Multiple roles of the nuclear receptors for oxysterols liver X receptor to maintain male fertility.
Oxysterol nuclear receptors liver X receptor (LXR)alpha and LXRbeta 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 LXRalpha, LXRbeta, and both, of which only the lxralpha;beta-/- mice are infertile by 5 months of age. We demonstrate that LXRalpha-deficient mice had lower levels of testicular testosterone that correlated with a higher apoptotic rate of the germ cells. LXRbeta-deficient mice showed increased lipid accumulation in the Sertoli cells and a lower proliferation rate of the germ cells. In lxralpha;beta-/- 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 lxralpha;beta-/- mice, with a higher accumulation of all-trans retinoid receptor alpha, all-trans retinoid receptor beta, and retinoic aldehyde dehydrogenase-2 mRNA. Combination of these alterations might explain the deleterious phenotype of infertility observed only in lxralpha;beta-/- 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.
Volle
David H
DH
Physiologie Comparée et Endocrinologie Moléculaire, Unité Mixte de Recherche, Centre National de la Recherche Scientifique (CNRS) 6547, 63177 Aubière Cedex, France.
Mouzat
Kévin
K
Duggavathi
Rajesha
R
Siddeek
Bénazir
B
Déchelotte
Pierre
P
Sion
Benoît
B
Veyssière
Georges
G
Benahmed
Mohamed
M
Lobaccaro
Jean-Marc A
JM
D000818:Animals; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005298:Fertility / Q000502:physiology*; D005854:Germ Cells; D007248:Infertility, Male / Q000235:genetics*; D008055:Lipids / Q000502:physiology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D057093:Orphan Nuclear Receptors; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000502:physiology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008055:Lipids; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear