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J. Biol. Chem., Vol. 282, Issue 19, 14205-14212, May 11, 2007

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Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase^*

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

From the Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, the Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China, the ^¶Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, and the ^||Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27708

Free fatty acid (FFA) is believed to be a major environmental factor linking obesity to Type II diabetes. We have recently reported that FFA can induce gluconeogenesis in hepatocytes through p38 mitogen-activated protein kinase (p38). In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. An siRNA against p38 prevented oleate suppression of the insulin-induced phosphorylation of Akt. Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulin-induced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance.

Received for publication, October 16, 2006 , and in revised form, February 20, 2007.

^* This work was supported in part by an Investigator Development Fund from the Hamner Institutes for Health Sciences CIIT 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: The Hamner Institutes for Health Sciences, Six Davis Dr., P.O. Box 12137, Research Triangle Park, NC 27709. E-mail: wcao{at}thehamner.org.

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