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Multiple Roles of the Nuclear Receptors for Oxysterols Liver X Receptor to Maintain Male Fertility

Physiologie Comparée et Endocrinologie Moléculaire (D.H.V., K.M., G.V., J.-M.A.L.) and Research Center for Human Nutrition, Unité Mixte de Recherche, Centre National de la Recherche Scientifique (CNRS) 6547, 63177 Aubière Cedex, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (D.H.V., R.D.), CNRS/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Louis Pasteur, 67400 Illkirch, France; Centre Hospitalier Universitaire Clermont-Ferrand (P.D.), Service d’Anatomie Pathologique, Hôtel Dieu, 63058 Clermont-Ferrand, France; Laboratoire de Biologie du Développement et de la Reproduction (B.Sio.), Equipe d’Accueil 975 Université d’Auvergne, 63001 Clermont-Ferrand, France; and INSERM Unité 407 (B.Sid., M.B.), Faculté de Médecine Lyon-Sud, 69921 Oullins Cedex, France

Address all correspondence and requests for reprints to: Jean-Marc A. Lobaccaro, Unité Mixte de Recherche Centre National de la Recherche Scientifique-Université Blaise Pascal 6547, 24 avenue des Landais, 63177 Aubière Cedex, France. E-mail: j-marc.lobaccaro{at}univ-bpclermont.fr.

Oxysterol nuclear receptors liver X receptor (LXR) and LXRß are known to regulate lipid homeostasis in cells exposed to high amounts of cholesterol and/or fatty acids. In order to elucidate the specific and redundant roles of the LXRs in the testis, we explored the reproductive phenotypes of mice deficient of LXR, LXRß, and both, of which only the lxr;ß^–/– mice are infertile by 5 months of age. We demonstrate that LXR-deficient mice had lower levels of testicular testosterone that correlated with a higher apoptotic rate of the germ cells. LXRß-deficient mice showed increased lipid accumulation in the Sertoli cells and a lower proliferation rate of the germ cells. In lxr;ß^–/– mice, fatty acid metabolism was affected through a decrease of srebp1c and increase in scd1 mRNA expression. The retinoid acid signaling pathway was also altered in lxr;ß^–/– mice, with a higher accumulation of all-trans retinoid receptor , all-trans retinoid receptor ß, and retinoic aldehyde dehydrogenase-2 mRNA. Combination of these alterations might explain the deleterious phenotype of infertility observed only in lxr;ß^–/– mice, even though lipid homeostasis seemed to be first altered. Wild-type mice treated with a specific LXR agonist showed an increase of testosterone production involving both LXR isoforms. Altogether, these data identify new roles of each LXR, collaborating to maintain both integrity and functions of the testis.

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Nuclear Receptors:   RARα  |  RARβ  |  RARγ  |  LXRβ  |  LXRα

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