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J. Biol. Chem., Vol. 282, Issue 7, 4693-4701, February 16, 2007

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Oxysterol Nuclear Receptor LXR Regulates Cholesterol Homeostasis and Contractile Function in Mouse Uterus^*

Kevin Mouzat¹, Magali Prod'Homme, David H. Volle², Benoit Sion, Pierre Déchelotte^¶, Karine Gauthier^||, Jean-Marc Vanacker^||, and Jean-Marc A. Lobaccaro, Professor of the Université Blaise Pascal³

From the UMR CNRS 6547, "LXRs, Oxysterols, and Steroidogenic Tissues," and Research Center for Human Nutrition, 63177 Aubière, France, Laboratoire de Biologie du Développement et de la Reproduction, Université d'Auvergne, 63058 Clermont-Ferrand, France, ^¶CHU Clermont-Ferrand, Service d'Anatomie Pathologique, Hôtel Dieu, Boulevard Léon Malfreyt, 63058 Clermont-Ferrand, France, and ^||INSERM EMI 0229, 34298 Montpellier, France

The uterus is an organ where lipid distribution plays a critical role for its function. Here we show that nuclear receptor for oxysterols LXR prevents accumulation of cholesteryl esters in mouse myometrium by controlling expression of genes involved in cholesterol efflux and storage (abca1 and abcg1). Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased in wild-type mice, whereas under basal conditions, lxr;^-/- mice exhibited a marked decrease in abcg1 accumulation. This change resulted in a phenotype of cholesteryl ester accumulation. Besides, a defect of contractile activity induced by oxytocin or PGF2 was observed in mice lacking LXR. These results imply that LXR provides a safety valve to limit cholesteryl ester levels as a basal protective mechanism in the uterus against cholesterol accumulation and is necessary for a correct induction of contractions.

Received for publication, July 14, 2006 , and in revised form, December 12, 2006.

^* This work was supported by the Centre National de la Recherche Scientifique, the Université Blaise Pascal, Fondation pour la Recherche Médicale Grant INE2000-407031/1, and the Fondation BNP-Paribas. 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 Recipient of a doctoral fellowship from the Ministère de l'Education Nationale de Recherche et de la Technologie.

² Present address: Institute of Genetics and Molecular and Cellular Biology, 67404 Illkirch Cedex, France.

³ To whom correspondence should be addressed: UMR CNRS-Université Blaise Pascal 6547 and Research Center for Human Nutrition, 24 Ave. des Landais, 63177 Aubière Cedex, France. Tel.: 33-473-40-74-16; Fax: 33-473-40-70-42; E-mail: j-marc.lobaccaro{at}univ-bpclermont.fr.

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