Ligand-dependent contribution of RXRbeta to cholesterol homeostasis in Sertoli cells.
We show that mice expressing retinoid X receptor beta (RXRbeta) impaired in its transcriptional activation function AF-2 (Rxrb(af20) mutation) do not display the spermatid release defects observed in RXRbeta-null mutants, indicating that the role of RXRbeta in spermatid release is ligand-independent. In contrast, like RXRbeta-null mutants, Rxrb(af20) mice accumulate cholesteryl esters in Sertoli cells (SCs) due to reduced ABCA1 transporter-mediated cholesterol efflux. We provide genetic and molecular evidence that cholesterol homeostasis in SCs does not require PPARalpha and beta, but depends upon the TIF2 coactivator and RXRbeta/LXRbeta heterodimers, in which RXRbeta AF-2 is transcriptionally active. Our results also indicate that RXRbeta may be activated by a ligand distinct from 9-cis retinoic acid.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut Clinique de la Souris, CNRS/INSERM/ULP, Collège de France, BP10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
Bénédicte
B
Mascrez
Norbert B
NB
Ghyselinck
Mitsuhiro
M
Watanabe
Jean-Sébastien
JS
Annicotte
Pierre
P
Chambon
Johan
J
Auwerx
Manuel
M
Mark
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D020868:Gene Silencing; D051548:Histone Acetyltransferases; D006706:Homeostasis; D007120:Immunochemistry; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D057093:Orphan Nuclear Receptors; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D049230:Retinoid X Receptor beta / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism* / Q000502:physiology; D013087:Spermatids / Q000166:cytology / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D049230:Retinoid X Receptor beta; D014157:Transcription Factors; D002784:Cholesterol; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1