Identification of the functions of liver X receptor-β in Sertoli cells using a targeted expression-rescue model

Abstract

Liver X receptors (LXRs) are key regulators of lipid homeostasis and are involved in multiple testicular functions. The Lxrα-/-;Lxrβ-/- mice have illuminated the roles of both isoforms in maintenance of the epithelium in the seminiferous tubules, spermatogenesis, and T production. The requirement for LXRβ in Sertoli cells have been emphasized by early abnormal cholesteryl ester accumulation in the Lxrβ-/-and Lxrα-/-;Lxrβ-/- mice. Other phenotypes, such as germ cell lossand hypogonadism, occur later in life in the Lxrα-/-;Lxrβ-/- mice. Thus, LXRβ expression in Sertoli cells seems to be essential for normal testicular physiology. To decipher the roles of LXRβ within the Sertoli cells, we generated Lxrα-/-;Lxrβ-/-:AMH-Lxrβ transgenic mice, which reexpress Lxrβ in Sertoli cells in the context of Lxrα-/-;Lxrβ-/- mice. In addition to lipid homeostasis, LXRβ is necessary for maintaining the blood-testis barrier and the integrity of the germ cell epithelium. LXRβ is also implicated in the paracrine action of Sertoli cells on Leydig cells to modulate T synthesis. The Lxrα-/-;Lxrβ-/- and Lxrα-/-;Lxrβ-/-:AMH-Lxrβ mice exhibit lipid accumulation in germ cells after theAbcg8down-regulation, suggesting an intricate LXRβ-dependent cooperation between the Sertoli cells and germ cells to ensure spermiogenesis. Further analysis revealed also peritubular smooth muscle defects (abnormal lipid accumulation and disorganized smooth muscle actin) and spermatozoa stagnation in theseminiferous tubules. Togetherthe present work elucidates specific roles of LXRβ in Sertoli cell physiology in vivo beyond lipid homeostasis.