LXR regulate cholesterol homeostasis in the proximal mouse epididymis.

Abstract

Oxysterol nuclear receptors liver x receptors (LXRalpha and LXRbeta) regulate lipid homeostasis when cells have to face high amounts of cholesterol and/or fatty acids. Male mice invalidated for both lxr (LXR-/-) are infertile by 5 months of age, and become sterile by the age of 9 months. The epididymis was previously shown to be affected by the gene invalidation, a phenotype specifically located in the two proximal segments of this organ. We demonstrate here that cholesteryl esters are accumulated in a specific cell type of the epididymal epithelium, the apical cells, in these two first segments, in LXR-/- male mice. These accumulations are correlated to a decrease in the amount of a specific membrane cholesterol transporter, ATP-binding cassette A1 (ABCA1) in the caput epididymidis of LXR-/- mice. This decrease is due to a transcriptional down-regulation, and we further demonstrate that ABCA1, in the two first segments of the caput epididymidis, is located in the apical cells, and that its accumulation is lost in these cells for LXR-/- male mice as soon as 4 months of age. These data bring new elements in the cholesterol trafficking pathways in the epididymis, and will help a better understanding of the molecular mechanisms occurring in this organ in relation to the sperm cells maturation process.