Target Information

Target General Infomation
Target ID
T51426
Former ID
TTDS00272
Target Name
Bile acid receptor
Gene Name
NR1H4
Synonyms
Farnesoid X receptor; Farnesoid X-activated receptor; Farnesol receptor HRR-1; Nuclear farnesoid X receptor; RXR-interacting protein 14; Retinoid X receptor-interacting protein14; NR1H4
Target Type
Successful
Disease Anticholelithogenic [ICD10: K80]
Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78]
Insomnia [ICD9: 307.41, 307.42, 327.0, 780.51, 780.52; ICD10: F51.0, G47.0]
Osteoarthritis [ICD9: 715; ICD10: M15-M19, M47]
Primary biliary cholangitis [ICD10: K00-K95]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Unspecified [ICD code not available]
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.
BioChemical Class
Nuclear hormone receptor
Target Validation
T51426
UniProt ID
Q96RI1
Sequence
MVMQFQGLENPIQISPHCSCTPSGFFMEMMSMKPAKGVLTEQVAGPLGQNLEVEPYSQYS
NVQFPQVQPQISSSSYYSNLGFYPQQPEEWYSPGIYELRRMPAETLYQGETEVAEMPVTK
KPRMGASAGRIKGDELCVVCGDRASGYHYNALTCEGCKGFFRRSITKNAVYKCKNGGNCV
MDMYMRRKCQECRLRKCKEMGMLAECMYTGLLTEIQCKSKRLRKNVKQHADQTVNEDSEG
RDLRQVTSTTKSCREKTELTPDQQTLLHFIMDSYNKQRMPQEITNKILKEEFSAEENFLI
LTEMATNHVQVLVEFTKKLPGFQTLDHEDQIALLKGSAVEAMFLRSAEIFNKKLPSGHSD
LLEERIRNSGISDEYITPMFSFYKSIGELKMTQEEYALLTAIVILSPDRQYIKDREAVEK
LQEPLLDVLQKLCKIHQPENPQHFACLLGRLTELRTFNHHHAEMLMSWRVNDHKFTPLLC
EIWDVQ
Structure
1OSH; 1OSK; 3BEJ; 3DCT; 3DCU; 3FLI; 3FXV; 3GD2; 3HC5; 3HC6; 3L1B; 3OKH; 3OKI; 3OLF; 3OMK; 3OMM; 3OOF; 3OOK; 3P88; 3P89; 3RUT; 3RUU; 3RVF; 4II6
Drugs and Mode of Action
Drug(s) Chenodiol Drug Info Approved Anticholelithogenic [551871]
Cholic acid - Asklepion Drug Info Approved Unspecified [551871]
Guggulsterone Drug Info Approved Osteoarthritis [536258], [539790]
obeticholic acid Drug Info Approved Primary biliary cholangitis [889440]
Chenodeoxycholate Drug Info Phase 2 Discovery agent [522682]
Turofexorate isopropyl Drug Info Phase 1 Hyperlipidaemia [548483]
obeticholic acid Drug Info Clinical trial Insomnia [526211]
SB-756050 Drug Info Discontinued in Phase 2 Type 2 diabetes [548743]
SKF-97426 Drug Info Discontinued in Phase 2 Hyperlipidaemia [545280]
Agonist 1,1-bisphosphonate esters Drug Info [535129]
22R-hydroxycholesterol Drug Info [527938]
Chenodeoxycholate Drug Info [535475]
GW4065 Drug Info [535475]
Research programme: farnesoid X receptor agonists, Roche Drug Info [543895]
SB-756050 Drug Info [550963]
SR-45023A (Apomine) Drug Info [535129]
Inhibitor 12-O-deacetyl-12-epi-19-deoxy-21-hydroxyscalarin Drug Info [529138]
AGN-34 Drug Info [527690]
E-GUGGULSTERONE Drug Info [529138]
Fexaramine Drug Info [551393]
Modulator Chenodiol Drug Info [556264]
Cholic acid - Asklepion Drug Info [556264]
obeticholic acid Drug Info [889440]
SKF-97426 Drug Info [533930]
Turofexorate isopropyl Drug Info [529912]
Antagonist Guggulsterone Drug Info [536996]
Lithocholate Drug Info [535475]
Binder GW4064 Drug Info [535475]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Bile secretion
Pathway Interaction Database RXR and RAR heterodimerization with other nuclear receptor
Reactome Recycling of bile acids and salts
PPARA activates gene expression
Endogenous sterols
WikiPathways Nuclear Receptors in Lipid Metabolism and Toxicity
Nuclear Receptors Meta-Pathway
Farnesoid X Receptor Pathway
Drug Induction of Bile Acid Pathway
References
Ref 522682ClinicalTrials.gov (NCT00912301) Cheno Effect on Transit in Health and IBS-C. U.S. National Institutes of Health.
Ref 526211Nuclear receptors and lipid physiology: opening the X-files. Science. 2001 Nov 30;294(5548):1866-70.
Ref 536258Treating insomnia: Current and investigational pharmacological approaches. Pharmacol Ther. 2006 Dec;112(3):612-29. Epub 2006 Jul 28.
Ref 539790(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2745).
Ref 545280Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002680)
Ref 548483Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025892)
Ref 548743Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028284)
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
Ref 8894402016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. doi: 10.1038/nrd.2017.14.
Ref 527690J Med Chem. 2005 Aug 25;48(17):5383-403.Farnesoid X receptor: from structure to potential clinical applications.
Ref 527938Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor. J Pharmacol Exp Ther. 2006 Apr;317(1):317-25. Epub 2005 Dec 21.
Ref 529138J Nat Prod. 2007 Nov;70(11):1691-5. Epub 2007 Nov 8.Scalarane sesterterpenes from a marine sponge of the genus Spongia and their FXR antagonistic activity.
Ref 529912A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G543-52.
Ref 533930SK&F 97426-A a more potent bile acid sequestrant and hypocholesterolaemic agent than cholestyramine in the hamster. Atherosclerosis. 1993 Jun;101(1):51-60.
Ref 535129The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases. Curr Pharm Des. 2001 Mar;7(4):231-59.
Ref 535475Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. J Biol Chem. 2002 Aug 30;277(35):31441-7. Epub 2002 Jun 6.
Ref 536996Effect of guggulsterone and cembranoids of Commiphora mukul on pancreatic phospholipase A(2): role in hypocholesterolemia. J Nat Prod. 2009 Jan;72(1):24-8.
Ref 543895(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 603).
Ref 550963Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 556264Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
Ref 8894402016 FDA drug approvals. Nat Rev Drug Discov. 2017 Feb 2;16(2):73-76. doi: 10.1038/nrd.2017.14.

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