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Gene Review

NR1H4  -  nuclear receptor subfamily 1, group H,...

Homo sapiens

Synonyms: BAR, Bile acid receptor, FXR, Farnesoid X-activated receptor, Farnesol receptor HRR-1, ...
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Disease relevance of NR1H4


High impact information on NR1H4


Chemical compound and disease context of NR1H4


Biological context of NR1H4


Anatomical context of NR1H4

  • Expression of the farnesoid X receptor (FXR; NR1H4) is limited to the liver, intestine, kidney, and adrenal gland [15].
  • VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium [13].
  • Treatment of human hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein [16].
  • OBJECTIVES: To determine the role of PPARs, farnesoid X receptor (FXR) and other orphan nuclear hormone receptors in sebaceous gland function in vitro by investigating the biochemical effects of appropriate ligands, and by establishing the RNA and protein expression patterns of a number of nuclear receptors in sebaceous glands ex vivo [17].
  • FXR cis-element binding and FXR protein were reduced primarily in nuclear but not cytoplasmic extracts from familial intrahepatic cholestasis-1-negative Caco-2 cells [18].

Associations of NR1H4 with chemical compounds


Physical interactions of NR1H4


Regulatory relationships of NR1H4

  • Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner [16].
  • Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel [2].
  • FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity [3].
  • The goal of this study is to elucidate the mechanism of CYP7A1 transcription by bile acid-activated farnesoid X receptor (FXR) in its native promoter and cellular context and to identify FXR response elements in the gene [24].
  • In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids [25].

Other interactions of NR1H4

  • Because VPAC1 expression was previously shown to be regulated by nuclear receptors, we tested the hypothesis that it may be regulated by the farnesoid X receptor (FXR) [13].
  • The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes [26].
  • The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes [21].
  • The rank order and absolute potency was conserved (CDCA IC(50) = 8.7 microM, DCA IC(50) = 27.2 microM, UDCA and CA inactive) consistent with bile acid repression of CYP7A1 being mediated by FXR [27].
  • We demonstrate that the farnesoid X receptor (FXR; NR1H4), which regulates a variety of genes involved in lipoprotein metabolism, also regulates the expression of PDK4 [28].

Analytical, diagnostic and therapeutic context of NR1H4

  • A mammalian two-hybrid assay was utilized to assess the ability of FXR to recruit SRC-1 in a ligand-dependent manner [27].
  • Furthermore, we show by chromatin immunoprecipitation that the ligand-dependent activation of the human BSEP locus is associated with a simultaneous increase of FXR and CARM1 occupation [29].
  • 5'-Deletion, mutagenesis, and gel shift analysis identified a heretofore unknown element at positions -103/-84 consisting of an inverted repeat of two consensus receptor-binding hexads separated by 8 nucleotides (IR8), which was required for the response to bile acid-activated FXR [30].
  • Northern blot analysis confirmed the up-regulation of kininogen expression by FXR agonists [25].
  • AlphaA-crystallin was identified in a microarray screen as one of the most highly induced genes after treatment of HepG2 cells with the synthetic FXR ligand GW4064 [31].


  1. Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis. Honda, A., Salen, G., Matsuzaki, Y., Batta, A.K., Xu, G., Hirayama, T., Tint, G.S., Doy, M., Shefer, S. J. Lipid Res. (2005) [Pubmed]
  2. The farnesoid x receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Swales, K.E., Korbonits, M., Carpenter, R., Walsh, D.T., Warner, T.D., Bishop-Bailey, D. Cancer Res. (2006) [Pubmed]
  3. FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Barbier, O., Torra, I.P., Sirvent, A., Claudel, T., Blanquart, C., Duran-Sandoval, D., Kuipers, F., Kosykh, V., Fruchart, J.C., Staels, B. Gastroenterology (2003) [Pubmed]
  4. Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding. Kassam, A., Miao, B., Young, P.R., Mukherjee, R. J. Biol. Chem. (2003) [Pubmed]
  5. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Chiang, J.Y. Endocr. Rev. (2002) [Pubmed]
  6. Bile acids: natural ligands for an orphan nuclear receptor. Parks, D.J., Blanchard, S.G., Bledsoe, R.K., Chandra, G., Consler, T.G., Kliewer, S.A., Stimmel, J.B., Willson, T.M., Zavacki, A.M., Moore, D.D., Lehmann, J.M. Science (1999) [Pubmed]
  7. Identification of a nuclear receptor for bile acids. Makishima, M., Okamoto, A.Y., Repa, J.J., Tu, H., Learned, R.M., Luk, A., Hull, M.V., Lustig, K.D., Mangelsdorf, D.J., Shan, B. Science (1999) [Pubmed]
  8. Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis. Bertolotti, M., Gabbi, C., Anzivino, C., Mitro, N., Godio, C., De Fabiani, E., Crestani, M., Del Puppo, M., Ricchi, M., Carulli, L., Rossi, A., Loria, P., Carulli, N. Eur. J. Clin. Invest. (2006) [Pubmed]
  9. The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors. Redinger, R.N. Can. J. Gastroenterol. (2003) [Pubmed]
  10. The transport of glutamine into mammalian cells. McGivan, J.D., Bungard, C.I. Front. Biosci. (2007) [Pubmed]
  11. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. Fiorucci, S., Rizzo, G., Antonelli, E., Renga, B., Mencarelli, A., Riccardi, L., Morelli, A., Pruzanski, M., Pellicciari, R. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  12. Comparison of heart rate reserve versus 85% of age-predicted maximum heart rate as a measure of chronotropic response in patients undergoing dobutamine stress echocardiography. Bangalore, S., Yao, S.S., Chaudhry, F.A. Am. J. Cardiol. (2006) [Pubmed]
  13. VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Chignard, N., Mergey, M., Barbu, V., Finzi, L., Tiret, E., Paul, A., Housset, C. Hepatology (2005) [Pubmed]
  14. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Plass, J.R., Mol, O., Heegsma, J., Geuken, M., Faber, K.N., Jansen, P.L., Müller, M. Hepatology (2002) [Pubmed]
  15. FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine. Lee, H., Zhang, Y., Lee, F.Y., Nelson, S.F., Gonzalez, F.J., Edwards, P.A. J. Lipid Res. (2006) [Pubmed]
  16. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. Anisfeld, A.M., Kast-Woelbern, H.R., Meyer, M.E., Jones, S.A., Zhang, Y., Williams, K.J., Willson, T., Edwards, P.A. J. Biol. Chem. (2003) [Pubmed]
  17. Peroxisome proliferator-activated receptor and farnesoid X receptor ligands differentially regulate sebaceous differentiation in human sebaceous gland organ cultures in vitro. Downie, M.M., Sanders, D.A., Maier, L.M., Stock, D.M., Kealey, T. Br. J. Dermatol. (2004) [Pubmed]
  18. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Chen, F., Ananthanarayanan, M., Emre, S., Neimark, E., Bull, L.N., Knisely, A.S., Strautnieks, S.S., Thompson, R.J., Magid, M.S., Gordon, R., Balasubramanian, N., Suchy, F.J., Shneider, B.L. Gastroenterology (2004) [Pubmed]
  19. A natural product ligand of the oxysterol receptor, liver X receptor. Bramlett, K.S., Houck, K.A., Borchert, K.M., Dowless, M.S., Kulanthaivel, P., Zhang, Y., Beyer, T.P., Schmidt, R., Thomas, J.S., Michael, L.F., Barr, R., Montrose, C., Eacho, P.I., Cao, G., Burris, T.P. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  20. The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. Lew, J.L., Zhao, A., Yu, J., Huang, L., De Pedro, N., Peláez, F., Wright, S.D., Cui, J. J. Biol. Chem. (2004) [Pubmed]
  21. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Landrier, J.F., Eloranta, J.J., Vavricka, S.R., Kullak-Ublick, G.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  22. Identification of DRIP205 as a coactivator for the Farnesoid X receptor. Pineda Torra, I., Freedman, L.P., Garabedian, M.J. J. Biol. Chem. (2004) [Pubmed]
  23. Identification of the promoter elements involved in the stimulation of ASCT2 expression by glutamine availability in HepG2 cells and the probable involvement of FXR/RXR dimers. Bungard, C.I., McGivan, J.D. Arch. Biochem. Biophys. (2005) [Pubmed]
  24. Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. Chiang, J.Y., Kimmel, R., Weinberger, C., Stroup, D. J. Biol. Chem. (2000) [Pubmed]
  25. Human kininogen gene is transactivated by the farnesoid X receptor. Zhao, A., Lew, J.L., Huang, L., Yu, J., Zhang, T., Hrywna, Y., Thompson, J.R., de Pedro, N., Blevins, R.A., Peláez, F., Wright, S.D., Cui, J. J. Biol. Chem. (2003) [Pubmed]
  26. The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes. Rizzo, G., Renga, B., Antonelli, E., Passeri, D., Pellicciari, R., Fiorucci, S. Mol. Pharmacol. (2005) [Pubmed]
  27. Correlation of farnesoid X receptor coactivator recruitment and cholesterol 7alpha-hydroxylase gene repression by bile acids. Bramlett, K.S., Yao, S., Burris, T.P. Mol. Genet. Metab. (2000) [Pubmed]
  28. Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Savkur, R.S., Bramlett, K.S., Michael, L.F., Burris, T.P. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  29. Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1. Ananthanarayanan, M., Li, S., Balasubramaniyan, N., Suchy, F.J., Walsh, M.J. J. Biol. Chem. (2004) [Pubmed]
  30. The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element. Prieur, X., Coste, H., Rodriguez, J.C. J. Biol. Chem. (2003) [Pubmed]
  31. Alpha-crystallin is a target gene of the farnesoid X-activated receptor in human livers. Lee, F.Y., Kast-Woelbern, H.R., Chang, J., Luo, G., Jones, S.A., Fishbein, M.C., Edwards, P.A. J. Biol. Chem. (2005) [Pubmed]
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