The liver X receptor-{beta} is essential for maintaining cholesterol homeostasis in the testis.
The liver X receptor (LXR)alpha and -beta has been found to play a central role in maintaining cellular cholesterol homeostasis. In this study we comprehensively investigated the effect of deleting LXRalpha and -beta on testicular morphology and function. In the absence of LXRbeta, excessive cholesterol accumulated in the Sertoli cells from 2.5 months, resulting in severe cellular disruption and dysregulation of spermatogenesis by 10 months of age. This correlated with gene expression analyses that clearly indicated that LXRbeta was the dominant transcript in the testis Although the LXRalpha(-/-) testis was normal, the LXRalpha(-/-)beta(-/-) testis presented with a more severe phenotype than the LXRbeta(-/-) mice, and males were infertile by 4 months of age, indicating LXRalpha may partially rescue the testicular phenotype. Although Leydig cells did not accumulate excessive cholesterol, declining serum and intratesticular androgen levels with age suggested that these cells were in fact less functional. Treatment of a Sertoli cell line with the LXR agonist T0901317 led to increased expression of known LXR target genes like ATP binding cassette-G1 and sterol regulatory binding protein-1c; similar results were observed in wild-type testis after in vivo administration, suggesting the LXR is functioning in the same way as in other tissues. Ordinarily increased levels of cholesterol activate intracellular sensors to decrease these levels; however, the increasing amount of cholesterol in the Sertoli cells indicates improper control of cholesterol metabolism when LXRbeta is absent. Although the precise molecular mechanism at this time remains unclear, our study highlights the crucial role for LXRbeta in retaining cholesterol homeostasis in Sertoli cells.
Robertson
Kirsten M
KM
Karolinska Institutet, Department of Biosciences at Novum, Huddinge 14157, Sweden. kirsten.robertson@biosci.ki.se
Schuster
Gertrud U
GU
Steffensen
Knut R
KR
Hovatta
Outi
O
Meaney
Steve
S
Hultenby
Kjell
K
Johansson
Lisen C
LC
Svechnikov
Konstantin
K
Söder
Olle
O
Gustafsson
Jan-Ake
JA
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006888:Hydroxycholesterols / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D007985:Leydig Cells / Q000378:metabolism; D000071518:Liver X Receptors; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D012670:Seminiferous Epithelium / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D013739:Testosterone / Q000097:blood; D014280:Triglycerides / Q000378:metabolism
D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002784:Cholesterol