NR1H4_HUMAN
ID NR1H4_HUMAN Reviewed; 486 AA.
AC Q96RI1; A1L4K5; B7Z412; B7ZM06; F8VYG8; Q8NFP5; Q8NFP6; Q92943;
DT 27-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 2.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Bile acid receptor;
DE AltName: Full=Farnesoid X-activated receptor;
DE AltName: Full=Farnesol receptor HRR-1;
DE AltName: Full=Nuclear receptor subfamily 1 group H member 4;
DE AltName: Full=Retinoid X receptor-interacting protein 14;
DE Short=RXR-interacting protein 14;
GN Name=NR1H4; Synonyms=BAR, FXR, HRR1, RIP14;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Papetti M., Wood N., Lohmar P.D., Bowman M.R.;
RT "The identification of the cDNA coding for HRR-1, a novel human farnesol
RT receptor.";
RL Submitted (AUG-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Han J.-I., Bok S.-H., Jeong T.-S.;
RT "Functional analysis of human farnesol receptor (NR1H4) splicing variant.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE SPLICING
RP (ISOFORMS 3 AND 4).
RX PubMed=12062799; DOI=10.1016/s0378-1119(02)00557-7;
RA Huber R.M., Murphy K., Miao B., Link J.R., Cunningham M.R., Rupar M.J.,
RA Gunyuzlu P.L., Haws T.F. Jr., Kassam A., Powell F., Hollis G.F.,
RA Young P.R., Mukherjee R., Burn T.C.;
RT "Generation of multiple farnesoid-X-receptor isoforms through the use of
RT alternative promoters.";
RL Gene 290:35-43(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION IN BA HOMEOSTASIS.
RX PubMed=10514450; DOI=10.1074/jbc.274.42.29749;
RA Grober J., Zaghini I., Fujii H., Jones S.A., Kliewer S.A., Willson T.M.,
RA Ono T., Besnard P.;
RT "Identification of a bile acid-responsive element in the human ileal bile
RT acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-
RT retinoic acid receptor heterodimer.";
RL J. Biol. Chem. 274:29749-29754(1999).
RN [9]
RP FUNCTION IN BA HOEMOSTASIS.
RX PubMed=10334992; DOI=10.1126/science.284.5418.1362;
RA Makishima M., Okamoto A.Y., Repa J.J., Tu H., Learned R.M., Luk A.,
RA Hull M.V., Lustig K.D., Mangelsdorf D.J., Shan B.;
RT "Identification of a nuclear receptor for bile acids.";
RL Science 284:1362-1365(1999).
RN [10]
RP FUNCTION IN BA HOEMOSTASIS.
RX PubMed=10334993; DOI=10.1126/science.284.5418.1365;
RA Parks D.J., Blanchard S.G., Bledsoe R.K., Chandra G., Consler T.G.,
RA Kliewer S.A., Stimmel J.B., Willson T.M., Zavacki A.M., Moore D.D.,
RA Lehmann J.M.;
RT "Bile acids: natural ligands for an orphan nuclear receptor.";
RL Science 284:1365-1368(1999).
RN [11]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=11579204; DOI=10.1210/mend.15.10.0712;
RA Kast H.R., Nguyen C.M., Sinal C.J., Jones S.A., Laffitte B.A., Reue K.,
RA Gonzalez F.J., Willson T.M., Edwards P.A.;
RT "Farnesoid X-activated receptor induces apolipoprotein C-II transcription:
RT a molecular mechanism linking plasma triglyceride levels to bile acids.";
RL Mol. Endocrinol. 15:1720-1728(2001).
RN [12]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=11927623; DOI=10.1172/jci14505;
RA Claudel T., Sturm E., Duez H., Torra I.P., Sirvent A., Kosykh V.,
RA Fruchart J.C., Dallongeville J., Hum D.W., Kuipers F., Staels B.;
RT "Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I
RT transcription via a negative FXR response element.";
RL J. Clin. Invest. 109:961-971(2002).
RN [13]
RP FUNCTION IN BA HOMEOSTASIS.
RX PubMed=12815072; DOI=10.1101/gad.1083503;
RA Holt J.A., Luo G., Billin A.N., Bisi J., McNeill Y.Y., Kozarsky K.F.,
RA Donahee M., Wang D.Y., Mansfield T.A., Kliewer S.A., Goodwin B.,
RA Jones S.A.;
RT "Definition of a novel growth factor-dependent signal cascade for the
RT suppression of bile acid biosynthesis.";
RL Genes Dev. 17:1581-1591(2003).
RN [14]
RP FUNCTION IN BA HOMEOSTASIS.
RX PubMed=12806625; DOI=10.1016/s0016-5085(03)00388-3;
RA Barbier O., Torra I.P., Sirvent A., Claudel T., Blanquart C.,
RA Duran-Sandoval D., Kuipers F., Kosykh V., Fruchart J.C., Staels B.;
RT "FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of
RT negative feedback control of FXR activity.";
RL Gastroenterology 124:1926-1940(2003).
RN [15]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=12891557; DOI=10.1016/s0016-5085(03)00896-5;
RA Claudel T., Inoue Y., Barbier O., Duran-Sandoval D., Kosykh V.,
RA Fruchart J., Fruchart J.C., Gonzalez F.J., Staels B.;
RT "Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII
RT expression.";
RL Gastroenterology 125:544-555(2003).
RN [16]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=12660231; DOI=10.1074/jbc.m302505200;
RA Anisfeld A.M., Kast-Woelbern H.R., Meyer M.E., Jones S.A., Zhang Y.,
RA Williams K.J., Willson T., Edwards P.A.;
RT "Syndecan-1 expression is regulated in an isoform-specific manner by the
RT farnesoid-X receptor.";
RL J. Biol. Chem. 278:20420-20428(2003).
RN [17]
RP FUNCTION IN BA HOMEOSTASIS.
RX PubMed=12754200; DOI=10.1074/jbc.m302128200;
RA Pircher P.C., Kitto J.L., Petrowski M.L., Tangirala R.K., Bischoff E.D.,
RA Schulman I.G., Westin S.K.;
RT "Farnesoid X receptor regulates bile acid-amino acid conjugation.";
RL J. Biol. Chem. 278:27703-27711(2003).
RN [18]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=12554753; DOI=10.1210/me.2002-0120;
RA Pineda Torra I., Claudel T., Duval C., Kosykh V., Fruchart J.C., Staels B.;
RT "Bile acids induce the expression of the human peroxisome proliferator-
RT activated receptor alpha gene via activation of the farnesoid X receptor.";
RL Mol. Endocrinol. 17:259-272(2003).
RN [19]
RP INTERACTION WITH PPARGC1A.
RX PubMed=15202934; DOI=10.1042/bj20040432;
RA Kanaya E., Shiraki T., Jingami H.;
RT "The nuclear bile acid receptor FXR is activated by PGC-1alpha in a ligand-
RT dependent manner.";
RL Biochem. J. 382:913-921(2004).
RN [20]
RP INTERACTION WITH NCOA1, AND LIGAND-BINDING.
RX PubMed=14684751; DOI=10.1074/jbc.m306422200;
RA Lew J.L., Zhao A., Yu J., Huang L., De Pedro N., Pelaez F., Wright S.D.,
RA Cui J.;
RT "The farnesoid X receptor controls gene expression in a ligand- and
RT promoter-selective fashion.";
RL J. Biol. Chem. 279:8856-8861(2004).
RN [21]
RP FUNCTION IN BA HOEMOSTASIS.
RX PubMed=15239098; DOI=10.1002/hep.20295;
RA Neimark E., Chen F., Li X., Shneider B.L.;
RT "Bile acid-induced negative feedback regulation of the human ileal bile
RT acid transporter.";
RL Hepatology 40:149-156(2004).
RN [22]
RP INTERACTION WITH MED1.
RX PubMed=15187081; DOI=10.1074/jbc.m405126200;
RA Pineda Torra I., Freedman L.P., Garabedian M.J.;
RT "Identification of DRIP205 as a coactivator for the Farnesoid X receptor.";
RL J. Biol. Chem. 279:36184-36191(2004).
RN [23]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=15337761; DOI=10.1074/jbc.m404255200;
RA Hirokane H., Nakahara M., Tachibana S., Shimizu M., Sato R.;
RT "Bile acid reduces the secretion of very low density lipoprotein by
RT repressing microsomal triglyceride transfer protein gene expression
RT mediated by hepatocyte nuclear factor-4.";
RL J. Biol. Chem. 279:45685-45692(2004).
RN [24]
RP FUNCTION IN BA HOMEOSTASIS, AND INTERACTION WITH CARM1.
RX PubMed=15471871; DOI=10.1074/jbc.m410021200;
RA Ananthanarayanan M., Li S., Balasubramaniyan N., Suchy F.J., Walsh M.J.;
RT "Ligand-dependent activation of the farnesoid X-receptor directs arginine
RT methylation of histone H3 by CARM1.";
RL J. Biol. Chem. 279:54348-54357(2004).
RN [25]
RP INTERACTION WITH PRMT1.
RX PubMed=15911693; DOI=10.1124/mol.105.012104;
RA Rizzo G., Renga B., Antonelli E., Passeri D., Pellicciari R., Fiorucci S.;
RT "The methyl transferase PRMT1 functions as co-activator of farnesoid X
RT receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR
RT responsive genes.";
RL Mol. Pharmacol. 68:551-558(2005).
RN [26]
RP FUNCTION IN BA HOEMOSTASIS.
RX PubMed=16269519; DOI=10.1152/ajpgi.00430.2005;
RA Landrier J.-F., Eloranta J.J., Vavricka S.R., Kullak-Ublick G.A.;
RT "The nuclear receptor for bile acids, FXR, transactivates human organic
RT solute transporter-alpha and -beta genes.";
RL Am. J. Physiol. 290:G476-G485(2006).
RN [27]
RP FUNCTION IN BA HOEMOSTASIS.
RX PubMed=16946559; DOI=10.2133/dmpk.21.315;
RA Miyata M., Matsuda Y., Tsuchiya H., Kitada H., Akase T., Shimada M.,
RA Nagata K., Gonzalez F.J., Yamazoe Y.;
RT "Chenodeoxycholic acid-mediated activation of the farnesoid X receptor
RT negatively regulates hydroxysteroid sulfotransferase.";
RL Drug Metab. Pharmacokinet. 21:315-323(2006).
RN [28]
RP POSSIBLE INVOLVEMENT IN INTRAHEPATIC CHOLESTASIS OF PREGNANCY.
RX PubMed=17681172; DOI=10.1053/j.gastro.2007.05.015;
RA Van Mil S.W., Milona A., Dixon P.H., Mullenbach R., Geenes V.L.,
RA Chambers J., Shevchuk V., Moore G.E., Lammert F., Glantz A.G.,
RA Mattsson L.A., Whittaker J., Parker M.G., White R., Williamson C.;
RT "Functional variants of the central bile acid sensor FXR identified in
RT intrahepatic cholestasis of pregnancy.";
RL Gastroenterology 133:507-516(2007).
RN [29]
RP FUNCTION IN BA HEMOSTASIS, AND INTERACTION WITH GPS2.
RX PubMed=17895379; DOI=10.1073/pnas.0706736104;
RA Sanyal S., Baavner A., Haroniti A., Nilsson L.M., Lundaasen T.,
RA Rehnmark S., Witt M.R., Einarsson C., Talianidis I., Gustafsson J.A.,
RA Treuter E.;
RT "Involvement of corepressor complex subunit GPS2 in transcriptional
RT pathways governing human bile acid biosynthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:15665-15670(2007).
RN [30]
RP PHOSPHORYLATION AT THR-456, AND MUTAGENESIS OF THR-456.
RX PubMed=18668687; DOI=10.1002/hep.22431;
RA Frankenberg T., Miloh T., Chen F.Y., Ananthanarayanan M., Sun A.Q.,
RA Balasubramaniyan N., Arias I., Setchell K.D., Suchy F.J., Shneider B.L.;
RT "The membrane protein ATPase class I type 8B member 1 signals through
RT protein kinase C zeta to activate the farnesoid X receptor.";
RL Hepatology 48:1896-1905(2008).
RN [31]
RP POSSIBLE INVOLVEMENT IN CHOLESTEROL CHOLELITHIASIS.
RX PubMed=17931734; DOI=10.1016/j.jhep.2007.07.027;
RA Kovacs P., Kress R., Rocha J., Kurtz U., Miquel J.F., Nervi F.,
RA Mendez-Sanchez N., Uribe M., Bock H.H., Schirin-Sokhan R., Stumvoll M.,
RA Moessner J., Lammert F., Wittenburg H.;
RT "Variation of the gene encoding the nuclear bile salt receptor FXR and
RT gallstone susceptibility in mice and humans.";
RL J. Hepatol. 48:116-124(2008).
RN [32]
RP PHOSPHORYLATION AT SER-145 AND SER-164, INTERACTION WITH PPARGC1A, AND
RP MUTAGENESIS OF SER-145 AND SER-164.
RX PubMed=18755856; DOI=10.1210/me.2008-0092;
RA Gineste R., Sirvent A., Paumelle R., Helleboid S., Aquilina A., Darteil R.,
RA Hum D.W., Fruchart J.C., Staels B.;
RT "Phosphorylation of farnesoid X receptor by protein kinase C promotes its
RT transcriptional activity.";
RL Mol. Endocrinol. 22:2433-2447(2008).
RN [33]
RP INTERACTION WITH XRCC5 AND XRCC6.
RX PubMed=19833092; DOI=10.1016/j.bbrc.2009.10.040;
RA Ohno M., Kunimoto M., Nishizuka M., Osada S., Imagawa M.;
RT "Ku proteins function as corepressors to regulate farnesoid X receptor-
RT mediated gene expression.";
RL Biochem. Biophys. Res. Commun. 390:738-742(2009).
RN [34]
RP TISSUE SPECIFICITY.
RX PubMed=19393742; DOI=10.1016/j.bbadis.2009.04.004;
RA Renga B., Migliorati M., Mencarelli A., Fiorucci S.;
RT "Reciprocal regulation of the bile acid-activated receptor FXR and the
RT interferon-gamma-STAT-1 pathway in macrophages.";
RL Biochim. Biophys. Acta 1792:564-573(2009).
RN [35]
RP ACETYLATION AT LYS-167 AND LYS-227 BY EP300.
RX PubMed=19883617; DOI=10.1016/j.cmet.2009.09.009;
RA Kemper J.K., Xiao Z., Ponugoti B., Miao J., Fang S., Kanamaluru D.,
RA Tsang S., Wu S.Y., Chiang C.M., Veenstra T.D.;
RT "FXR acetylation is normally dynamically regulated by p300 and SIRT1 but
RT constitutively elevated in metabolic disease states.";
RL Cell Metab. 10:392-404(2009).
RN [36]
RP FUNCTION IN INTESTINAL INNATE IMMUNITY, TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, AND SUMOYLATION.
RX PubMed=19864602; DOI=10.4049/jimmunol.0803978;
RA Vavassori P., Mencarelli A., Renga B., Distrutti E., Fiorucci S.;
RT "The bile acid receptor FXR is a modulator of intestinal innate immunity.";
RL J. Immunol. 183:6251-6261(2009).
RN [37]
RP FUNCTION IN BA HOMEOSTASIS.
RX PubMed=19085950; DOI=10.1002/hep.22627;
RA Song K.H., Li T., Owsley E., Strom S., Chiang J.Y.;
RT "Bile acids activate fibroblast growth factor 19 signaling in human
RT hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.";
RL Hepatology 49:297-305(2009).
RN [38]
RP INTERACTION WITH SMARCA4.
RX PubMed=19805516; DOI=10.1128/mcb.00825-09;
RA Miao J., Fang S., Lee J., Comstock C., Knudsen K.E., Kemper J.K.;
RT "Functional specificities of Brm and Brg-1 Swi/Snf ATPases in the feedback
RT regulation of hepatic bile acid biosynthesis.";
RL Mol. Cell. Biol. 29:6170-6181(2009).
RN [39]
RP INTERACTION WITH PAGR1 AND NCOA6.
RX PubMed=19556342; DOI=10.1210/me.2009-0099;
RA Kim D.H., Lee J., Lee B., Lee J.W.;
RT "ASCOM controls farnesoid X receptor transactivation through its associated
RT histone H3 lysine 4 methyltransferase activity.";
RL Mol. Endocrinol. 23:1556-1562(2009).
RN [40]
RP FUNCTION IN GLUCOSE HOMEOSTASIS, AND TISSUE SPECIFICITY.
RX PubMed=20447400; DOI=10.1016/j.febslet.2010.04.068;
RA Popescu I.R., Helleboid-Chapman A., Lucas A., Vandewalle B., Dumont J.,
RA Bouchaert E., Derudas B., Kerr-Conte J., Caron S., Pattou F., Staels B.;
RT "The nuclear receptor FXR is expressed in pancreatic beta-cells and
RT protects human islets from lipotoxicity.";
RL FEBS Lett. 584:2845-2851(2010).
RN [41]
RP REVIEW.
RX PubMed=21383957; DOI=10.1621/nrs.08005;
RA Modica S., Gadaleta R.M., Moschetta A.;
RT "Deciphering the nuclear bile acid receptor FXR paradigm.";
RL Nucl. Recept. Signal. 8:E005-E005(2010).
RN [42]
RP FUNCTION IN INTESTINAL INFLAMMATION.
RX PubMed=21242261; DOI=10.1136/gut.2010.212159;
RA Gadaleta R.M., van Erpecum K.J., Oldenburg B., Willemsen E.C., Renooij W.,
RA Murzilli S., Klomp L.W., Siersema P.D., Schipper M.E., Danese S., Penna G.,
RA Laverny G., Adorini L., Moschetta A., van Mil S.W.;
RT "Farnesoid X receptor activation inhibits inflammation and preserves the
RT intestinal barrier in inflammatory bowel disease.";
RL Gut 60:463-472(2011).
RN [43]
RP FUNCTION IN LIPID HOMEOSTASIS.
RX PubMed=21804189; DOI=10.1172/jci45277;
RA Chennamsetty I., Claudel T., Kostner K.M., Baghdasaryan A., Kratky D.,
RA Levak-Frank S., Frank S., Gonzalez F.J., Trauner M., Kostner G.M.;
RT "Farnesoid X receptor represses hepatic human APOA gene expression.";
RL J. Clin. Invest. 121:3724-3734(2011).
RN [44]
RP REVIEW.
RX PubMed=22820415; DOI=10.1016/j.bbalip.2012.07.004;
RA Hollman D.A., Milona A., van Erpecum K.J., van Mil S.W.;
RT "Anti-inflammatory and metabolic actions of FXR: insights into molecular
RT mechanisms.";
RL Biochim. Biophys. Acta 1821:1443-1452(2012).
RN [45]
RP METHYLATION AT LYS-220 BY SETD7.
RX PubMed=22345554; DOI=10.1152/ajpgi.00441.2011;
RA Balasubramaniyan N., Ananthanarayanan M., Suchy F.J.;
RT "Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates
RT the expression of FXR target genes.";
RL Am. J. Physiol. 302:G937-G947(2012).
RN [46]
RP POSSIBLE INVOLVEMENT IN PRIMARY BILIARY CIRRHOSIS.
RX PubMed=23235576; DOI=10.1002/14651858.cd000551.pub3;
RA Rudic J.S., Poropat G., Krstic M.N., Bjelakovic G., Gluud C.;
RT "Ursodeoxycholic acid for primary biliary cirrhosis.";
RL Cochrane Database Syst. Rev. 12:CD000551-CD000551(2012).
RN [47]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=23928191; DOI=10.1016/j.bcp.2013.07.022;
RA Vaquero J., Monte M.J., Dominguez M., Muntane J., Marin J.J.;
RT "Differential activation of the human farnesoid X receptor depends on the
RT pattern of expressed isoforms and the bile acid pool composition.";
RL Biochem. Pharmacol. 86:926-939(2013).
RN [48]
RP SUMOYLATION AT LYS-132 AND LYS-289, AND MUTAGENESIS OF LYS-132; LYS-289 AND
RP GLU-291.
RX PubMed=23546875; DOI=10.1074/jbc.m112.443937;
RA Balasubramaniyan N., Luo Y., Sun A.Q., Suchy F.J.;
RT "SUMOylation of the farnesoid X receptor (FXR) regulates the expression of
RT FXR target genes.";
RL J. Biol. Chem. 288:13850-13862(2013).
RN [49]
RP MUTAGENESIS OF LYS-132; LYS-167; LYS-220; LYS-227; LYS-353 AND LYS-474, AND
RP INTERACTION WITH RXRA AND SETD7.
RX PubMed=23462506; DOI=10.1124/mol.113.084772;
RA Sun A.Q., Luo Y., Backos D.S., Xu S., Balasubramaniyan N., Reigan P.,
RA Suchy F.J.;
RT "Identification of functionally relevant lysine residues that modulate
RT human farnesoid X receptor activation.";
RL Mol. Pharmacol. 83:1078-1086(2013).
RN [50]
RP INVOLVEMENT IN PFIC5, VARIANT PFIC5 LYS-149 INS, CHARACTERIZATION OF
RP VARIANT PFIC5 LYS-149 INS (ISOFORM 4), AND FUNCTION (ISOFORM 4).
RX PubMed=26888176; DOI=10.1038/ncomms10713;
RA Gomez-Ospina N., Potter C.J., Xiao R., Manickam K., Kim M.S., Kim K.H.,
RA Shneider B.L., Picarsic J.L., Jacobson T.A., Zhang J., He W., Liu P.,
RA Knisely A.S., Finegold M.J., Muzny D.M., Boerwinkle E., Lupski J.R.,
RA Plon S.E., Gibbs R.A., Eng C.M., Yang Y., Washington G.C., Porteus M.H.,
RA Berquist W.E., Kambham N., Singh R.J., Xia F., Enns G.M., Moore D.D.;
RT "Mutations in the nuclear bile acid receptor FXR cause progressive familial
RT intrahepatic cholestasis.";
RL Nat. Commun. 7:10713-10713(2016).
RN [51]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 258-476 IN COMPLEX WITH SYNTHETIC
RP AGONIST FEXARAMINE, FUNCTION, AND INTERACTION WITH NCOA1.
RX PubMed=12718892; DOI=10.1016/s1097-2765(03)00104-7;
RA Downes M., Verdecia M.A., Roecker A.J., Hughes R., Hogenesch J.B.,
RA Kast-Woelbern H.R., Bowman M.E., Ferrer J.L., Anisfeld A.M., Edwards P.A.,
RA Rosenfeld J.M., Alvarez J.G., Noel J.P., Nicolaou K.C., Evans R.M.;
RT "A chemical, genetic, and structural analysis of the nuclear bile acid
RT receptor FXR.";
RL Mol. Cell 11:1079-1092(2003).
RN [52]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 241-469 IN COMPLEXES WITH
RP CHENODEOXYCHOLIC ACID ANALOGS AND NCOA2 COACTIVATOR PEPTIDE.
RX PubMed=12718893; DOI=10.1016/s1097-2765(03)00112-6;
RA Mi L.Z., Devarakonda S., Harp J.M., Han Q., Pellicciari R., Willson T.M.,
RA Khorasanizadeh S., Rastinejad F.;
RT "Structural basis for bile acid binding and activation of the nuclear
RT receptor FXR.";
RL Mol. Cell 11:1093-1100(2003).
RN [53]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 252-486 IN COMPLEX WITH SYNTHETIC
RP AGONIST, FUNCTION, AND INTERACTION WITH NCOA1.
RX PubMed=18621523; DOI=10.1016/j.bmcl.2008.06.073;
RA Akwabi-Ameyaw A., Bass J.Y., Caldwell R.D., Caravella J.A., Chen L.,
RA Creech K.L., Deaton D.N., Jones S.A., Kaldor I., Liu Y., Madauss K.P.,
RA Marr H.B., McFadyen R.B., Miller A.B., Iii F.N., Parks D.J., Spearing P.K.,
RA Todd D., Williams S.P., Wisely G.B.;
RT "Conformationally constrained farnesoid X receptor (FXR) agonists:
RT Naphthoic acid-based analogs of GW 4064.";
RL Bioorg. Med. Chem. Lett. 18:4339-4343(2008).
RN [54]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 249-486 IN COMPLEX WITH STEROID
RP ANALOG MFA-1 AND NCOA1 PEPTIDE, INTERACTION WITH NCOA1, AND DOMAIN.
RX PubMed=18391212; DOI=10.1073/pnas.0710981105;
RA Soisson S.M., Parthasarathy G., Adams A.D., Sahoo S., Sitlani A.,
RA Sparrow C., Cui J., Becker J.W.;
RT "Identification of a potent synthetic FXR agonist with an unexpected mode
RT of binding and activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:5337-5342(2008).
RN [55]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 260-486 IN COMPLEX WITH SYNTHETIC
RP AGONIST, FUNCTION, AND INTERACTION WITH NCOA1.
RX PubMed=19410460; DOI=10.1016/j.bmcl.2009.04.047;
RA Bass J.Y., Caldwell R.D., Caravella J.A., Chen L., Creech K.L.,
RA Deaton D.N., Madauss K.P., Marr H.B., McFadyen R.B., Miller A.B.,
RA Parks D.J., Todd D., Williams S.P., Wisely G.B.;
RT "Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist
RT GW4064.";
RL Bioorg. Med. Chem. Lett. 19:2969-2973(2009).
RN [56]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 257-486 IN COMPLEX WITH SYNTHETIC
RP AGONIST, FUNCTION, AND INTERACTION WITH NCOA1.
RX PubMed=19586769; DOI=10.1016/j.bmcl.2009.06.062;
RA Akwabi-Ameyaw A., Bass J.Y., Caldwell R.D., Caravella J.A., Chen L.,
RA Creech K.L., Deaton D.N., Madauss K.P., Marr H.B., McFadyen R.B.,
RA Miller A.B., Navas F. III, Parks D.J., Spearing P.K., Todd D.,
RA Williams S.P., Bruce Wisely G.;
RT "FXR agonist activity of conformationally constrained analogs of GW 4064.";
RL Bioorg. Med. Chem. Lett. 19:4733-4739(2009).
RN [57]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 258-486 IN COMPLEX WITH SYNTHETIC
RP AGONIST.
RX PubMed=19159286; DOI=10.1021/jm8014124;
RA Flatt B., Martin R., Wang T.L., Mahaney P., Murphy B., Gu X.H., Foster P.,
RA Li J., Pircher P., Petrowski M., Schulman I., Westin S., Wrobel J., Yan G.,
RA Bischoff E., Daige C., Mohan R.;
RT "Discovery of XL335 (WAY-362450), a highly potent, selective, and orally
RT active agonist of the farnesoid X receptor (FXR).";
RL J. Med. Chem. 52:904-907(2009).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 248-476 IN COMPLEX WITH SYNTHETIC
RP AGONIST.
RX PubMed=20095622; DOI=10.1021/jm901650u;
RA Lundquist J.T., Harnish D.C., Kim C.Y., Mehlmann J.F., Unwalla R.J.,
RA Phipps K.M., Crawley M.L., Commons T., Green D.M., Xu W., Hum W.T.,
RA Eta J.E., Feingold I., Patel V., Evans M.J., Lai K., Borges-Marcucci L.,
RA Mahaney P.E., Wrobel J.E.;
RT "Improvement of physiochemical properties of the tetrahydroazepinoindole
RT series of farnesoid X receptor (FXR) agonists: beneficial modulation of
RT lipids in primates.";
RL J. Med. Chem. 53:1774-1787(2010).
RN [59] {ECO:0007744|PDB:6A5Y}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 258-485 IN COMPLEX WITH RXRA;
RP SYNTHETIC AGONISTS AND NCOA1 PEPTIDE, AND MUTAGENESIS OF ARG-455.
RX PubMed=30275017; DOI=10.1074/jbc.ra118.004652;
RA Wang N., Zou Q., Xu J., Zhang J., Liu J.;
RT "Ligand binding and heterodimerization with retinoid X receptor alpha
RT (RXRalpha) induce farnesoid X receptor (FXR) conformational changes
RT affecting coactivator binding.";
RL J. Biol. Chem. 293:18180-18191(2018).
CC -!- FUNCTION: Ligand-activated transcription factor. Receptor for bile
CC acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid,
CC deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential
CC role in BA homeostasis through the regulation of genes involved in BA
CC synthesis, conjugation and enterohepatic circulation. Also regulates
CC lipid and glucose homeostasis and is involved innate immune response
CC (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415).
CC The FXR-RXR heterodimer binds predominantly to farnesoid X receptor
CC response elements (FXREs) containing two inverted repeats of the
CC consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1
CC nucleotide (IR-1) but also to tandem repeat DR1 sites with lower
CC affinity, and can be activated by either FXR or RXR-specific ligands.
CC It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1
CC bound to coregulatory nuclear responsive element (NRE) halfsites
CC located in close proximity to FXREs modulate transcriptional activity
CC (By similarity). In the liver activates transcription of the
CC corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1
CC (involved in BA synthesis) implicating at least in part histone
CC demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP
CC (involved in hepatic uptake of conjugated BAs). Activates transcription
CC of the repressor MAFG (involved in regulation of BA synthesis) (By
CC similarity). Activates transcription of SLC27A5/BACS and BAAT (involved
CC in BA conjugation), ABCB11/BSEP (involved in bile salt export) by
CC directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2
CC (involved in secretion of conjugated BAs) and ABCB4 (involved in
CC secretion of phosphatidylcholine in the small intestine)
CC (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates
CC transcription of SLC27A5/BACS and BAAT (involved in BA conjugation),
CC ABCB11/BSEP (involved in bile salt export) by directly recruiting
CC histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion
CC of conjugated BAs) and ABCB4 (involved in secretion of
CC phosphatidylcholine in the small intestine) (PubMed:10514450,
CC PubMed:15239098, PubMed:16269519). In the intestine activates FGF19
CC expression and secretion leading to hepatic CYP7A1 repression
CC (PubMed:12815072, PubMed:19085950). The function also involves the
CC coordinated induction of hepatic KLB/beta-klotho expression (By
CC similarity). Regulates transcription of liver UGT2B4 and SULT2A1
CC involved in BA detoxification; binding to the UGT2B4 promoter seems to
CC imply a monomeric transactivation independent of RXRA (PubMed:12806625,
CC PubMed:16946559). Modulates lipid homeostasis by activating liver
CC NR0B2/SHP-mediated repression of SREBF1 (involved in de novo
CC lipogenesis), expression of PLTP (involved in HDL formation), SCARB1
CC (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved
CC in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the
CC hepatic uptake of LDL and IDL remnants), and inhibiting expression of
CC MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753,
CC PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein
CC lipase activity implicated in triglyceride clearance)
CC (PubMed:11579204). Transrepresses APOA1 involving a monomeric
CC competition with NR2A1 for binding to a DR1 element (PubMed:11927623,
CC PubMed:21804189). Also reduces triglyceride clearance by inhibiting
CC expression of ANGPTL3 and APOC3 (both involved in inhibition of
CC lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis
CC by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-
CC mediated repression of respective genes. Modulates glycogen synthesis
CC (inducing phosphorylation of glycogen synthase kinase-3) (By
CC similarity). Modulates glucose-stimulated insulin secretion and is
CC involved in insulin resistance (PubMed:20447400). Involved in
CC intestinal innate immunity. Plays a role in protecting the distal small
CC intestine against bacterial overgrowth and preservation of the
CC epithelial barrier (By similarity). Down-regulates inflammatory
CC cytokine expression in several types of immune cells including
CC macrophages and mononuclear cells (PubMed:21242261). Mediates trans-
CC repression of TLR4-induced cytokine expression; the function seems to
CC require its sumoylation and prevents N-CoR nuclear receptor corepressor
CC clearance from target genes such as IL1B and NOS2 (PubMed:19864602).
CC Involved in the TLR9-mediated protective mechanism in intestinal
CC inflammation. Plays an anti-inflammatory role in liver inflammation;
CC proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B
CC signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641,
CC ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992,
CC ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450,
CC ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623,
CC ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231,
CC ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200,
CC ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072,
CC ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751,
CC ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761,
CC ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519,
CC ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379,
CC ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950,
CC ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769,
CC ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400,
CC ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189,
CC ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957,
CC ECO:0000305|PubMed:22820415}.
CC -!- FUNCTION: [Isoform 1]: Promotes transcriptional activation of target
CC genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB
CC (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity
CC for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not
CC inducible by taurine- and glycine-amidated CDCA.
CC {ECO:0000269|PubMed:23928191}.
CC -!- FUNCTION: [Isoform 2]: Promotes transcriptional activation of target
CC genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA),
CC NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB
CC (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible
CC by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}.
CC -!- FUNCTION: [Isoform 3]: Promotes transcriptional activation of target
CC genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB
CC (inducible by unconjugated CDCA and DCA) and IBAP; low activity for
CC ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not
CC inducible by taurine- and glycine-amidated CDCA.
CC {ECO:0000269|PubMed:23928191}.
CC -!- FUNCTION: [Isoform 4]: Promotes transcriptional activation of target
CC genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA),
CC NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB
CC (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient
CC isoform compared to isoforms 1 to 3; not inducible by taurine- and
CC glycine-amidated CDCA. {ECO:0000269|PubMed:23928191,
CC ECO:0000269|PubMed:26888176}.
CC -!- SUBUNIT: Heterodimer (via C-terminus) with RXRA (via DBD); the
CC heterodimerization enhances the binding affinity for LXXLL motifs from
CC coactivators (PubMed:23462506, PubMed:30275017). Binds DNA
CC predominantly as a heterodimer with RXRA. After activation by agonist
CC binding interacts with coactivators. Interacts with NCOA1, NCOA2,
CC PPARGC1A, CARM1, SETD7, PRMT1, GPS2, SMARCA4 and MED1 (PubMed:15202934,
CC PubMed:14684751, PubMed:15187081, PubMed:15471871, PubMed:15911693,
CC PubMed:17895379, PubMed:18755856, PubMed:19805516, PubMed:23462506,
CC PubMed:12718892, PubMed:12718893, PubMed:18621523, PubMed:18391212,
CC PubMed:19410460, PubMed:19586769). Interacts with EP300 and SMARCD1 (By
CC similarity). Interacts with XRCC5 and XRCC6; decreasing NR1H4/FXR
CC transactivation activity towards ABCB11/BSEP (PubMed:19833092).
CC Interacts with PAGR1 AND NCOA6; indicative for an association with an
CC MLL2/MLL3 complex (ASCOM) (PubMed:19556342).
CC {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735,
CC ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12718893,
CC ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15187081,
CC ECO:0000269|PubMed:15202934, ECO:0000269|PubMed:15471871,
CC ECO:0000269|PubMed:15911693, ECO:0000269|PubMed:17895379,
CC ECO:0000269|PubMed:18391212, ECO:0000269|PubMed:18621523,
CC ECO:0000269|PubMed:19159286, ECO:0000269|PubMed:19410460,
CC ECO:0000269|PubMed:19556342, ECO:0000269|PubMed:19586769,
CC ECO:0000269|PubMed:19805516, ECO:0000269|PubMed:19833092,
CC ECO:0000269|PubMed:23462506, ECO:0000269|PubMed:30275017}.
CC -!- INTERACTION:
CC Q96RI1; Q15788: NCOA1; NbExp=4; IntAct=EBI-1250177, EBI-455189;
CC Q96RI1; Q8WTS6: SETD7; NbExp=5; IntAct=EBI-1250177, EBI-1268586;
CC Q96RI1-1; P28702: RXRB; NbExp=7; IntAct=EBI-12417284, EBI-748576;
CC Q96RI1-1; P28702-3: RXRB; NbExp=3; IntAct=EBI-12417284, EBI-16429492;
CC Q96RI1-1; P48443: RXRG; NbExp=3; IntAct=EBI-12417284, EBI-712405;
CC Q96RI1-2; Q15788: NCOA1; NbExp=5; IntAct=EBI-9640524, EBI-455189;
CC Q96RI1-2; P78527: PRKDC; NbExp=4; IntAct=EBI-9640524, EBI-352053;
CC Q96RI1-3; P03372: ESR1; NbExp=2; IntAct=EBI-10921781, EBI-78473;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:19864602}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Nucleus
CC {ECO:0000269|PubMed:23928191}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:23928191}.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Nucleus
CC {ECO:0000269|PubMed:23928191}.
CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Nucleus
CC {ECO:0000269|PubMed:23928191}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=FXRalpha2(+), FXRalpha1, FXRbeta1;
CC IsoId=Q96RI1-3; Sequence=Displayed;
CC Name=2; Synonyms=FXRalpha2(-), FXRalpha4, FXRbeta2;
CC IsoId=Q96RI1-4; Sequence=VSP_003665;
CC Name=3; Synonyms=FXRalpha1(+), FXRalpha1;
CC IsoId=Q96RI1-1; Sequence=VSP_010135;
CC Name=4; Synonyms=FXRalpha1(-), FXRalpha2;
CC IsoId=Q96RI1-2; Sequence=VSP_010135, VSP_003665;
CC Name=5;
CC IsoId=Q96RI1-5; Sequence=VSP_010135, VSP_044547;
CC -!- TISSUE SPECIFICITY: Liver and hepatocyte-related cells express mainly
CC FXRalpha1-type isoforms with isoform 3 and isoform 4 in approximately
CC equal proportions. In intestine and kidney mainly FXRalpha2-type
CC isoforms are expressed with isoform 1 and isoform 2 in approximately
CC equal proportions. Expressed in pancreatic beta cells and macrophages.
CC {ECO:0000269|PubMed:19393742, ECO:0000269|PubMed:19864602,
CC ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:23928191}.
CC -!- PTM: Acetylated by EP300. Lys-227 as is the major acetylation site for
CC EP300; the dynamicly regulated acetylation inhibits heterodimerization
CC with RXRA and transactivation activity. Deacetylated by SIRT1.
CC {ECO:0000269|PubMed:18755856}.
CC -!- PTM: Methylation may increase transactivation of target genes.
CC {ECO:0000269|PubMed:22345554}.
CC -!- PTM: Phosphorylation by PKC/PRKCA increases transactivation activity by
CC promoting association with PPARGC1A. {ECO:0000269|PubMed:18755856}.
CC -!- PTM: Sumoylated upon ligand binding. {ECO:0000269|PubMed:19864602,
CC ECO:0000269|PubMed:23546875}.
CC -!- DISEASE: Note=May be involved in intrahepatic cholestasis of pregnancy.
CC {ECO:0000305|PubMed:17681172}.
CC -!- DISEASE: Note=May be involved in cholesterol cholelithiasis.
CC {ECO:0000305|PubMed:17931734}.
CC -!- DISEASE: Cholestasis, progressive familial intrahepatic, 5 (PFIC5)
CC [MIM:617049]: A disorder characterized by early onset of cholestasis
CC that progresses to hepatic fibrosis, cirrhosis, and end-stage liver
CC disease before adulthood. PFIC5 is an autosomal recessive, severe form
CC characterized by onset of intralobular cholestasis in the neonatal
CC period. {ECO:0000269|PubMed:26888176}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Ursodeoxycholic acid (UDCA), a natural agonist of FXR,
CC is approved to treat primary biliary cirrhosis. However, effects are
CC discussed controversial. UDCA is also used to dissolve (cholesterol)
CC gallstones as alternative to surgery. {ECO:0000305|PubMed:23235576}.
CC -!- MISCELLANEOUS: [Isoform 1]: Produced by alternative promoter usage.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative splicing of isoform
CC 1. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Produced by alternative splicing of isoform
CC 3. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: Produced by alternative splicing of isoform
CC 3. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BC144183; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Farnesoid X receptor entry;
CC URL="https://en.wikipedia.org/wiki/Farnesoid_X_receptor";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U68233; AAB08107.1; -; mRNA.
DR EMBL; AF384555; AAK60271.1; -; mRNA.
DR EMBL; AF478445; AAM53550.1; -; mRNA.
DR EMBL; AF478446; AAM53551.1; -; mRNA.
DR EMBL; AK296612; BAH12398.1; -; mRNA.
DR EMBL; AC010200; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471054; EAW97639.1; -; Genomic_DNA.
DR EMBL; BC144183; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC144184; AAI44185.1; -; mRNA.
DR EMBL; BC130573; AAI30574.1; -; mRNA.
DR CCDS; CCDS55873.1; -. [Q96RI1-1]
DR CCDS; CCDS55874.1; -. [Q96RI1-5]
DR CCDS; CCDS55875.1; -. [Q96RI1-4]
DR CCDS; CCDS55876.1; -. [Q96RI1-3]
DR CCDS; CCDS9078.1; -. [Q96RI1-2]
DR RefSeq; NP_001193906.1; NM_001206977.1. [Q96RI1-1]
DR RefSeq; NP_001193907.1; NM_001206978.1. [Q96RI1-5]
DR RefSeq; NP_001193908.1; NM_001206979.1. [Q96RI1-1]
DR RefSeq; NP_001193921.1; NM_001206992.1. [Q96RI1-4]
DR RefSeq; NP_001193922.1; NM_001206993.1. [Q96RI1-3]
DR RefSeq; NP_005114.1; NM_005123.3. [Q96RI1-2]
DR RefSeq; XP_011537342.1; XM_011539040.2. [Q96RI1-1]
DR PDB; 1OSH; X-ray; 1.80 A; A=258-486.
DR PDB; 3BEJ; X-ray; 1.90 A; A/B=249-486.
DR PDB; 3DCT; X-ray; 2.50 A; A=252-486.
DR PDB; 3DCU; X-ray; 2.95 A; A=252-486.
DR PDB; 3FLI; X-ray; 2.00 A; A=258-486.
DR PDB; 3FXV; X-ray; 2.26 A; A=258-486.
DR PDB; 3GD2; X-ray; 3.20 A; A=260-486.
DR PDB; 3HC5; X-ray; 2.60 A; A=257-486.
DR PDB; 3HC6; X-ray; 3.20 A; A=257-486.
DR PDB; 3L1B; X-ray; 1.90 A; A=258-486.
DR PDB; 3OKH; X-ray; 2.50 A; A=258-486.
DR PDB; 3OKI; X-ray; 2.00 A; A/C=258-486.
DR PDB; 3OLF; X-ray; 1.90 A; A/C=258-486.
DR PDB; 3OMK; X-ray; 1.90 A; A/C=258-486.
DR PDB; 3OMM; X-ray; 2.10 A; A/C=258-486.
DR PDB; 3OOF; X-ray; 2.29 A; A/C=258-486.
DR PDB; 3OOK; X-ray; 2.29 A; A/C=258-486.
DR PDB; 3P88; X-ray; 2.95 A; A=258-486.
DR PDB; 3P89; X-ray; 2.30 A; A=258-486.
DR PDB; 3RUT; X-ray; 3.00 A; A=258-486.
DR PDB; 3RUU; X-ray; 2.50 A; A=258-486.
DR PDB; 3RVF; X-ray; 3.10 A; A=257-486.
DR PDB; 4OIV; X-ray; 1.70 A; A/B=258-483.
DR PDB; 4QE6; X-ray; 1.65 A; A=258-486.
DR PDB; 4QE8; X-ray; 2.62 A; A/B=258-486.
DR PDB; 4WVD; X-ray; 2.90 A; A/B=258-468.
DR PDB; 5IAW; X-ray; 2.58 A; A/B=259-486.
DR PDB; 5ICK; X-ray; 2.47 A; A/B=258-486.
DR PDB; 5Q0I; X-ray; 1.70 A; A=258-486.
DR PDB; 5Q0J; X-ray; 2.00 A; A/C=258-486.
DR PDB; 5Q0K; X-ray; 1.80 A; A=258-486.
DR PDB; 5Q0L; X-ray; 2.50 A; A/C=258-486.
DR PDB; 5Q0M; X-ray; 2.20 A; A=258-486.
DR PDB; 5Q0N; X-ray; 2.40 A; A/C=258-486.
DR PDB; 5Q0O; X-ray; 1.90 A; A/C=258-486.
DR PDB; 5Q0P; X-ray; 1.80 A; A/C=258-486.
DR PDB; 5Q0Q; X-ray; 2.60 A; A/C=258-486.
DR PDB; 5Q0R; X-ray; 1.91 A; A=258-486.
DR PDB; 5Q0S; X-ray; 2.50 A; A/C=258-486.
DR PDB; 5Q0T; X-ray; 2.14 A; A=258-486.
DR PDB; 5Q0U; X-ray; 1.90 A; A/C=258-486.
DR PDB; 5Q0V; X-ray; 1.87 A; A/C=258-486.
DR PDB; 5Q0W; X-ray; 1.90 A; A=258-486.
DR PDB; 5Q0X; X-ray; 2.26 A; A=258-486.
DR PDB; 5Q0Y; X-ray; 2.20 A; A/C=258-486.
DR PDB; 5Q0Z; X-ray; 2.26 A; A/C=258-486.
DR PDB; 5Q10; X-ray; 2.20 A; A=258-486.
DR PDB; 5Q11; X-ray; 2.20 A; A=258-486.
DR PDB; 5Q12; X-ray; 2.00 A; A=258-486.
DR PDB; 5Q13; X-ray; 1.90 A; A/C=258-486.
DR PDB; 5Q14; X-ray; 1.85 A; A/C=258-486.
DR PDB; 5Q15; X-ray; 1.90 A; A/C=258-486.
DR PDB; 5Q16; X-ray; 2.00 A; A/C=258-486.
DR PDB; 5Q17; X-ray; 2.10 A; A=258-486.
DR PDB; 5Q18; X-ray; 1.90 A; A/C=258-486.
DR PDB; 5Q19; X-ray; 1.98 A; A/C=258-486.
DR PDB; 5Q1A; X-ray; 2.00 A; A/C=258-486.
DR PDB; 5Q1B; X-ray; 2.30 A; A/C=258-486.
DR PDB; 5Q1C; X-ray; 2.30 A; A/C=258-486.
DR PDB; 5Q1D; X-ray; 1.89 A; A/C=258-486.
DR PDB; 5Q1E; X-ray; 1.85 A; A=258-486.
DR PDB; 5Q1F; X-ray; 2.30 A; A/C=258-486.
DR PDB; 5Q1G; X-ray; 2.00 A; A=258-486.
DR PDB; 5Q1H; X-ray; 2.20 A; A/C/E/G=258-486.
DR PDB; 5Q1I; X-ray; 1.95 A; A=258-486.
DR PDB; 5WZX; X-ray; 2.95 A; A/B=258-485.
DR PDB; 5Y1J; X-ray; 2.00 A; A=258-485.
DR PDB; 5Y44; X-ray; 2.35 A; A=258-485.
DR PDB; 5Y49; X-ray; 2.40 A; A/B=259-485.
DR PDB; 5YXB; X-ray; 2.95 A; A=258-486.
DR PDB; 5YXD; X-ray; 2.98 A; A=258-486.
DR PDB; 5YXJ; X-ray; 2.62 A; A/B=258-486.
DR PDB; 5YXL; X-ray; 2.24 A; A/C=258-486.
DR PDB; 5Z12; X-ray; 2.75 A; A/D=259-486.
DR PDB; 6A5W; X-ray; 2.88 A; A/C=258-485.
DR PDB; 6A5X; X-ray; 2.60 A; A=258-486.
DR PDB; 6A5Y; X-ray; 2.10 A; A=258-485.
DR PDB; 6A5Z; X-ray; 2.95 A; A/H=258-486.
DR PDB; 6A60; X-ray; 3.05 A; A=258-486.
DR PDB; 6HL0; X-ray; 1.66 A; A=258-486.
DR PDB; 6HL1; X-ray; 1.60 A; A=258-486.
DR PDB; 6ITM; X-ray; 2.50 A; A/C=257-486.
DR PDB; 7D42; X-ray; 2.70 A; A=258-484.
DR PDB; 7VUE; X-ray; 2.60 A; A=259-484.
DR PDBsum; 1OSH; -.
DR PDBsum; 3BEJ; -.
DR PDBsum; 3DCT; -.
DR PDBsum; 3DCU; -.
DR PDBsum; 3FLI; -.
DR PDBsum; 3FXV; -.
DR PDBsum; 3GD2; -.
DR PDBsum; 3HC5; -.
DR PDBsum; 3HC6; -.
DR PDBsum; 3L1B; -.
DR PDBsum; 3OKH; -.
DR PDBsum; 3OKI; -.
DR PDBsum; 3OLF; -.
DR PDBsum; 3OMK; -.
DR PDBsum; 3OMM; -.
DR PDBsum; 3OOF; -.
DR PDBsum; 3OOK; -.
DR PDBsum; 3P88; -.
DR PDBsum; 3P89; -.
DR PDBsum; 3RUT; -.
DR PDBsum; 3RUU; -.
DR PDBsum; 3RVF; -.
DR PDBsum; 4OIV; -.
DR PDBsum; 4QE6; -.
DR PDBsum; 4QE8; -.
DR PDBsum; 4WVD; -.
DR PDBsum; 5IAW; -.
DR PDBsum; 5ICK; -.
DR PDBsum; 5Q0I; -.
DR PDBsum; 5Q0J; -.
DR PDBsum; 5Q0K; -.
DR PDBsum; 5Q0L; -.
DR PDBsum; 5Q0M; -.
DR PDBsum; 5Q0N; -.
DR PDBsum; 5Q0O; -.
DR PDBsum; 5Q0P; -.
DR PDBsum; 5Q0Q; -.
DR PDBsum; 5Q0R; -.
DR PDBsum; 5Q0S; -.
DR PDBsum; 5Q0T; -.
DR PDBsum; 5Q0U; -.
DR PDBsum; 5Q0V; -.
DR PDBsum; 5Q0W; -.
DR PDBsum; 5Q0X; -.
DR PDBsum; 5Q0Y; -.
DR PDBsum; 5Q0Z; -.
DR PDBsum; 5Q10; -.
DR PDBsum; 5Q11; -.
DR PDBsum; 5Q12; -.
DR PDBsum; 5Q13; -.
DR PDBsum; 5Q14; -.
DR PDBsum; 5Q15; -.
DR PDBsum; 5Q16; -.
DR PDBsum; 5Q17; -.
DR PDBsum; 5Q18; -.
DR PDBsum; 5Q19; -.
DR PDBsum; 5Q1A; -.
DR PDBsum; 5Q1B; -.
DR PDBsum; 5Q1C; -.
DR PDBsum; 5Q1D; -.
DR PDBsum; 5Q1E; -.
DR PDBsum; 5Q1F; -.
DR PDBsum; 5Q1G; -.
DR PDBsum; 5Q1H; -.
DR PDBsum; 5Q1I; -.
DR PDBsum; 5WZX; -.
DR PDBsum; 5Y1J; -.
DR PDBsum; 5Y44; -.
DR PDBsum; 5Y49; -.
DR PDBsum; 5YXB; -.
DR PDBsum; 5YXD; -.
DR PDBsum; 5YXJ; -.
DR PDBsum; 5YXL; -.
DR PDBsum; 5Z12; -.
DR PDBsum; 6A5W; -.
DR PDBsum; 6A5X; -.
DR PDBsum; 6A5Y; -.
DR PDBsum; 6A5Z; -.
DR PDBsum; 6A60; -.
DR PDBsum; 6HL0; -.
DR PDBsum; 6HL1; -.
DR PDBsum; 6ITM; -.
DR PDBsum; 7D42; -.
DR PDBsum; 7VUE; -.
DR AlphaFoldDB; Q96RI1; -.
DR SMR; Q96RI1; -.
DR BioGRID; 115296; 28.
DR DIP; DIP-39370N; -.
DR IntAct; Q96RI1; 14.
DR MINT; Q96RI1; -.
DR STRING; 9606.ENSP00000447149; -.
DR BindingDB; Q96RI1; -.
DR ChEMBL; CHEMBL2047; -.
DR DrugBank; DB08220; (8alpha,10alpha,13alpha,17beta)-17-[(4-hydroxyphenyl)carbonyl]androsta-3,5-diene-3-carboxylic acid.
DR DrugBank; DB00132; alpha-Linolenic acid.
DR DrugBank; DB04557; Arachidonic Acid.
DR DrugBank; DB06777; Chenodeoxycholic acid.
DR DrugBank; DB02659; Cholic Acid.
DR DrugBank; DB03619; Deoxycholic acid.
DR DrugBank; DB02509; Farnesol.
DR DrugBank; DB02545; Fexaramine.
DR DrugBank; DB11605; Myrrh.
DR DrugBank; DB05990; Obeticholic acid.
DR DrugBank; DB04348; Taurocholic acid.
DR DrugBank; DB16343; Tropifexor.
DR DrugBank; DB01586; Ursodeoxycholic acid.
DR DrugCentral; Q96RI1; -.
DR GuidetoPHARMACOLOGY; 603; -.
DR SwissLipids; SLP:000001581; -.
DR iPTMnet; Q96RI1; -.
DR PhosphoSitePlus; Q96RI1; -.
DR BioMuta; NR1H4; -.
DR DMDM; 46577705; -.
DR jPOST; Q96RI1; -.
DR MassIVE; Q96RI1; -.
DR PaxDb; Q96RI1; -.
DR PeptideAtlas; Q96RI1; -.
DR PRIDE; Q96RI1; -.
DR ProteomicsDB; 29204; -.
DR ProteomicsDB; 77963; -. [Q96RI1-3]
DR ProteomicsDB; 77964; -. [Q96RI1-1]
DR ProteomicsDB; 77965; -. [Q96RI1-2]
DR ProteomicsDB; 77966; -. [Q96RI1-4]
DR Antibodypedia; 17868; 447 antibodies from 37 providers.
DR DNASU; 9971; -.
DR Ensembl; ENST00000188403.7; ENSP00000188403.7; ENSG00000012504.15. [Q96RI1-4]
DR Ensembl; ENST00000392986.8; ENSP00000376712.3; ENSG00000012504.15. [Q96RI1-1]
DR Ensembl; ENST00000548884.5; ENSP00000448506.1; ENSG00000012504.15. [Q96RI1-2]
DR Ensembl; ENST00000549996.5; ENSP00000448978.1; ENSG00000012504.15. [Q96RI1-5]
DR Ensembl; ENST00000551379.5; ENSP00000447149.1; ENSG00000012504.15. [Q96RI1-3]
DR Ensembl; ENST00000648861.1; ENSP00000496908.1; ENSG00000012504.15. [Q96RI1-1]
DR GeneID; 9971; -.
DR KEGG; hsa:9971; -.
DR MANE-Select; ENST00000392986.8; ENSP00000376712.3; NM_001206979.2; NP_001193908.1. [Q96RI1-1]
DR UCSC; uc001thp.3; human. [Q96RI1-3]
DR CTD; 9971; -.
DR DisGeNET; 9971; -.
DR GeneCards; NR1H4; -.
DR HGNC; HGNC:7967; NR1H4.
DR HPA; ENSG00000012504; Tissue enhanced (intestine, liver).
DR MalaCards; NR1H4; -.
DR MIM; 603826; gene.
DR MIM; 617049; phenotype.
DR neXtProt; NX_Q96RI1; -.
DR OpenTargets; ENSG00000012504; -.
DR Orphanet; 69665; Intrahepatic cholestasis of pregnancy.
DR Orphanet; 480476; Progressive familial intrahepatic cholestasis type 5.
DR PharmGKB; PA31752; -.
DR VEuPathDB; HostDB:ENSG00000012504; -.
DR eggNOG; KOG3575; Eukaryota.
DR GeneTree; ENSGT00940000158037; -.
DR HOGENOM; CLU_007368_12_3_1; -.
DR InParanoid; Q96RI1; -.
DR OMA; IPSETFF; -.
DR OrthoDB; 1137281at2759; -.
DR PhylomeDB; Q96RI1; -.
DR TreeFam; TF316304; -.
DR PathwayCommons; Q96RI1; -.
DR Reactome; R-HSA-159418; Recycling of bile acids and salts.
DR Reactome; R-HSA-192105; Synthesis of bile acids and bile salts.
DR Reactome; R-HSA-193368; Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
DR Reactome; R-HSA-193807; Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-211976; Endogenous sterols.
DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway.
DR Reactome; R-HSA-4090294; SUMOylation of intracellular receptors. [Q96RI1-2]
DR SignaLink; Q96RI1; -.
DR SIGNOR; Q96RI1; -.
DR BioGRID-ORCS; 9971; 7 hits in 1093 CRISPR screens.
DR ChiTaRS; NR1H4; human.
DR EvolutionaryTrace; Q96RI1; -.
DR GeneWiki; Farnesoid_X_receptor; -.
DR GenomeRNAi; 9971; -.
DR Pharos; Q96RI1; Tclin.
DR PRO; PR:Q96RI1; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q96RI1; protein.
DR Bgee; ENSG00000012504; Expressed in right lobe of liver and 109 other tissues.
DR ExpressionAtlas; Q96RI1; baseline and differential.
DR Genevisible; Q96RI1; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0000791; C:euchromatin; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0043235; C:receptor complex; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; ISS:BHF-UCL.
DR GO; GO:0038181; F:bile acid receptor activity; IDA:UniProtKB.
DR GO; GO:1902122; F:chenodeoxycholic acid binding; IDA:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL.
DR GO; GO:0004879; F:nuclear receptor activity; IDA:ParkinsonsUK-UCL.
DR GO; GO:0016922; F:nuclear receptor binding; TAS:BHF-UCL.
DR GO; GO:0046965; F:nuclear retinoid X receptor binding; IEA:Ensembl.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IMP:UniProtKB.
DR GO; GO:0001221; F:transcription coregulator binding; IPI:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0008206; P:bile acid metabolic process; IEA:Ensembl.
DR GO; GO:0038183; P:bile acid signaling pathway; ISS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0007043; P:cell-cell junction assembly; IEA:Ensembl.
DR GO; GO:0001678; P:cellular glucose homeostasis; IEA:Ensembl.
DR GO; GO:1903413; P:cellular response to bile acid; IDA:UniProtKB.
DR GO; GO:0071398; P:cellular response to fatty acid; IDA:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0071417; P:cellular response to organonitrogen compound; ISS:BHF-UCL.
DR GO; GO:0035356; P:cellular triglyceride homeostasis; IDA:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:0055089; P:fatty acid homeostasis; IEA:Ensembl.
DR GO; GO:0034971; P:histone H3-R17 methylation; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0038185; P:intracellular bile acid receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0030522; P:intracellular receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IBA:GO_Central.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IDA:UniProtKB.
DR GO; GO:0032692; P:negative regulation of interleukin-1 production; IEA:Ensembl.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0071638; P:negative regulation of monocyte chemotactic protein-1 production; IEA:Ensembl.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IDA:UniProtKB.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0010903; P:negative regulation of very-low-density lipoprotein particle remodeling; IDA:MGI.
DR GO; GO:0001080; P:nitrogen catabolite activation of transcription from RNA polymerase II promoter; IC:BHF-UCL.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:Ensembl.
DR GO; GO:1904179; P:positive regulation of adipose tissue development; IEA:Ensembl.
DR GO; GO:2001250; P:positive regulation of ammonia assimilation cycle; IEA:Ensembl.
DR GO; GO:2000213; P:positive regulation of glutamate metabolic process; ISS:BHF-UCL.
DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:UniProtKB.
DR GO; GO:1905695; P:positive regulation of phosphatidic acid biosynthetic process; IDA:ParkinsonsUK-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MGI.
DR GO; GO:0070857; P:regulation of bile acid biosynthetic process; TAS:BHF-UCL.
DR GO; GO:0090181; P:regulation of cholesterol metabolic process; TAS:BHF-UCL.
DR GO; GO:0061178; P:regulation of insulin secretion involved in cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0010988; P:regulation of low-density lipoprotein particle clearance; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0034255; P:regulation of urea metabolic process; ISS:BHF-UCL.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProtKB.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; IEA:Ensembl.
DR GO; GO:0006366; P:transcription by RNA polymerase II; IEA:Ensembl.
DR CDD; cd06936; NR_LBD_Fxr; 1.
DR DisProt; DP01914; -.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR IDEAL; IID00391; -.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR044114; NR_LBD_NR1H4.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001728; ThyrH_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR PRINTS; PR00546; THYROIDHORMR.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Activator; Alternative promoter usage;
KW Alternative splicing; Disease variant; DNA-binding; Immunity;
KW Inflammatory response; Innate immunity; Intrahepatic cholestasis;
KW Isopeptide bond; Metal-binding; Methylation; Nucleus; Phosphoprotein;
KW Receptor; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..486
FT /note="Bile acid receptor"
FT /id="PRO_0000053538"
FT DOMAIN 262..486
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 134..209
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 137..157
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 173..197
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT BINDING 345
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0007744|PDB:4QE6"
FT BINDING 375
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0007744|PDB:4QE6"
FT BINDING 383
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0007744|PDB:4QE6"
FT BINDING 461
FT /ligand="chenodeoxycholate"
FT /ligand_id="ChEBI:CHEBI:36234"
FT /ligand_note="agonist"
FT /evidence="ECO:0007744|PDB:4QE6"
FT MOD_RES 145
FT /note="Phosphoserine; by PKC/PRKCA"
FT /evidence="ECO:0000269|PubMed:18755856"
FT MOD_RES 164
FT /note="Phosphoserine; by PKC/PRKCA"
FT /evidence="ECO:0000269|PubMed:18755856"
FT MOD_RES 167
FT /note="N6-acetyllysine; by EP300"
FT MOD_RES 220
FT /note="N6-methyllysine; by SETD7"
FT /evidence="ECO:0000269|PubMed:22345554"
FT MOD_RES 227
FT /note="N6-acetyllysine; by EP300"
FT MOD_RES 456
FT /note="Phosphothreonine; by PKC/PRKCZ"
FT /evidence="ECO:0000305|PubMed:18668687"
FT CROSSLNK 132
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000305|PubMed:23546875"
FT CROSSLNK 289
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO1)"
FT /evidence="ECO:0000305|PubMed:23546875"
FT VAR_SEQ 1..36
FT /note="MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAK -> MGSKMNLIEHSH
FT LPTTDEFSFSENLF (in isoform 3, isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.1,
FT ECO:0000303|Ref.2"
FT /id="VSP_010135"
FT VAR_SEQ 159..209
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044547"
FT VAR_SEQ 207..210
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:12062799, ECO:0000303|Ref.2"
FT /id="VSP_003665"
FT VARIANT 149
FT /note="Y -> YK (in PFIC5; loss of isoform 4 transcription
FT regulatory region sequence-specific DNA binding activity;
FT loss of isoform 4 function in regulation of transcription
FT DNA-templated)"
FT /evidence="ECO:0000269|PubMed:26888176"
FT /id="VAR_077017"
FT MUTAGEN 132
FT /note="K->R: Abrogates SUMO1-mediated inhibition of ligand-
FT induced transcactivation at ABCB11/BSEP and NR0B2/SHP
FT promoters; when associated with R-289 and A-291."
FT /evidence="ECO:0000269|PubMed:23546875"
FT MUTAGEN 132
FT /note="K->R: Decreases transcriptional activation
FT SLC51A/OSTA, SLC51B/OSTB and ABCB11/BSEP, no effect on
FT interaction with RXRA and SETD7."
FT /evidence="ECO:0000269|PubMed:23462506"
FT MUTAGEN 145
FT /note="S->A: Impairs ligand-dependent transactivation
FT activity, impairs interaction with PPARGC1A; when
FT associated with A-164."
FT /evidence="ECO:0000269|PubMed:18755856"
FT MUTAGEN 164
FT /note="S->A: Impairs ligand-dependent transactivation
FT activity, impairs interaction with PPARGC1A; when
FT associated with A-145."
FT /evidence="ECO:0000269|PubMed:18755856"
FT MUTAGEN 167
FT /note="K->R: Decreases transcriptional activation of
FT SLC51B/OSTB, no effect on SLC51A/OSTA and ABCB11/BSEP, no
FT effect on interaction with RXRA and SETD7."
FT /evidence="ECO:0000269|PubMed:23462506"
FT MUTAGEN 220
FT /note="K->R: Decreases transcriptional activation of
FT SLC51B/OSTB, no effect on SLC51A/OSTA and ABCB11/BSEP,
FT impairs interaction with RXRA and SETD7."
FT /evidence="ECO:0000269|PubMed:23462506"
FT MUTAGEN 227
FT /note="K->R: Decreases transcriptional activation
FT SC51A/OSTA, SLC51B/OSTB and ABCB11/BSEP, impairs
FT interaction with RXRA and enhances interaction with SETD7,
FT decreases association with ABCB11/BSEP promoter."
FT /evidence="ECO:0000269|PubMed:23462506"
FT MUTAGEN 289
FT /note="K->R: Abrogates SUMO1-mediated inhibition of ligand-
FT induced transcactivation at ABCB11/BSEP and NR0B2/SHP
FT promoters; when associated with R-132 and A-291."
FT /evidence="ECO:0000269|PubMed:23546875"
FT MUTAGEN 291
FT /note="E->A: Abrogates SUMO1-mediated inhibition of ligand-
FT induced transcactivation at ABCB11/BSEP and NR0B2/SHP
FT promoters; when associated with R-132 and R-289."
FT /evidence="ECO:0000269|PubMed:23546875"
FT MUTAGEN 353
FT /note="K->R: Decreases transcriptional activation
FT SLC51A/OSTA, SLC51B/OSTB and ABCB11/BSEP, no effect on
FT interaction with RXRA and SETD7, decreases association with
FT ABCB11/BSEP promoter."
FT /evidence="ECO:0000269|PubMed:23462506"
FT MUTAGEN 455
FT /note="R->S: As a heterodimer with RXRA, impaired
FT transcriptional activity."
FT /evidence="ECO:0000269|PubMed:30275017"
FT MUTAGEN 456
FT /note="T->A: Impairs transcriptional activation of
FT ABCB11/BSEP."
FT /evidence="ECO:0000269|PubMed:18668687"
FT MUTAGEN 474
FT /note="K->R: Decreases transcriptional activation
FT SLC51A/OSTA, SLC51B/OSTB and ABCB11/BSEP, no effect on
FT interaction with RXRA and impairs interaction with SETD7."
FT /evidence="ECO:0000269|PubMed:23462506"
FT CONFLICT 198
FT /note="K -> R (in Ref. 7; AAI44185)"
FT /evidence="ECO:0000305"
FT CONFLICT 217
FT /note="C -> V (in Ref. 7; BC144183)"
FT /evidence="ECO:0000305"
FT HELIX 261..274
FT /evidence="ECO:0007829|PDB:6HL1"
FT HELIX 281..289
FT /evidence="ECO:0007829|PDB:6HL1"
FT HELIX 294..317
FT /evidence="ECO:0007829|PDB:6HL1"
FT HELIX 322..324
FT /evidence="ECO:0007829|PDB:6HL1"
FT HELIX 327..349
FT /evidence="ECO:0007829|PDB:6HL1"
FT STRAND 350..353
FT /evidence="ECO:0007829|PDB:5YXD"
FT TURN 354..356
FT /evidence="ECO:0007829|PDB:4OIV"
FT STRAND 357..359
FT /evidence="ECO:0007829|PDB:5Y49"
FT HELIX 360..367
FT /evidence="ECO:0007829|PDB:6HL1"
FT STRAND 369..371
FT /evidence="ECO:0007829|PDB:5Q0I"
FT HELIX 373..387
FT /evidence="ECO:0007829|PDB:6HL1"
FT TURN 388..390
FT /evidence="ECO:0007829|PDB:4OIV"
FT HELIX 393..404
FT /evidence="ECO:0007829|PDB:6HL1"
FT STRAND 409..411
FT /evidence="ECO:0007829|PDB:5Q0I"
FT HELIX 415..436
FT /evidence="ECO:0007829|PDB:6HL1"
FT STRAND 438..440
FT /evidence="ECO:0007829|PDB:6A5X"
FT HELIX 443..465
FT /evidence="ECO:0007829|PDB:6HL1"
FT HELIX 470..472
FT /evidence="ECO:0007829|PDB:6HL0"
FT HELIX 477..483
FT /evidence="ECO:0007829|PDB:6HL1"
SQ SEQUENCE 486 AA; 55914 MW; C23283576A8CF76B CRC64;
MVMQFQGLEN PIQISPHCSC TPSGFFMEMM SMKPAKGVLT EQVAGPLGQN LEVEPYSQYS
NVQFPQVQPQ ISSSSYYSNL GFYPQQPEEW YSPGIYELRR MPAETLYQGE TEVAEMPVTK
KPRMGASAGR IKGDELCVVC GDRASGYHYN ALTCEGCKGF FRRSITKNAV YKCKNGGNCV
MDMYMRRKCQ ECRLRKCKEM GMLAECMYTG LLTEIQCKSK RLRKNVKQHA DQTVNEDSEG
RDLRQVTSTT KSCREKTELT PDQQTLLHFI MDSYNKQRMP QEITNKILKE EFSAEENFLI
LTEMATNHVQ VLVEFTKKLP GFQTLDHEDQ IALLKGSAVE AMFLRSAEIF NKKLPSGHSD
LLEERIRNSG ISDEYITPMF SFYKSIGELK MTQEEYALLT AIVILSPDRQ YIKDREAVEK
LQEPLLDVLQ KLCKIHQPEN PQHFACLLGR LTELRTFNHH HAEMLMSWRV NDHKFTPLLC
EIWDVQ
