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Submitted on October 27, 2004
Accepted on March 3, 2005
is essential for maintaining cholesterol homeostasis in the testis
Department of Biosciences at Novum, Karolinska Institutet, Huddinge 14157, Sweden; Department of Obstetrics and Gynecology Karolinska Institutet, Division of Clinical Chemistry, Karolinska Institutet, and Department of Clinical Research Center Huddinge University Hospital, Huddinge 14157, Sweden; Department of Medicine and Molecular Nutrition Unit at Novum, Karolinska Institutet, Huddinge 14157, Sweden; and Pediatric Endocrinology Unit, Department of Women and Child Health, Karolinska Institutet and Hospital, Stockholm 17176, Sweden
* To whom correspondence should be addressed. E-mail: kirsten.robertson{at}biosci.ki.se.
The Liver X Receptor (LXR
,
) has been found to play a central role in maintaining cellular cholesterol homeostasis. In this study we comprehensively investigated the effect of deleting LXR and on testicular morphology and function. In the absence of LXR, 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 LXR was the dominant transcript in the testis Although the LXR-/- testis was normal, the LXR-/--/- testis presented with a more severe phenotype than the LXR-/- mice and males were infertile by 4 months of age, indicating LXR may partially rescue the testicular phenotype. Although Leydig cells did not accumulate excessive cholesterol, declining serum and intra-testicular 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 ABCG1 and SREBP1c; similar results were observed in WT testis following 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 LXR is absent. Although the precise molecular mechanism at this time remains unclear, our study highlights the crucial role for LXR in retaining cholesterol homeostasis in Sertoli cells.
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