Multiple Roles of the Nuclear Receptors for Oxysterols Liver X Receptor to Maintain Male Fertility

Abstract

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.

Liver X receptors as therapeutic targets for managing cholesterol: implications for inflammatory conditions

“…[69][70][71] In contrast to the selective role of LXRα for maintaining cholesterol balance in the adrenal gland, LXRβ was found to be important for lipid homeostasis in the testis. However, LXRα-null mice had lower testicular testosterone levels and a higher rate of apoptosis.…”

“…However, LXRα-null mice had lower testicular testosterone levels and a higher rate of apoptosis. [69,71] In wildtype mice treated with LXR ligand, StAR and HSD3B1 were increased resulting in elevated testicular testosterone. The different roles of the LXRs in these steroidogenic organs are thought to be due to the presence of tissue specific cofactors.…”

Liver X Receptor: A Cardinal Target for Atherosclerosis and Beyond

“…Meanwhile, the lack of both LXRs leads to a dramatic decline in proliferation and increase in apoptosis. This may be one explanation for the complete loss of germ cells, resulting in infertility 102) . Retinoic acid, a metabolite of vitamin A, mediates the growth and development of vitamin A and appears to play a vital role in various testicular functions.…”

“…In addition, LXRs regulate lipid and retinoic acid metabolism via the transcriptional activation of enzymes and membrane transporters. The lack of LXRα and LXRβ results in severe infertility due to impairment in various pathways, of which aberration in lipid metabolism appears to have a central effect 102) .…”

“…In contrast, LXRβ controls lipid metabolism in Sertoli cells by regulating cholesterol export, as well as germ cell proliferation. Moreover, both LXRs together regulate ligand-induced steroidogenesis, fatty acid metabolism and, surprisingly, the retinoic acid signaling pathway in the testis 102) . Spermatogenesis is maintained by a delicate balance between cell proliferation, differentiation and death 103,104) .…”