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J. Biol. Chem., Vol. 283, Issue 7, 3694-3701, February 15, 2008

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Regulation of Anti-atherogenic Apolipoprotein M Gene Expression by the Orphan Nuclear Receptor LRH-1^*

Nicolas Venteclef, Anna Haroniti, Jean-Jacques Tousaint, Iannis Talianidis, and Philippe Delerive¹

From the Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, 25 Avenue du Quebec, 91951 Les Ulis, France and the Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Athens, Greece

The orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) has been reported to play a crucial role in early development, in the control of the hepatic inflammatory response, in intestinal cell crypt renewal as well as in bile acid biosynthesis and reverse cholesterol transport (RCT). Here, we report the identification of apolipoprotein M (APOM) as a novel target gene for LRH-1. Using gene-silencing experiments, adenovirus-mediated overexpression, transient transfection, and chromatin immunoprecipitation (ChIP) assays, it is shown that LRH-1 directly regulates human and mouse APOM transcription by binding to an LRH-1 response element located in the proximal APOM promoter region. In addition, we demonstrate that bile acids suppress APOM expression in a SHP-dependent manner in vitro and in vivo by inhibiting LRH-1 transcriptional activity on the APOM promoter as demonstrated by in vivo ChIP assay. Taken together, our results demonstrate that LRH-1 is a novel regulator of APOM transcription and further extend the role of this orphan nuclear receptor in lipoprotein metabolism and cholesterol homeostasis.

Received for publication, August 2, 2007 , and in revised form, September 25, 2007.

^* This work was supported in part by the EU FP6 Grant LSHM-CT-2006-037498 (to A. H. and I. T.). 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: GlaxoSmithKline R&D, CVU CEDD, 25 Ave. du Quebec, 91951 Les Ulis, France. Fax: 33-0-169074892; E-mail: delerive{at}hotmail.com.

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