LXRB, NR1H2, or NER, is a member of the steroid hormone nuclear receptor gene family, which also includes receptors for
vitamin D, thyroid hormone, and retinoic acid. NER encodes a polypeptide of 461 amino acids and
contains both the DNA-binding and ligand-binding domains seen in other nuclear receptors. The LX receptors (LXRs) were originally identified as orphan members of the nuclear receptor superfamily because
their ligands were unknown. Like other receptors in the family, LXRs heterodimerize with retinoid X receptor and bind to specific response elements (LXREs) characterized by direct repeats separated by 4 nucleotides.
Two genes (alpha and beta) are known to encode LXR proteins. LXR-alpha (LXRA) is expressed most highly
in the liver and to a lesser extent in the kidney, small intestine, spleen, and adrenal gland. In contrast to the restricted expression pattern of LXR-alpha, LXR-beta is ubiquitously expressed (Song et al., 1995 ).
NCBI Summary:
The LX receptors (LXRs) were originally identified as orphan members of the nuclear receptor superfamily because their ligands were unknown. Like other receptors in the family, LXRs heterodimerize with retinoid X receptor (see MIM 180245) and bind to specific response elements (LXREs) characterized by direct repeats separated by 4 nucleotides. Two genes, alpha (LXRA, MIM 602423) and beta, are known to encode LXR proteins (Song et al., 1995 [PubMed 7625741]).[supplied by OMIM]
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
LXR-alpha and LXR-beta regulate the metabolism of several important lipids, including cholesterol in bile acids. It
was proposed that LXRs regulate these pathways through their interaction with specific, naturally occurring oxysterols.
Using a ligand-binding assay that incorporates scintillation proximity technology to circumvent many of the problems
associated with assaying extremely hydrophobic ligands, Janowski et al. (1999) demonstrated that these oxysterols bind
directly to LXRs at concentrations that occur in vivo.
Cellular localization
Nuclear
Comment
Ovarian function
Steroid metabolism, Luteolysis, Oocyte maturation
Comment
Liver X Receptor Modulation of Gene Expression Leading to Pro-Luteolytic Effects in Primate Luteal Cells. Bogan RL et al. The expression of genes involved in cholesterol efflux increase, while those involved in extracellular cholesterol uptake decrease, during spontaneous functional regression of the primate corpus luteum (CL). This may result from liver x receptor (LXR, official symbols NR1H3 and NR1H2, respectively) alpha and/or beta control of luteal gene transcription as these nuclear receptor superfamily members are key regulators of cellular cholesterol homeostasis. Therefore, studies were conducted to assess endogenous LXR ligands in the primate CL through the luteal phase, and determine the effect of synthetic or natural LXR ligands on cholesterol efflux and uptake in functional primate luteal cells. Using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS), three LXR ligands were identified and quantified in the rhesus macaque CL including 22R-hydroxycholesterol (22ROH), 27-hydroxycholesterol (27OH), and desmosterol. Levels of 22ROH paralleled serum progesterone (P4) concentrations whereas mean levels of 27OH tended to be higher following the loss of P4 synthesis. Desmosterol was present throughout the luteal phase. Functional macaque luteal cells treated with the synthetic LXR agonist T0901317 (T09) or physiologically relevant concentrations of the endogenous luteal ligands 22ROH, 27OH, and desmosterol, had increased expression of various known LXR target genes and greater cholesterol efflux. Additionally, T09 reduced low density lipoprotein receptor (LDLR) protein and extracellular LDL uptake while 27OH decreased LDLR protein, most-likely via a post-translational mechanism. Collectively, these data support the hypothesis that LXR activation causes increased cholesterol efflux and decreased extracellular cholesterol uptake. In theory, these effects could deplete the primate CL of cholesterol needed for steroidogenesis, ultimately contributing to functional regression.
Reduced fertility and inability of oocytes to resume meiosis in mice deficient of the Lxr genes. Steffensen KR et al. Cholesterol precursors act as activators of the nuclear hormone receptor, liver X receptor (LXR). One of these LXR-activating ligands is meiosis activating sterol (MAS), which also induces resumption of meiosis in oocytes from mice in vitro. Whether LXR participates in the regulation of oocyte maturation and whether the expression of either one of the two paralogues of LXR (alpha and beta) affect fertility of mice has, however, not yet been clarified. Female mice lacking Lxra, Lxrb or both genes (Lxra(-/-), Lxrb(-/-) and Lxrab(-/-), respectively) conceive less frequently and have significantly fewer pups per litter as compared to wild type mice. Both Lxra and Lxrb mRNA were found to be expressed in mouse oocytes. The relative expression of, in particular, Lxrb was almost two orders of magnitude higher than in liver, brain and testis. A water-soluble LXR agonist caused naked oocytes, but not cumulus enclosed oocytes (CEO), from wild type mice to resume meiosis significantly more often than control oocytes. Follicle stimulating hormone (FSH) is a potent stimulator of meiosis in CEO from wild type mice, but was without effect in mice lacking both Lxr genes. Zymosterol, a MAS active substance, induced resumption of meiosis in oocytes from Lxrab(-/-) mice, but significantly less effectively than in oocytes from wild type mice. Taken together, LXRs seem to affect ovarian function, suggesting specific roles of cholesterol precursors in regulation of female reproduction.
Inhibition of progesterone production in human luteinized granulosa cells treated with LXR agonists. Drouineaud V et al. Progesterone production by luteal cells is dependent on the supply of cholesterol by lipoproteins. The aim of this study was to determine whether the liver X receptors (LXRs) contribute to cholesterol homeostasis and progesterone secretion in human luteinized granulosa cells. Cells were isolated from follicular aspirates of patients undergoing in vitro fertilization. Luteinization was induced by a 7-day treatment with human chorionic gonadotrophin. LXR beta was expressed at higher levels than LXR alpha in granulosa cells and its expression was increased during luteinization. Treatment of luteinized granulosa cells by LXR agonists induced a significant time- and dose-dependent reduction in progesterone secretion (50% reductions after a 7-day treatment with 1-microM of either GW3965 or T0901317). mRNA levels of steroidogenic genes including steroidogenic acute regulatory protein and P450 side-chain cleavage were only moderately affected by LXR activation, with a significant reduction that was observed at 10 microM agonist concentration. Cellular cholesterol was markedly reduced after treatment with LXR agonists as a result of an increased cholesterol efflux that was related to the induction of LXR target genes (ABCA1, ABCG1, apo E, PLTP). Our study identifies LXRs as new, key actors contributing to regulation of cholesterol metabolism and steroidogenesis in luteinized granulosa cells.
The Reverse Cholesterol Transport System as a Potential Mediator of Luteolysis in the Primate Corpus Luteum. Bogan R et al. The cessation of progesterone (P4) production (i.e., functional regression), arguably the key event in luteolysis of the primate corpus luteum (CL), is poorly understood. Previously, we found that genes encoding proteins involved in cholesterol uptake decreased while those involved in cholesterol efflux (reverse cholesterol transport; RCT) increased in expression during spontaneous functional regression of the rhesus macaque CL, thereby potentially depleting the cholesterol reserves needed for steroidogenesis. Therefore, a comprehensive analysis of the components necessary for RCT was performed. RCT components were expressed (mRNA and/or protein) in the macaque CL including cholesterol sensors (liver x receptors alpha or NR1H3; and beta or NR1H2), efflux proteins (ATP-binding cassette subfamilies A1 or ABCA1; and G1 or ABCG1), acceptors (apolipoproteins A1 or APOA1; and E or APOE), and plasma proteins facilitating high-density lipoprotein (HDL) formation (lecithin:cholesterol acyltransferase or LCAT; phospholipid transfer protein or PLTP). ABCA1, APOE, PLTP and NR1H3 increased, while lipoprotein receptors decreased, in expression (mRNA and/or protein) through the period of functional regression. The expression of APOA1 and APOE, as well as NR1H3, was greatest in the CL and tissues involved in regulating cholesterol homeostasis. Immunolocalization studies revealed that RCT proteins and lipoprotein receptors were expressed in large luteal cells, which possess intracellular cholesterol reserves during periods of progesterone synthesis. Lipid staining revealed changes in luteal cholesterol ester/lipid distribution that occurred following functional regression. These results indicate that decreased cholesterol uptake and increased RCT may be critical for the initiation of primate luteolysis by limiting intracellular cholesterol pools required for steroidogenesis.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
Liver X receptor (LXR) and the reproductive system--a potential novel target for therapeutic intervention. Beltowski J et al. Liver X receptor (LXR) alpha and beta are ligand-activated transcription factors that regulate the expression of genes involved in the removal of cholesterol from cells by high-density lipoproteins, the transport of cholesterol to the liver and the biliary excretion of cholesterol. LXRs are activated by oxygenated cholesterol derivatives such as 24(S),25-epoxycholesterol or 24(S)-, 25- and 27-hydroxycholesterol. In this review, we will discuss the role of LXR in the reproductive system and perspectives on the application of LXR agonists in the treatment of reproductive pathologies. Interestingly, progressive age-related impairment of fertility is observed in both female and male LXR knockout mice. Reduced fertility in female LXR knockout mice is associated with resistance to follicular fluid meiosis-activating sterol (FF-MAS), the intermediate of cholesterol synthesis generated in the ovaries that is responsible for stimulating oocyte meiosis partially in a LXR-dependent manner. Female mice lacking both LXR isoforms exhibit symptoms of ovarian hyperstimulation syndrome when treated with pharmacological doses of gonadotropins. LXR agonists have mainly been considered as potential anti-atherosclerotic medications. However, experimental studies suggest that natural or synthetic LXR agonists may also effectively treat some reproductive pathologies, such as infertility, impaired uterine contractility, hormone-dependent cancers and insulin resistance in patients with polycystic ovarian syndrome. However, the specific adverse effects of LXR agonists on the reproductive system must also be considered. Adverse effects of LXR agonists include impaired trophoblast invasion, excessive transplacental cholesterol transport from the mother to the fetus leading to fetal hypercholesterolemia, and augmented estrogen deficiency after menopause.
Follicle stages
Comment
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Reduced fertility and inability of oocytes to resume meiosis in mice deficient of the Lxr genes. Steffensen KR et al. Cholesterol precursors act as activators of the nuclear hormone receptor, liver X receptor (LXR). One of these LXR-activating ligands is meiosis activating sterol (MAS), which also induces resumption of meiosis in oocytes from mice in vitro. Whether LXR participates in the regulation of oocyte maturation and whether the expression of either one of the two paralogues of LXR (alpha and beta) affect fertility of mice has, however, not yet been clarified. Female mice lacking Lxra, Lxrb or both genes (Lxra(-/-), Lxrb(-/-) and Lxrab(-/-), respectively) conceive less frequently and have significantly fewer pups per litter as compared to wild type mice. Both Lxra and Lxrb mRNA were found to be expressed in mouse oocytes. The relative expression of, in particular, Lxrb was almost two orders of magnitude higher than in liver, brain and testis. A water-soluble LXR agonist caused naked oocytes, but not cumulus enclosed oocytes (CEO), from wild type mice to resume meiosis significantly more often than control oocytes. Follicle stimulating hormone (FSH) is a potent stimulator of meiosis in CEO from wild type mice, but was without effect in mice lacking both Lxr genes. Zymosterol, a MAS active substance, induced resumption of meiosis in oocytes from Lxrab(-/-) mice, but significantly less effectively than in oocytes from wild type mice. Taken together, LXRs seem to affect ovarian function, suggesting specific roles of cholesterol precursors in regulation of female reproduction.