Emerging roles for LXRs and LRH-1 in female reproduction

Nutritional status is known to control female reproductive physiology. Many reproductive pathologies such as anorexia nervosa, dystocia and preeclampsia, have been linked to body mass index and to metabolic syndrome. Lipid metabolism has also been associated with ovarian, uterine and placental functions. Among the regulators of lipid homeostasis, the Liver X Receptors (LXRs) and the Liver Receptor Homolog-1 (LRH-1), two members of the nuclear receptor superfamily, play a central role. LXRs are sensitive to intracellular cholesterol concentration and decrease plasma cholesterol, allowing to considering them as “cholesterol sensors”. LRH-1 shares many target-genes with LXRs and has been considered for a long time as a real orphan nuclear receptor, but recent findings showed that phospholipids are ligands for this nuclear receptor. Acting in concert, LXRs and LRH-1 could thus be sensitive to slight modifications in cellular lipid balance, tightly maintaining their cellular concentrations. These last years, the use of transgenic mice clarified the roles of these nuclear receptors in many physiological functions. This review will be focused on the roles of LXRs and LRH-1 on female reproduction. Their contribution to ovarian endocrine and exocrine functions, as well as uterine and placental physiology will be discussed. The future challenge will thus be to target these nuclear receptors to prevent lipid-associated reproductive diseases in women.

► Regulation of cholesterol homeostasis is a key-point in female reproduction.
► Nuclear receptors LXR and LRH-1 regulate numerous functions in female reproductive tissues.
► Abnormal signaling pathways of LXR and LRH-1 have been associated to human related disease.
► Modulating LXR and LRH-1 transcriptional activity could be a future strategy to control female reproduction.