Alternative titles; symbols
HGNC Approved Gene Symbol: NR1H2
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:50,376,457-50,383,388 (from NCBI)
The liver X receptors, LXRA (NR1H3; 602423) and LXRB, form a subfamily of the nuclear receptor superfamily and are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. The inducible LXRA is highly expressed in liver, adrenal gland, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRB is ubiquitously expressed. Ligand-activated LXRs form obligate heterodimers with retinoid X receptors (RXRs; see 180245) and regulate expression of target genes containing LXR response elements (summary by Korf et al., 2009).
Shinar et al. (1994) determined that NER encodes a polypeptide of 461 amino acids and contains both the DNA-binding and ligand-binding domains seen in other nuclear receptors. A single 2.3-kb transcript was seen in all cells and tissues tested. 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).
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. To characterize further the structural determinants required for potent LXR ligands, they synthesized and tested a series of related compounds for binding to LXRs and activation of transcription. Their results supported the hypothesis that naturally occurring oxysterols are physiologic ligands for LXRs and showed that a rational, structure-based approach can be used to design potent LXR ligands for pharmacologic use.
In an elegant series of experiments designed to understand the effect of retinoid X receptor (RXR; see 180245) activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor, FXR (603826), are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1 (600046), and the rate-limiting enzyme of bile acid synthesis, CYP7A1 (118455), respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
LXR activity is critical for physiologic lipid metabolism and transport. Tangirala et al. (2002) linked LXR signaling pathways to the pathogenesis of cardiovascular disease. Bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. The results demonstrated that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimicked many aspects of Tangier disease (205400), a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identified LXRs as targets for therapeutic intervention in cardiovascular disease.
Zelcer et al. (2009) demonstrated that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of LDL uptake. LXR inhibits the LDL receptor (LDLR; 606945) pathway through the transcriptional induction of IDOL (MYLIP; 610082), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduced, whereas LXR knockout increased, LDLR protein levels in vivo in a tissue-selective manner. IDOL knockdown in hepatocytes increased LDLR protein levels and promoted LDL uptake. Conversely, Zelcer et al. (2009) found that adenovirus-mediated expression of IDOL in mouse liver promoted LDLR degradation and elevated plasma LDL levels. Zelcer et al. (2009) concluded that the LXR-IDOL-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.
Using Lxra and Lxrb double-knockout mice and Lxr agonists, Cui et al. (2011) observed Lxr-dependent amelioration of experimental autoimmune encephalomyelitis. Lxr overexpression decreased, whereas Lxr deficiency promoted, cytokine-driven mouse Th17 cell differentiation and polarization in vitro. In mouse, Srebp1 (SREBF1; 184756) was recruited to the E-box element on the Il17 (603149) promoter upon Lxr activation and interacted with Ahr (600253) to inhibit Il17 transcriptional activity. LXR activation in human cells also suppressed Th17 cell differentiation, promoted SREBP1 expression, and decreased AHR expression. Mutation and coimmunoprecipitation analyses showed that the putative active-site domain of mouse Ahr and the N-terminal acidic region of mouse Srebp1 were essential for Ahr-Srebp1 interaction. Cui et al. (2011) concluded that a downstream target of LXR, SREBP1, antagonizes AHR to suppress Th17 cell generation and autoimmunity.
By FISH, Le Beau et al. (1995) mapped the NR1H2 gene to 19q13.3.
Repa et al. (2002) presented evidence for the direct control of the ATP-binding cassette sterol transporters Abca1 (600046), Abcg5 (605459), and Abcg8 (605460) by the liver X receptors. The intensity of hepatic and jejunal staining for Abcg5/g8 and Abca1 was increased in normal mice fed cholesterol or other Lxr agonists. Cholesterol feeding resulted in upregulation of Abcg5 and Abcg8 in the Lxrb-null mice, but not in the Lxra-null or double-knockout mice, suggesting that Lxra is required for sterol upregulation of Abcg5/g8 in this model. In a rat hepatoma cell line, Lxr-dependent transcription of the Abcg5/g8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by the liver X receptors.
Andersson et al. (2005) inactivated Lxrb in mice and found that only male mice displayed a pathologic phenotype, developing adult-onset motor neuron degeneration. At 7 months of age, mutant males showed impaired motor coordination, lipid accumulation and loss of motor neurons in the spinal cord, axonal atrophy, and astrogliosis.
Bradley et al. (2007) generated Lxra-null/Apoe (107741)-null mice and observed extreme cholesterol accumulation in peripheral tissues, a dramatic increase in whole-body cholesterol burden, and accelerated atherosclerosis, which suggested that the level of Lxr pathway activation in macrophages achieved by Lxrb and endogenous ligand was unable to maintain homeostasis in the setting of hypercholesterolemia. Treatment of Lxra-null/Apoe-null mice with the highly efficacious synthetic Lxr agonist GW3965, however, ameliorated the cholesterol overload phenotype and reduced atherosclerosis. Bradley et al. (2007) concluded that LXRA has an essential role in maintaining peripheral cholesterol homeostasis in the context of hypercholesterolemia.
Kim et al. (2008) found that a 3-week administration of beta-sitosterol, a known motor neuron toxin, to male Lxrb-null mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of dopaminergic neurons in the substantia nigra. Beta-sitosterol toxicity became apparent at age 5 months of age and was progressive thereafter, as manifest by severely impaired motor function. Wildtype mice were not affected by beta-sitosterol administration. Eight-month-old Lxrb-null mice showed an activation of microglia in the substantia nigra and cytoplasmic aggregates in spinal cord motor neurons even in the absence of beta-sitosterol administration. Brain cholesterol concentrations were higher in Lxrb-null mice compared to wildtype, and treatment with beta-sitosterol reduced brain cholesterol in both wildtype and Lxrb-null mice. Kim et al. (2008) concluded that multiple mechanisms are involved in the sensitivity of Lxrb-null mice to beta-sitosterol, including activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol. Kim et al. (2008) noted that ingestion of plant sterols had been implicated in the pathogenesis of the ALS-PD complex of Guam (105500), a neurodegenerative motor disorder.
Using mice lacking Lxra or Lxrb, Bensinger et al. (2008) showed that T-cell activation triggered induction of the oxysterol-metabolizing enzyme Sult2b1 (604125), suppression of the Lxr pathway for cholesterol transport, and promotion of the Srebp2 (SREBF2; 600481) pathway for cholesterol synthesis. Proliferation was inhibited by Lxr ligation during T-cell activation by mitogen, but cells from mice lacking Lxrb had a proliferative advantage. Lymphocytes lacking Abcg1 (603076) were not inhibited in the presence of Lxr agonists, indicating that transport of sterols by ABCG1 is required for LXR agonist-mediated inhibition. Mice lacking Lxrb displayed lymphoid hyperplasia and enhanced responses to antigenic challenge. Bensinger et al. (2008) concluded that cellular cholesterol levels in dividing T cells are maintained, in part, through reciprocal regulation of LXR and SREBP transcriptional programs, and that LXR signaling is a metabolic checkpoint that modulates cell proliferation and immunity.
Using RT-PCR analysis of Cd11c (ITGAX; 151510)-positive lung and alveolar cells from mice infected intratracheally with Mycobacterium tuberculosis, Korf et al. (2009) detected increased expression of Lxra and Lxrb and their target genes, Apoe and Abca1, as well as Pparg (601487) and Srebp1. Mice deficient in Lxra or both Lxra and Lxrb, but not mice deficient in Lxrb only, were more susceptible to infection than wildtype mice in terms of bacterial burden and in size and number of granulomatous lesions. Double-knockout mice failed to mount an early neutrophilic response and showed dysregulation in the expression of inflammatory factors by Cd11c cells. Diminished Th1 and Th17 function, but not Th2 function, was also found in lungs of infected mice. Treatment with Lxr agonists resulted in a 10-fold decrease in bacterial burden and increased Th1 and Th17 function. Korf et al. (2009) concluded that the neutrophil-IL17 axis depends on LXR signaling and is important in resistance to M. tuberculosis infection.
Andersson, S., Gustafsson, N., Warner, M., Gustafsson, J.-A. Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc. Nat. Acad. Sci. 102: 3857-3862, 2005. Note: Erratum: Proc. Nat. Acad. Sci. 103: 8298 only, 2006. [PubMed: 15738425] [Full Text: https://doi.org/10.1073/pnas.0500634102]
Bensinger, S. J., Bradley, M. N., Joseph, S. B., Zelcer, N., Janssen, E. M., Hausner, M. A., Shih, R., Parks, J. S., Edwards, P. A., Jamieson, B. D., Tontonoz, P. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134: 97-111, 2008. [PubMed: 18614014] [Full Text: https://doi.org/10.1016/j.cell.2008.04.052]
Bradley, M. N., Hong, C., Chen, M., Joseph, S. B., Wilpitz, D. C., Wang, X., Lusis, A. J., Collins, A., Hseuh, W. A., Collins, J. L., Tangirala, R. K., Tontonoz, P. Ligand activation of LXR-beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR-alpha and apoE. J. Clin. Invest. 117: 2337-2346, 2007. [PubMed: 17657314] [Full Text: https://doi.org/10.1172/JCI31909]
Cui, G., Qin, X., Wu, L., Zhang, Y., Sheng, X., Yu, Q., Sheng, H., Xi, B., Zhang, J. Z., Zang, Y. Q. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J. Clin. Invest. 121: 658-670, 2011. [PubMed: 21266776] [Full Text: https://doi.org/10.1172/JCI42974]
Janowski, B. A., Grogan, M. J., Jones, S. A., Wisely, G. B., Kliewer, S. A., Corey, E. J., Mangelsdorf, D. J. Structural requirements of ligands for the oxysterol liver X receptors LXR-alpha and LXR-beta. Proc. Nat. Acad. Sci. 96: 266-271, 1999. [PubMed: 9874807] [Full Text: https://doi.org/10.1073/pnas.96.1.266]
Kim, H.-J., Fan, X., Gabbi, C., Yakimchuk, K., Parini, P., Warner, M., Gustafsson, J.-A. Liver X receptor-beta (LXR-beta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia. Proc. Nat. Acad. Sci. 105: 2094-2099, 2008. [PubMed: 18238900] [Full Text: https://doi.org/10.1073/pnas.0711599105]
Korf, H., Vander Beken, S., Romano, M., Steffensen, K. R., Stijlemans, B., Gustafsson, J.-A., Grooten, J., Huygen, K. Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice. J. Clin. Invest. 119: 1626-1637, 2009. [PubMed: 19436111] [Full Text: https://doi.org/10.1172/JCI35288]
Le Beau, M. M., Song, C., Davis, E. M., Hiipakka, R. A., Kokontis, J. M., Liao, S. Assignment of the human ubiquitous receptor gene (UNR) to 19q13.3 using fluorescence in situ hybridization. Genomics 26: 166-168, 1995. [PubMed: 7782080] [Full Text: https://doi.org/10.1016/0888-7543(95)80100-z]
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., Mangelsdorf, D. J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6: 507-515, 2000. [PubMed: 11030331] [Full Text: https://doi.org/10.1016/s1097-2765(00)00050-2]
Repa, J. J., Berge, K. E., Pomajzl, C., Richardson, J. A., Hobbs, H., Mangelsdorf, D. J. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277: 18793-18800, 2002. [PubMed: 11901146] [Full Text: https://doi.org/10.1074/jbc.M109927200]
Repa, J. J., Turley, S. D., Lobaccaro, J.-M. A., Medina, J., Li, L., Lustig, K., Shan, B., Heyman, R. A., Dletschy, J. M., Mangelsdorf, D. J. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524-1529, 2000. [PubMed: 10968783] [Full Text: https://doi.org/10.1126/science.289.5484.1524]
Shinar, D. M., Endo, N., Rutledge, S. J., Vogel, R., Rodan, G. A., Schmidt, A. NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. Gene 147: 273-276, 1994. [PubMed: 7926814] [Full Text: https://doi.org/10.1016/0378-1119(94)90080-9]
Song, C., Hiipakka, R. A., Kokontis, J. M., Liao, S. Ubiquitous receptor: structures, immunocytochemical localization, and modulation of gene activation by receptors for retinoic acids and thyroid hormones. Ann. N.Y. Acad. Sci. 761: 38-49, 1995. [PubMed: 7625741] [Full Text: https://doi.org/10.1111/j.1749-6632.1995.tb31367.x]
Tangirala, R. K., Bischoff, E. D., Joseph, S. B., Wagner, B. L., Walczak, R., Laffitte, B. A., Daige, C. L., Thomas, D., Heyman, R. A., Mangelsdorf, D. J., Wang, X., Lusis, A. J., Tontonoz, P., Schulman, I. G. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Nat. Acad. Sci. 99: 11896-11901, 2002. [PubMed: 12193651] [Full Text: https://doi.org/10.1073/pnas.182199799]
Zelcer, N., Hong, C., Boyadjian, R., Tontonoz, P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325: 100-104, 2009. [PubMed: 19520913] [Full Text: https://doi.org/10.1126/science.1168974]