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Gene Review

Nr1h3  -  nuclear receptor subfamily 1, group H,...

Mus musculus

Synonyms: AU018371, LXR, LXR alpha, Liver X receptor alpha, Lxra, ...
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Disease relevance of Nr1h3

  • To test if attenuation of LXR signaling may enhance prostate cancer progression from an androgen-dependent state to an androgen-independent state, castrated mice carrying 104-S tumors were given the synthetic LXR agonist T0901317 by gavage [1].
  • In cultured rat hepatoma and primary hepatocyte cells, fatty acids and the sulfur-substituted fatty acid analog, tetradecylthioacetic acid, robustly induce LXR alpha (up to 3.5- and 7-fold, respectively) but not LXR beta (also called OR-1) mRNA steady state levels, with unsaturated fatty acids being more effective than saturated fatty acids [2].
  • We propose that induction of peroxisomal beta-oxidation by LXR agonists may serve as a counterregulatory mechanism for responding to the hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, additional studies are warranted [3].
  • Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis [4].
  • We have previously demonstrated that LXR alpha is down-regulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXR alpha expression in insulin-resistant conditions [5].

High impact information on Nr1h3

  • We now show that LXR signaling not only regulates macrophage cholesterol metabolism but also impacts antimicrobial responses [6].
  • LXR-null macrophages undergo accelerated apoptosis when challenged with LM and exhibit defective bacterial clearance in vivo [6].
  • LXR-dependent gene expression is important for macrophage survival and the innate immune response [6].
  • Our results demonstrate that LXR-dependent gene expression plays an unexpected role in innate immunity and suggest that common nuclear receptor pathways mediate macrophage responses to modified lipoproteins and intracellular pathogens [6].
  • These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXR alpha as the major sensor of dietary cholesterol [7].

Chemical compound and disease context of Nr1h3


Biological context of Nr1h3

  • Although activation of LXR leads to the induction of SREBP-1c gene expression and precursor protein, it has a very poor effect in inducing the mature nuclear form of the transcription factor [13].
  • Interestingly, the previously identified PPAR response element (PPRE) in the murine LXR alpha gene is not conserved in humans; however, a different PPRE is present in the human LXR 5'-flanking region [14].
  • Intriguingly, this element overlaps with a direct repeat 4, which serves as binding site for liver X receptor (LXR)/retinoid X receptor heterodimers, suggesting novel cross-talk between SREBP and LXR/retinoid X receptor in gene regulation [15].
  • In transfection studies, WT but not MUT TR-beta antagonized induction of this promoter by LXR-alpha [16].
  • LXR alpha (liver X receptor, also called RLD-1) is a nuclear receptor, highly expressed in tissues that play a role in lipid homeostasis [2].

Anatomical context of Nr1h3


Associations of Nr1h3 with chemical compounds

  • Macrophage lipid loading leads to ligand activation of LXRs and to induction of a pathway for cholesterol efflux involving the LXR target genes ABCA1 and apoE [14].
  • Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice [20].
  • 17beta-Estradiol was shown to decrease mRNA expression of liver X receptor (LXR) alpha after 10 h of treatment compared with the vehicle control [21].
  • Surprisingly, high plasma beta-sitosterol and campesterol concentrations were even further elevated in Abcg5-null mice on treatment with the synthetic LXR agonist T0901317 (0.015% dietary supplementation, 10 days), whereas these concentrations were reduced by approximately 75% in wild-type mice [22].
  • Ligand activation of these receptors in vivo induces expression of the LXR target gene SREBP-1c and increases plasma triglyceride levels [23].

Physical interactions of Nr1h3


Regulatory relationships of Nr1h3

  • The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism [13].
  • These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPAR gamma ligands [14].
  • We further show that the ability of LXR ligands to regulate MMP-9 expression is strictly receptor-dependent and is not observed in macrophages obtained from LXRalphabeta null mice [27].
  • Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling [24].
  • Additionally, LXR activation stimulated the excretion of plasma-derived [ 3 H]cholesterol into the fecal neutral sterol fraction in Mdr2 -/- mice [28].
  • Silencing of LXR-alpha mRNA expression in GH3 cells with small interfering RNA specific to LXR-alpha caused a loss of promoter activity induced by the LXR ligand, suggesting that LXR-alpha directly regulates the POMC gene promoter [29].

Other interactions of Nr1h3

  • Nuclear run-on assay indicated that the effect of LXR agonist on PLTP expression was at the transcriptional level [18].
  • Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPARalpha, and LXR results in responses that partially overlap with those of PP [30].
  • Exposure to FXR/LXRalpha modulators may affect the disposition of Ostalpha/beta substrates [31].
  • Due to its fatty acid structure, PFOA may activate other NRs, such as PPARbeta, PPARgamma, liver X receptor (LXR), or retinoid X receptor (RXR) [32].
  • The genes encoding the three enzymes of the classic peroxisomal beta-oxidation cycle, acyl-coenzyme A (acyl-CoA) oxidase, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, are activated by the LXR ligand, T0901317 [3].

Analytical, diagnostic and therapeutic context of Nr1h3

  • In addition, in vivo LXR alpha expression was induced by fatty acids, consistent with the in vitro cell culture data [2].
  • Sequence analyses indicated the presence of IR-1 regions in Ostalpha and Ostbeta promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXRalpha [31].
  • In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis [4].
  • In situ hybridization analyses of tissues from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation [8].
  • Affymetrix microarray data and Northern blot assays demonstrated that phospholipid transfer protein (PLTP) was induced 6-fold when either murine or human macrophages were incubated in the presence of ligands for the liver X receptor (LXR) and the retinoid X receptor [33].


  1. Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist. Chuu, C.P., Hiipakka, R.A., Kokontis, J.M., Fukuchi, J., Chen, R.Y., Liao, S. Cancer Res. (2006) [Pubmed]
  2. Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Tobin, K.A., Steineger, H.H., Alberti, S., Spydevold, O., Auwerx, J., Gustafsson, J.A., Nebb, H.I. Mol. Endocrinol. (2000) [Pubmed]
  3. Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. Hu, T., Foxworthy, P., Siesky, A., Ficorilli, J.V., Gao, H., Li, S., Christe, M., Ryan, T., Cao, G., Eacho, P., Michael, M.D., Michael, L.F. Endocrinology (2005) [Pubmed]
  4. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. 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. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor alpha. Dalen, K.T., Ulven, S.M., Bamberg, K., Gustafsson, J.A., Nebb, H.I. J. Biol. Chem. (2003) [Pubmed]
  6. LXR-dependent gene expression is important for macrophage survival and the innate immune response. Joseph, S.B., Bradley, M.N., Castrillo, A., Bruhn, K.W., Mak, P.A., Pei, L., Hogenesch, J., O'connell, R.M., Cheng, G., Saez, E., Miller, J.F., Tontonoz, P. Cell (2004) [Pubmed]
  7. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Peet, D.J., Turley, S.D., Ma, W., Janowski, B.A., Lobaccaro, J.M., Hammer, R.E., Mangelsdorf, D.J. Cell (1998) [Pubmed]
  8. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. Repa, J.J., Berge, K.E., Pomajzl, C., Richardson, J.A., Hobbs, H., Mangelsdorf, D.J. J. Biol. Chem. (2002) [Pubmed]
  9. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Laffitte, B.A., Chao, L.C., Li, J., Walczak, R., Hummasti, S., Joseph, S.B., Castrillo, A., Wilpitz, D.C., Mangelsdorf, D.J., Collins, J.L., Saez, E., Tontonoz, P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  10. The Liver X Receptor (LXR) and Hepatic Lipogenesis: THE CARBOHYDRATE-RESPONSE ELEMENT-BINDING PROTEIN IS A TARGET GENE OF LXR. Cha, J.Y., Repa, J.J. J. Biol. Chem. (2007) [Pubmed]
  11. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. Fowler, A.J., Sheu, M.Y., Schmuth, M., Kao, J., Fluhr, J.W., Rhein, L., Collins, J.L., Willson, T.M., Mangelsdorf, D.J., Elias, P.M., Feingold, K.R. J. Invest. Dermatol. (2003) [Pubmed]
  12. The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice. Verreault, M., Senekeo-Effenberger, K., Trottier, J., Bonzo, J.A., Bélanger, J., Kaeding, J., Staels, B., Caron, P., Tukey, R.H., Barbier, O. Hepatology (2006) [Pubmed]
  13. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. Hegarty, B.D., Bobard, A., Hainault, I., Ferré, P., Bossard, P., Foufelle, F. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Autoregulation of the human liver X receptor alpha promoter. Laffitte, B.A., Joseph, S.B., Walczak, R., Pei, L., Wilpitz, D.C., Collins, J.L., Tontonoz, P. Mol. Cell. Biol. (2001) [Pubmed]
  15. Liver X receptor alpha interferes with SREBP1c-mediated Abcd2 expression. Novel cross-talk in gene regulation. Weinhofer, I., Kunze, M., Rampler, H., Bookout, A.L., Forss-Petter, S., Berger, J. J. Biol. Chem. (2005) [Pubmed]
  16. Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model. Hashimoto, K., Cohen, R.N., Yamada, M., Markan, K.R., Monden, T., Satoh, T., Mori, M., Wondisford, F.E. J. Biol. Chem. (2006) [Pubmed]
  17. The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Laffitte, B.A., Joseph, S.B., Chen, M., Castrillo, A., Repa, J., Wilpitz, D., Mangelsdorf, D., Tontonoz, P. Mol. Cell. Biol. (2003) [Pubmed]
  18. Phospholipid transfer protein is regulated by liver X receptors in vivo. Cao, G., Beyer, T.P., Yang, X.P., Schmidt, R.J., Zhang, Y., Bensch, W.R., Kauffman, R.F., Gao, H., Ryan, T.P., Liang, Y., Eacho, P.I., Jiang, X.C. J. Biol. Chem. (2002) [Pubmed]
  19. Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Whitney, K.D., Watson, M.A., Collins, J.L., Benson, W.G., Stone, T.M., Numerick, M.J., Tippin, T.K., Wilson, J.G., Winegar, D.A., Kliewer, S.A. Mol. Endocrinol. (2002) [Pubmed]
  20. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. Plōsch, T., Kok, T., Bloks, V.W., Smit, M.J., Havinga, R., Chimini, G., Groen, A.K., Kuipers, F. J. Biol. Chem. (2002) [Pubmed]
  21. Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue. Lundholm, L., Movérare, S., Steffensen, K.R., Nilsson, M., Otsuki, M., Ohlsson, C., Gustafsson, J.A., Dahlman-Wright, K. J. Mol. Endocrinol. (2004) [Pubmed]
  22. Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor. Plösch, T., Bloks, V.W., Terasawa, Y., Berdy, S., Siegler, K., Van Der Sluijs, F., Kema, I.P., Groen, A.K., Shan, B., Kuipers, F., Schwarz, M., Schwartz, M. Gastroenterology (2004) [Pubmed]
  23. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. Joseph, S.B., Laffitte, B.A., Patel, P.H., Watson, M.A., Matsukuma, K.E., Walczak, R., Collins, J.L., Osborne, T.F., Tontonoz, P. J. Biol. Chem. (2002) [Pubmed]
  24. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Ide, T., Shimano, H., Yoshikawa, T., Yahagi, N., Amemiya-Kudo, M., Matsuzaka, T., Nakakuki, M., Yatoh, S., Iizuka, Y., Tomita, S., Ohashi, K., Takahashi, A., Sone, H., Gotoda, T., Osuga, J., Ishibashi, S., Yamada, N. Mol. Endocrinol. (2003) [Pubmed]
  25. Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Malerød, L., Juvet, L.K., Hanssen-Bauer, A., Eskild, W., Berg, T. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  26. Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor. Quinet, E.M., Savio, D.A., Halpern, A.R., Chen, L., Miller, C.P., Nambi, P. J. Lipid Res. (2004) [Pubmed]
  27. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. Castrillo, A., Joseph, S.B., Marathe, C., Mangelsdorf, D.J., Tontonoz, P. J. Biol. Chem. (2003) [Pubmed]
  28. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Kruit, J.K., Plösch, T., Havinga, R., Boverhof, R., Groot, P.H., Groen, A.K., Kuipers, F. Gastroenterology (2005) [Pubmed]
  29. Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary. Matsumoto, S., Hashimoto, K., Yamada, M., Satoh, T., Hirato, J., Mori, M. Mol. Endocrinol. (2009) [Pubmed]
  30. Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor alpha, retinoid X receptor, and liver X receptor in mouse liver. Anderson, S.P., Dunn, C., Laughter, A., Yoon, L., Swanson, C., Stulnig, T.M., Steffensen, K.R., Chandraratna, R.A., Gustafsson, J.A., Corton, J.C. Mol. Pharmacol. (2004) [Pubmed]
  31. LXR Alpha Transactivates Mouse Organic Solute Transporter Alpha and Beta via IR-1 Elements Shared with FXR. Okuwaki, M., Takada, T., Iwayanagi, Y., Koh, S., Kariya, Y., Fujii, H., Suzuki, H. Pharm. Res. (2007) [Pubmed]
  32. Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha. Vanden Heuvel, J.P., Thompson, J.T., Frame, S.R., Gillies, P.J. Toxicol. Sci. (2006) [Pubmed]
  33. Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. Mak, P.A., Kast-Woelbern, H.R., Anisfeld, A.M., Edwards, P.A. J. Lipid Res. (2002) [Pubmed]
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