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J. Biol. Chem., Vol. 281, Issue 34, 24336-24344, August 25, 2006

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p38 Mitogen-activated Protein Kinase Mediates Free Fatty Acid-induced Gluconeogenesis in Hepatocytes^*

Qu Fan Collins, Yan Xiong, Edgar G. Lupo, Jr., Hui-Yu Liu, and Wenhong Cao^¶1

From the Division of Biological Sciences, Endocrine Biology Program, CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, the Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, China, and the ^¶Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708

Free fatty acids (FFA) are considered as a causative link between obesity and diabetes. In various animal models and in humans FFA can stimulate hepatic gluconeogenesis. Although the in vivo role of FFA in hepatic gluconeogenesis has been clearly established, the intracellular role of FFA and related signaling pathway remain unclear in the regulation of hepatic gluconeogenic gene transcription. In this study, we have identified p38 mitogen-activated protein kinase (p38) as a critical signaling component in FFA-induced transcription of key gluconeogenic genes. We show in primary hepatocytes that both mid- and long-chain fatty acids (saturated or unsaturated) could activate p38 and increase levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, and peroxisome proliferator-activated receptor coactivator (PGC-1) gene transcripts. The FFA-induced expression of PEPCK and PGC-1 genes and gluconeogenesis in isolated hepatocytes could be blocked by the inhibition of p38. Furthermore, PGC-1 phosphorylation by p38 was necessary for FFA-induced activation of the PEPCK promoter. Additionally, FFA stimulated phosphorylation of cAMP-response element-binding protein (CREB) through p38. The overexpression of the dominant-negative CREB prevented FFA-induced activation of the PEPCK promoter. Finally, we show that FFA activation of p38 requires protein kinase C. Together, our results indicate that p38 plays a critical role in FFA-induced transcription of gluconeogenic genes, and the known gluconeogenic regulators, PGC-1 and CREB, are also integral parts of FFA-stimulated transcription of gluconeogenic genes.

Received for publication, March 7, 2006 , and in revised form, June 22, 2006.

^* This study was supported by the Development Fund from the Chemical Industry Institute of Toxicology Centers for Health Research (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. S1 and S2.

¹ To whom correspondence should be addressed: Chemical Industry Institute of Toxicology Centers for Health Research, Six Davis Drive, P. O. Box 12137, Research Triangle Park, NC 27709. Tel.: 919-558-1396; Fax: 919-558-1305; E-mail: wcao{at}ciit.org.

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