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J. Biol. Chem., Vol. 282, Issue 7, 4975-4982, February 16, 2007

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p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis^*

Yan Xiong, Qu Fan Collins, Jie An^¶, Edgar Lupo, Jr., Hui-Yu Liu, Delong Liu^||, Jacques Robidoux, Zhenqi Liu^**, and Wenhong Cao¹

From the Endocrine Biology Program, ^||Center for Integrated Genomics, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, ^¶The Sarah W. Stedman Center for Nutrition and Metabolism, Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, 410078 Hunan, China, ^**Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and Division of Endocrinology, Department of Internal Medicine, Duke University, Medical Center, Durham, North Carolina 27710

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-1 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-1 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-1 and hepatic lipogenesis.

Received for publication, July 14, 2006 , and in revised form, November 21, 2006.

^* This work was supported by the Investigator Development Fund from the The Hamner Institutes for Health Sciences (to W. C.) and American Heart Association Grant SDG-0530244N (to W. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: The Hammer Institutes for Health Sciences, Six Davis Dr., P.O. Box 12137, Research Triangle Park, NC 27709. Tel.: 919-558-1396; E-mail: wcao{at}thehamner.org.

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