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J. Biol. Chem., Vol. 282, Issue 28, 20164-20171, July 13, 2007

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A Key Role for Orphan Nuclear Receptor Liver Receptor Homologue-1 in Activation of Fatty Acid Synthase Promoter by Liver X Receptor^*

Karen E. Matsukuma¹, Li Wang, Mary K. Bennett, and Timothy F. Osborne²

From the Department of Molecular Biology and Biochemistry School of Biological Sciences and the Center for Diabetes Research and Treatment, University of California, Irvine California 92697-3900 and Departments of Medicine and Pharmacology, University of Kansas Medical Center, Kansas City, Kansas 66160

Liver X receptor (LXR) activates fatty acid synthase (FAS) gene expression through binding to a DR-4 element in the promoter. We show that a distinct nuclear receptor half-site 21 bases downstream of the DR-4 element is also critical for the response of FAS to LXR but is not involved in LXR binding to DNA. This half-site specifically binds liver receptor homologue-1 (LRH-1) in vitro and in vivo, and we show LRH-1 is required for maximal LXR responsiveness of the endogenous FAS gene as well as from promoter reporter constructs. We also demonstrate that LRH-1 stimulation of the FAS LXR response is blocked by the addition of small heterodimer partner (SHP) and that FAS mRNA is overexpressed in SHP knock-out animals, providing evidence that FAS is an in vivo target of SHP repression. Taken together, these findings identify the first direct lipogenic gene target of LRH-1/SHP repression and provide a mechanistic explanation for bile acid repression of FAS and lipogenesis recently reported by others.

Received for publication, April 5, 2007 , and in revised form, May 18, 2007.

^* This work was supported in part by National Institutes of Health Grants HL48044 and DK 71021 (to T. O.). 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.

This is dedicated to the memory of Professor Edward K. Wagner who passed away while the original manuscript was being prepared.

¹ Supported by fellowships from the Achievement Rewards for College Scientists Foundation and the American Diabetes Association. A member of the Medical Scientist Training Program in the University of California Irvine School of Medicine.

² To whom correspondence should be addressed. Tel.: 949-824-2979; Fax: 949-824-8551; E-mail: tim.osborne{at}uci.edu.

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