Bile acid receptor

Details

Name
Bile 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 Name
NR1H4
Organism
Humans
Amino acid sequence
>lcl|BSEQ0003523|Bile acid receptor
MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAKGVLTEQVAGPLGQNLEVEPYSQYS
NVQFPQVQPQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTK
KPRMGASAGRIKGDELCVVCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCV
MDMYMRRKCQECRLRKCKEMGMLAECMYTGLLTEIQCKSKRLRKNVKQHADQTVNEDSEG
RDLRQVTSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLI
LTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSD
LLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEK
LQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLC
EIWDVQ
Number of residues
486
Molecular Weight
55913.915
Theoretical pI
6.81
GO Classification
Functions
bile acid binding / bile acid receptor activity / chenodeoxycholic acid binding / ligand-dependent nuclear receptor binding / RNA polymerase II distal enhancer sequence-specific DNA binding / RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding / sequence-specific DNA binding / steroid hormone receptor activity / thyroid hormone receptor activity / transcription coactivator activity / transcription corepressor activity / transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding / transcription factor activity, sequence-specific DNA binding / transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding / transcriptional activator activity, RNA polymerase II transcription factor binding / zinc ion binding
Processes
bile acid and bile salt transport / bile acid metabolic process / bile acid signaling pathway / cellular response to bile acid / cellular response to organonitrogen compound / gene expression / intracellular bile acid receptor signaling pathway / intracellular receptor signaling pathway / negative regulation of bile acid biosynthetic process / negative regulation of transcription from RNA polymerase II promoter / nitrogen catabolite activation of transcription from RNA polymerase II promoter / Notch signaling pathway / positive regulation of ammonia assimilation cycle / positive regulation of glutamate metabolic process / positive regulation of transcription from RNA polymerase II promoter / regulation of bile acid biosynthetic process / regulation of cholesterol metabolic process / regulation of urea metabolic process / signal transduction / small molecule metabolic process / transcription initiation from RNA polymerase II promoter
Components
nuclear euchromatin / nucleoplasm
General Function
Zinc ion binding
Specific Function
Ligand-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 Regions
Not Available
Cellular Location
Nucleus
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
Chromosome Location
12
Locus
12q23.1
External Identifiers
ResourceLink
UniProtKB IDQ96RI1
UniProtKB Entry NameNR1H4_HUMAN
GenBank Protein ID1546084
GenBank Gene IDU68233
GenAtlas IDNR1H4
HGNC IDHGNC:7967
General 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. [PubMed: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. [PubMed:14702039]
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  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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:22345554]
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  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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed: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. [PubMed:20095622]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02545FexaramineexperimentalunknownDetails
DB05990Obeticholic acidapprovedyesagonistDetails
DB08220(8alpha,10alpha,13alpha,17beta)-17-[(4-hydroxyphenyl)carbonyl]androsta-3,5-diene-3-carboxylic acidexperimentalunknownDetails
DB06777Chenodeoxycholic acidapprovedunknownotherDetails
DB11605MyrrhapprovedunknownantagonistDetails
DB02659Cholic AcidapprovedunknownDetails
DB03619Deoxycholic acidapprovedunknownDetails
DB00132alpha-Linolenic acidapproved, investigational, nutraceuticalunknownagonistDetails
DB04557Arachidonic AcidexperimentalunknownligandDetails
DB02509FarnesolexperimentalunknownagonistDetails
DB01586Ursodeoxycholic acidapproved, investigationalunknownDetails
DB04348Taurocholic acidapproved, experimentalunknownDetails