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J. Biol. Chem., Vol. 282, Issue 34, 24607-24614, August 24, 2007

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Activation of Bile Acid Biosynthesis by the p38 Mitogen-activated Protein Kinase (MAPK)

HEPATOCYTE NUCLEAR FACTOR-4 PHOSPHORYLATION BY THE p38 MAPK IS REQUIRED FOR CHOLESTEROL 7-HYDROXYLASE EXPRESSION^*

Zhumei Xu, Olga L. Tavares-Sanchez, Quanzhong Li, Josephine Fernando, Carmen M. Rodriguez, Elaine J. Studer, William M. Pandak^¶, Phillip B. Hylemon, and Gregorio Gil¹

From the Departments of Biochemistry and Molecular Biology, Microbiology and Immunology, and ^¶Medicine, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298-0614

Bile acids are required for intestinal absorption and biliary solubilization of cholesterol and lipids. In addition, bile acids play a crucial role in cholesterol homeostasis. One of the key enzymes in the bile acid biosynthetic pathways is cholesterol 7-hydroxylase/cytochrome P450 7-hydroxylase (7-hydroxylase), which is the rate-limiting and regulatory step of the "classic" pathway. Transcription of the 7-hydroxylase gene is highly regulated. Two nuclear receptors, hepatocyte nuclear factor 4 (HNF-4) and ₁-fetoprotein transcription factor, are required for both transcription and regulation by different physiological events. It has been shown that some mitogen-activated protein kinases, such as the c-Jun N-terminal kinase and the ERK, play important roles in the regulation of 7-hydroxylase transcription. In this study, we show evidence that the p38 kinase pathway plays an important role in 7-hydroxylase expression and hence in bile acid synthesis. Inhibition of p38 kinase activity in primary hepatocytes results in 5–10-fold reduction of 7-hydroxylase mRNA. This suppression is mediated, at least in part, through HNF-4. Inhibition of p38 kinase activity diminishes HNF-4 nuclear protein levels and its phosphorylation in vivo and in vitro, and it renders a less stable protein. Induction of the p38 kinase pathway by insulin results in an increase in HNF-4 protein and a concomitant induction of 7-hydroxylase expression that is blocked by inhibiting the p38 pathway. These studies show a functional link between the p38 signaling pathway, HNF-4, and bile acid synthesis.

Received for publication, December 14, 2006 , and in revised form, June 1, 2007.

^* This work was supported in part by National Institutes of Health Grant DK065049 (to G. G.). 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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Medical College of Virginia at Virginia Commonwealth University, P. O. Box 980614, Richmond, VA 23298-0614. Tel.: 804-828-0140; Fax: 804-828-0144; E-mail: ggil{at}vcu.edu.

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