Bile acid receptor

NameBile acid receptor
Synonyms
  • BAR
  • Farnesoid X-activated receptor
  • Farnesol receptor HRR-1
  • FXR
  • HRR1
  • Nuclear receptor subfamily 1 group H member 4
  • Retinoid X receptor-interacting protein 14
  • RIP14
  • RXR-interacting protein 14
Gene NameNR1H4
OrganismHuman
Amino acid sequence
>lcl|BSEQ0003523|Bile acid receptor
MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAKGVLTEQVAGPLGQNLEVEPYSQYS
NVQFPQVQPQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTK
KPRMGASAGRIKGDELCVVCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCV
MDMYMRRKCQECRLRKCKEMGMLAECMYTGLLTEIQCKSKRLRKNVKQHADQTVNEDSEG
RDLRQVTSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLI
LTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSD
LLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEK
LQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLC
EIWDVQ
Number of residues486
Molecular Weight55913.915
Theoretical pI6.81
GO Classification
Functions
  • bile acid receptor activity
  • chenodeoxycholic acid binding
  • bile acid binding
  • ligand-dependent nuclear receptor binding
  • RNA polymerase II distal enhancer sequence-specific DNA binding
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding
  • transcription corepressor activity
  • transcriptional activator activity, RNA polymerase II transcription factor binding
  • transcription factor activity, sequence-specific DNA binding
  • zinc ion binding
  • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding
  • steroid hormone receptor activity
  • thyroid hormone receptor activity
  • sequence-specific DNA binding
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
  • transcription coactivator activity
Processes
  • gene expression
  • regulation of urea metabolic process
  • regulation of cholesterol metabolic process
  • small molecule metabolic process
  • transcription initiation from RNA polymerase II promoter
  • positive regulation of transcription from RNA polymerase II promoter
  • negative regulation of transcription from RNA polymerase II promoter
  • cellular response to bile acid
  • cellular response to organonitrogen compound
  • intracellular receptor signaling pathway
  • intracellular bile acid receptor signaling pathway
  • Notch signaling pathway
  • signal transduction
  • negative regulation of bile acid biosynthetic process
  • nitrogen catabolite activation of transcription from RNA polymerase II promoter
  • bile acid metabolic process
  • positive regulation of ammonia assimilation cycle
  • bile acid and bile salt transport
  • positive regulation of glutamate metabolic process
  • regulation of bile acid biosynthetic process
  • bile acid signaling pathway
Components
  • nuclear euchromatin
  • nucleoplasm
General FunctionZinc ion binding
Specific FunctionLigand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID1546084
UniProtKB IDQ96RI1
UniProtKB Entry NameNR1H4_HUMAN
Cellular LocationNucleus
Gene sequence
>lcl|BSEQ0011269|Bile acid receptor (NR1H4)
ATGGGATCAAAAATGAATCTCATTGAACATTCCCATTTACCTACCACAGATGAATTTTCT
TTTTCTGAAAATTTATTTGGTGTTTTAACAGAACAAGTGGCAGGTCCTCTGGGACAGAAC
CTGGAAGTGGAACCATACTCGCAATACAGCAATGTTCAGTTTCCCCAAGTTCAACCACAG
ATTTCCTCGTCATCCTATTATTCCAACCTGGGTTTCTACCCCCAGCAGCCTGAAGAGTGG
TACTCTCCTGGAATATATGAACTCAGGCGTATGCCAGCTGAGACTCTCTACCAGGGAGAA
ACTGAGGTAGCAGAGATGCCTGTAACAAAGAAGCCCCGCATGGGCGCGTCAGCAGGGAGG
ATCAAAGGGGATGAGCTGTGTGTTGTTTGTGGAGACAGAGCCTCTGGATACCACTATAAT
GCACTGACCTGTGAGGGGTGTAAAGGTTTCTTCAGGAGAAGCATTACCAAAAACGCTGTG
TACAAGTGTAAAAACGGGGGCAACTGTGTGATGGATATGTACATGCGAAGAAAGTGTCAA
GAGTGTCGACTAAGGAAATGCAAAGAGATGGGAATGTTGGCTGAATGTATGTATACAGGC
TTGTTAACTGAAATTCAGTGTAAATCTAAGCGACTGAGAAAAAATGTGAAGCAGCATGCA
GATCAGACCGTGAATGAAGACAGTGAAGGTCGTGACTTGCGACAAGTGACCTCGACAACA
AAGTCATGCAGGGAGAAAACTGAACTCACCCCAGATCAACAGACTCTTCTACATTTTATT
ATGGATTCATATAACAAACAGAGGATGCCTCAGGAAATAACAAATAAAATTTTAAAAGAA
GAATTCAGTGCAGAAGAAAATTTTCTCATTTTGACGGAAATGGCAACCAATCATGTACAG
GTTCTTGTAGAATTCACAAAAAAGCTACCAGGATTTCAGACTTTGGACCATGAAGACCAG
ATTGCTTTGCTGAAAGGGTCTGCGGTTGAAGCTATGTTCCTTCGTTCAGCTGAGATTTTC
AATAAGAAACTTCCGTCTGGGCATTCTGACCTATTGGAAGAAAGAATTCGAAATAGTGGT
ATCTCTGATGAATATATAACACCTATGTTTAGTTTTTATAAAAGTATTGGGGAACTGAAA
ATGACTCAAGAGGAGTATGCTCTGCTTACAGCAATTGTTATCCTGTCTCCAGATAGACAA
TACATAAAGGATAGAGAGGCAGTAGAGAAGCTTCAGGAGCCACTTCTTGATGTGCTACAA
AAGTTGTGTAAGATTCACCAGCCTGAAAATCCTCAACACTTTGCCTGTCTCCTGGGTCGC
CTGACTGAATTACGGACATTCAATCATCACCACGCTGAGATGCTGATGTCATGGAGAGTA
AACGACCACAAGTTTACCCCACTTCTCTGTGAAATCTGGGACGTGCAGTGA
GenBank Gene IDU68233
GeneCard IDNot Available
GenAtlas IDNR1H4
HGNC IDHGNC:7967
Chromosome Location12
Locus12q23.1
References
  1. Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, Hollis GF, Young PR, Mukherjee R, Burn TC: Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene. 2002 May 15;290(1-2):35-43. 12062799
  2. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  3. Scherer SE, Muzny DM, Buhay CJ, Chen R, Cree A, Ding Y, Dugan-Rocha S, Gill R, Gunaratne P, Harris RA, Hawes AC, Hernandez J, Hodgson AV, Hume J, Jackson A, Khan ZM, Kovar-Smith C, Lewis LR, Lozado RJ, Metzker ML, Milosavljevic A, Miner GR, Montgomery KT, Morgan MB, Nazareth LV, Scott G, Sodergren E, Song XZ, Steffen D, Lovering RC, Wheeler DA, Worley KC, Yuan Y, Zhang Z, Adams CQ, Ansari-Lari MA, Ayele M, Brown MJ, Chen G, Chen Z, Clerc-Blankenburg KP, Davis C, Delgado O, Dinh HH, Draper H, Gonzalez-Garay ML, Havlak P, Jackson LR, Jacob LS, Kelly SH, Li L, Li Z, Liu J, Liu W, Lu J, Maheshwari M, Nguyen BV, Okwuonu GO, Pasternak S, Perez LM, Plopper FJ, Santibanez J, Shen H, Tabor PE, Verduzco D, Waldron L, Wang Q, Williams GA, Zhang J, Zhou J, Allen CC, Amin AG, Anyalebechi V, Bailey M, Barbaria JA, Bimage KE, Bryant NP, Burch PE, Burkett CE, Burrell KL, Calderon E, Cardenas V, Carter K, Casias K, Cavazos I, Cavazos SR, Ceasar H, Chacko J, Chan SN, Chavez D, Christopoulos C, Chu J, Cockrell R, Cox CD, Dang M, Dathorne SR, David R, Davis CM, Davy-Carroll L, Deshazo DR, Donlin JE, D'Souza L, Eaves KA, Egan A, Emery-Cohen AJ, Escotto M, Flagg N, Forbes LD, Gabisi AM, Garza M, Hamilton C, Henderson N, Hernandez O, Hines S, Hogues ME, Huang M, Idlebird DG, Johnson R, Jolivet A, Jones S, Kagan R, King LM, Leal B, Lebow H, Lee S, LeVan JM, Lewis LC, London P, Lorensuhewa LM, Loulseged H, Lovett DA, Lucier A, Lucier RL, Ma J, Madu RC, Mapua P, Martindale AD, Martinez E, Massey E, Mawhiney S, Meador MG, Mendez S, Mercado C, Mercado IC, Merritt CE, Miner ZL, Minja E, Mitchell T, Mohabbat F, Mohabbat K, Montgomery B, Moore N, Morris S, Munidasa M, Ngo RN, Nguyen NB, Nickerson E, Nwaokelemeh OO, Nwokenkwo S, Obregon M, Oguh M, Oragunye N, Oviedo RJ, Parish BJ, Parker DN, Parrish J, Parks KL, Paul HA, Payton BA, Perez A, Perrin W, Pickens A, Primus EL, Pu LL, Puazo M, Quiles MM, Quiroz JB, Rabata D, Reeves K, Ruiz SJ, Shao H, Sisson I, Sonaike T, Sorelle RP, Sutton AE, Svatek AF, Svetz LA, Tamerisa KS, Taylor TR, Teague B, Thomas N, Thorn RD, Trejos ZY, Trevino BK, Ukegbu ON, Urban JB, Vasquez LI, Vera VA, Villasana DM, Wang L, Ward-Moore S, Warren JT, Wei X, White F, Williamson AL, Wleczyk R, Wooden HS, Wooden SH, Yen J, Yoon L, Yoon V, Zorrilla SE, Nelson D, Kucherlapati R, Weinstock G, Gibbs RA: The finished DNA sequence of human chromosome 12. Nature. 2006 Mar 16;440(7082):346-51. 16541075
  4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  5. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B: Identification of a nuclear receptor for bile acids. Science. 1999 May 21;284(5418):1362-5. 10334992
  6. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM: Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999 May 21;284(5418):1365-8. 10334993
  7. Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA: Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003 Jul 1;17(13):1581-91. Epub 2003 Jun 18. 12815072
  8. Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK: BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation. Mol Cell Biol. 2003 Sep;23(17):6210-20. 12917342
  9. Ananthanarayanan M, Li S, Balasubramaniyan N, Suchy FJ, Walsh MJ: Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1. J Biol Chem. 2004 Dec 24;279(52):54348-57. Epub 2004 Oct 6. 15471871
  10. Balasubramaniyan N, Ananthanarayanan M, Suchy FJ: Direct methylation of FXR by Set7/9, a lysine methyltransferase, regulates the expression of FXR target genes. Am J Physiol Gastrointest Liver Physiol. 2012 May 1;302(9):G937-47. doi: 10.1152/ajpgi.00441.2011. Epub 2012 Feb 16. 22345554
  11. Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, Rosenfeld JM, Alvarez JG, Noel JP, Nicolaou KC, Evans RM: A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003 Apr;11(4):1079-92. 12718892
  12. Mi LZ, Devarakonda S, Harp JM, Han Q, Pellicciari R, Willson TM, Khorasanizadeh S, Rastinejad F: Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell. 2003 Apr;11(4):1093-100. 12718893
  13. Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Jones SA, Kaldor I, Liu Y, Madauss KP, Marr HB, McFadyen RB, Miller AB, Iii FN, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB: Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. doi: 10.1016/j.bmcl.2008.06.073. Epub 2008 Jun 28. 18621523
  14. Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW: Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5337-42. doi: 10.1073/pnas.0710981105. Epub 2008 Apr 7. 18391212
  15. Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Parks DJ, Todd D, Williams SP, Wisely GB: Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. doi: 10.1016/j.bmcl.2009.04.047. Epub 2009 Apr 18. 19410460
  16. Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Bruce Wisely G: FXR agonist activity of conformationally constrained analogs of GW 4064. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4733-9. doi: 10.1016/j.bmcl.2009.06.062. Epub 2009 Jun 21. 19586769
  17. Flatt B, Martin R, Wang TL, Mahaney P, Murphy B, Gu XH, Foster P, Li J, Pircher P, Petrowski M, Schulman I, Westin S, Wrobel J, Yan G, Bischoff E, Daige C, Mohan R: Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem. 2009 Feb 26;52(4):904-7. doi: 10.1021/jm8014124. 19159286
  18. Lundquist JT, Harnish DC, Kim CY, Mehlmann JF, Unwalla RJ, Phipps KM, Crawley ML, Commons T, Green DM, Xu W, Hum WT, Eta JE, Feingold I, Patel V, Evans MJ, Lai K, Borges-Marcucci L, Mahaney PE, Wrobel JE: Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates. J Med Chem. 2010 Feb 25;53(4):1774-87. doi: 10.1021/jm901650u. 20095622