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J. Biol. Chem., Vol. 283, Issue 22, 15089-15096, May 30, 2008

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Peroxisome Proliferator-activated Receptor- Coactivator-1 Activation of CYP7A1 during Food Restriction and Diabetes Is Still Inhibited by Small Heterodimer Partner^*

From the Department of Molecular Biology and Biochemistry, School of Biological Sciences, Center for Diabetes Research and Treatment, University of California, Irvine, California 92697-3900

Cholesterol 7-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor -coactivator-1 (PGC-1) induce expression of the Cyp7A1 gene and overexpression of PGC-1 in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1-RNA interference to induce acute disruption of PGC-1 in mice, here we show that PGC-1 is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1 and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1β could not substitute for PGC-1. We also show that transactivation of PGC-1 and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1 to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1 is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1 to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1 in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.

Received for publication, December 21, 2007 , and in revised form, March 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK71021 (to T. O.). This work was also supported by American Heart Association Scientist Development Grant 0730189N (to D. J. S.). 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: 3244 McGaugh Hall, University of California, Irvine CA 92697-3900. Tel.: 949-824-2979; Fax: 949-824-8551; E-mail: tfosborn{at}uci.edu.

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