Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

Abstract

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.

Keywords: breast cancer; cholesterol; female reproduction; liver X receptors; ovarian hyperstimulation syndrome.

Figure 1

Role of liver X receptors (LXRs) in oocyte meiosis and in estradiol synthesis. When follicle-stimulating hormone (FSH )reaches its receptor on the granulosa cells, it increases the concentration of follicular fluid meiosis-activating sterol (FFMAS) by increasing its synthesis, a ligand of LXRα/β. This in turn induces the final steps of the oocyte meiosis. In addition, when the LXRα/β is activated by a ligand (in this figure T0901317, a synthetic ligand, purple square), they increase the production of estradiol. α/β—LXRα, or LXRβ; E2—estradiol; FFMAS—follicular fluid meiosis-activating sterol (pink square).

Figure 2

Role of LXRs in progesterone production and luteolysis. When the human chorionic gonadotropin hormone (hCG) reaches its receptor, it increases (green arrow) the concentration of cholesterol, by acting on low density lipoprotein receptor (LDLR) (uptake) and sterol response binding element (SREBP2) (de novo synthesis), and favors the production of progesterone (P4). Activation of LXRα/β by one of their bona fide ligands, produced from the cholesterol oxidation, stimulates the production of ATP-binding cassette transporter (ABC) proteins, inducing a cholesterol depletion within the cell, a decrease in progesterone synthesis, and finally, the luteolysis. hCG also inhibits LXR transcriptional activity. α/β—LXRα or LXRβ; ABCs—ATP-binding cassette transporters; hCG—human chorionic gonadotropin; P4—progesterone. LXR ligands are represented by the purple square.

Figure 3

LXRβ controls the cholesterol homeostasis within the myometrium. When cholesterol (grey) raises to a critical concentration, its enzymatic transformation into LXR-activating oxysterols induces a higher accumulation of ATP-binding caste transporters and the efflux of cholesterol. A defect in the LXRβ-signaling pathway is linked to a higher accumulation of cholesteryl esters, a decrease response to oxytocin and prostaglandin (PG) F2α, and a defect in the contractility during the labor. ABCs—ATP-binding cassette transporters; LXRβ—liver X receptor β. Oxysterols are represented by the yellow square.

Figure 4

LXRs have beneficial effects on breast cancer proliferation. While increased synthesis and/or concentration of cholesterol induce cell proliferation, activation of LXRs blocks estrogen receptor (ER) α transcriptional effects directly by decreasing its transcription and by increasing sulfotransferase Family 2A Member 1 (SULT1A1), which in turn decreases the levels of circulating estrogens. ERα—estrogen receptor α; LXRα/β—liver X receptor α/β; SULT1E1—sulfotransferase E1.