NCBI Summary:
The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
General function
Receptor, DNA binding, Transcription factor
Comment
Cellular localization
Nuclear
Comment
candidate123
Ovarian function
Steroid metabolism, Luteolysis
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.
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
LH
Comment
hCG-Induced Down-Regulation of PPAR{gamma} and Liver X Receptors Promotes Periovulatory Progesterone Synthesis by Macaque Granulosa Cells. Puttabyatappa M et al. An ovulatory stimulus induces the rapid and dramatic increase in progesterone synthesis by the primate ovarian follicle. However, little is known about the early events leading to the shift from estrogen to progesterone production. Because steroidogenesis represents an aspect of cholesterol metabolism, it was hypothesized that transcription factors regulating cholesterol balance would be among the earliest to change in response to an ovulatory stimulus. Granulosa cells were isolated from rhesus monkey follicles following controlled ovarian stimulation protocols before or up to 24 hr after an ovulatory human chorionic gonadotropin (hCG) bolus. The peroxisome proliferator-activated receptor-? (PPARG) and the liver X receptors [nuclear receptor (NR)1H2, NR1H3] decreased within 3 hr of hCG, as did the reverse cholesterol transporters ATP-binding cassette (ABC)A1 and ABCG1. Treatment of granulosa cells isolated before an ovulatory stimulus with hCG and rosiglitizone resulted in an increase in NR1H3 and ABCG1, and decreased steroidogenic acute regulatory (STAR) protein and scavenger receptor-BI (SCARB1). A liver X receptor agonist attenuated hCG-induced progesterone synthesis in vitro and increased the expression of ABCA1 and ABCG1, and suppressed STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B, and SCARB1. These data suggest that an initial action of LH/CG on the primate preovulatory follicle is to rapidly reduce the expression of PPARG, resulting in reduced NR1H3 with the consequence shifting the balance from cholesterol efflux via ABCA1 and ABCG1 to cholesterol uptake (SCARB1) and metabolism (STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B). That the regulation of PPARG and the liver X receptors occurs within 3 hr strongly indicates that early events in the primate luteinizing follicle are critical to successful ovulation and luteal formation.
Ovarian localization
Oocyte, Large luteal cells
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.
Follicle stages
Antral, Preovulatory
Comment
The bile acid synthesis pathway is present and functional in the human ovary. Smith LP et al. BACKGROUND: Bile acids, end products of the pathway for cholesterol elimination, are required for dietary lipid and fat-soluble vitamin absorption and maintain the balance between cholesterol synthesis in the liver and cholesterol excretion. They are composed of a steroid structure and are primarily made in the liver by the oxidation of cholesterol. Cholesterol is also highly abundant in the human ovarian follicle, where it is used in the formation of the sex steroids. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe for the first time evidence that all aspects of the bile acid synthesis pathway are present in the human ovarian follicle, including the enzymes in both the classical and alternative pathways, the nuclear receptors known to regulate the pathway, and the end product bile acids. Furthermore, we provide functional evidence that bile acids are produced by the human follicular granulosa cells in response to cholesterol presence in the culture media. CONCLUSIONS/SIGNIFICANCE: These findings establish a novel pathway present in the human ovarian follicle that has the capacity to compete directly with sex steroid synthesis.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 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.
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Association Between Single Nucleotide Polymorphisms of Sterol Regulatory Element Binding Protein-2 and Liver X Receptor a Gene and Risk of Polycystic Ovary Syndrome in a Chinese Han Population. Zhao J 2014 et al.
To investigate associations of single nucleotide polymorphisms (SNPs) rs2228314 of sterol regulatory element-binding protein-2 (SREBP-2) or rs11039155 of liver X receptor a (LXRa) with susceptibility to polycystic ovary syndrome (PCOS) in a Chinese Han population. SREBP-2 rs2228314 and LXRa rs11039155 polymorphisms were genotyped in patients with PCOS and age- and sex-matched PCOS-free controls from a Chinese Han population. A total of 605 patients with PCOS and 615 controls were recruited in this study. We found that GC and CC genotypes of rs2228314, and variant C, were associated with a significantly increased risk of PCOS. In addition, GA and AA genotypes of rs11039155, as well as variant A, were also associated with a significantly increased risk of PCOS. Our results showed that SREBP-2 rs2228314 G to C change and variant C genotype as well as LXRa rs11039155 G to A change and variant A may contribute to PCOS in Chinese Han population.
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