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The Liver X Receptor-ß Is Essential for Maintaining Cholesterol Homeostasis in the Testis

Departments of Biosciences at Novum (K.M.R., G.U.S., K.R.S., L.C.J., J.-Å.G.) and Obstetrics and Gynecology (O.H.), Department of Medicine and Molecular Nutrition Unit at Novum (L.C.J.), Division of Clinical Chemistry (S.M.), Karolinska Institutet, Department of Clinical Research Center (K.H.), Huddinge University Hospital, Huddinge 14157, Sweden; and Pediatric Endocrinology Unit (K.S., O.S.) and Department of Women and Child Health, Karolinska Institutet and Hospital, Stockholm 17176, Sweden

Address all correspondence and requests for reprints to: Kirsten Robertson, Ph.D., Karolinska Institutet, Department of Biosciences at Novum, Huddinge 14157, Sweden. E-mail: kirsten.robertson{at}biosci.ki.se.

The liver X receptor (LXR) and -ß 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 -ß on testicular morphology and function. In the absence of LXRß, 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 LXRß was the dominant transcript in the testis Although the LXR^–/– testis was normal, the LXR^–/–ß^–/– testis presented with a more severe phenotype than the LXRß^–/– 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 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 LXRß is absent. Although the precise molecular mechanism at this time remains unclear, our study highlights the crucial role for LXRß in retaining cholesterol homeostasis in Sertoli cells.

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