs, and PGC-1beta and hepatic lipogenesis.

Highlights

Much is known about how hepatic lipogenesis is stimulated by metabolically important hormones such as insulin, whereas little is known about the mechanism by which hepatic lipogenesis is suppressed
Many factors may contribute to the development of the hypertriglyceridemia and fatty liver observed in this study
We have previously reported that the blockade of p38 can prevent activation of cAMP response element-binding protein in both liver and isolated hepatocytes [27, 28]. cAMP response element-binding protein has been previously shown to inhibit hepatic lipogenesis through stimulating expression of the Hairy Enhancer of Split-1 (HES-1) gene and suppressing expression of the peroxisome proliferator-activated receptor ␥ (PPAR␥) gene [52]

Summary

Introduction

The lipogenic process in the liver is primarily regulated by central lipogenic transcription factors, sterol regulatory element-binding proteins (SREBPs) SREBPs regulate lipogenesis by stimulating expression of their target genes, such as liver pyruvate kinase, acetyl CoA carboxylase, fatty acid synthase (FAS), Spot, diacylglycerol acyltransferase, and glycerol-3-phosphate acyltransferase (reviewed in Ref. 4). The “inactive” precursor form of SREBPs are integral membrane proteins of endoplasmic reticulum Upon sterol deprivation, they are cleaved through two sequential steps to release the N terminus, which is translocated into the nucleus to activate the transcription of target genes [6, 14, 15]. Peroxisome proliferator-activated receptor ␥ co-activator-1␤ (PGC-1␤) has been shown to interact with SREBP-1c as a coactivator in regulating the transcription of lipogenic genes [19]. Together our results support a critical role for p38 in the regulation of hepatic lipogenesis

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Results

Conclusion