TABLE 4

FXR

Receptor Nomenclature NR1H4
Receptor code 4.10.1:BA:1:H4
Other names BAR, HRR1, RIP14
Molecular information Hs: 486aa, Q96RI1, chr. 12q23.1
Rn: 469aa, Q62735, chr. 7q131
Mm: 488aa, Q60641, chr. 10 C22
DNA binding
   Structure RXR partner
   HRE core sequence AGTTCAnTGAACT
Partners
Agonists GW4064 (15 nM), fexaramine (250 nM), 22(R)-hydroxycholesterol (>3 μM), lithocholic acid (5 μM), chenodeoxycholic acid (5 μM), cholic acid (>10 μM), deoxycholic acid (100 μM), [EC50]3–8
Antagonists Guggulsterone (10 μM) [IC50]9
Coactivator
Corepressor
Biologically important isoforms FXRα 1 {Hs, Mm}2,10,11; FXRα 2 {Hs, Mm}2,10,11; FXRα 3 {Hs, Mm}2,10,11; FXRα 4 {Hs, Mm}2,10,11
Tissue distribution Liver, small intestine, colon, kidney, adrenal gland {Mm, Rn} [Northern blot, Q-PCR, in situ hybridization]1,2,11
Functional assay
Main target genes Activated: FGF19 {Hs},12 FGF15 {Mm},13 SHP {Hs, Rn, Mm},14,15 BSEP {Hs, Rn, Mm},16 IBABP {Hs, Mm},17 MDR3 {Hs},18 Mdr2 {Rn, Mm},19,20 MRP2 {Hs, Rn},21 OATP1B3 {Hs},22 BACS {Hs, Rn},23 ApoCII {Hs, Mm},24 C3 {Hs},13 PDK4 {Hs, Rn, Mm},25 PLTP {Hs, Mm},9 PPARα {Hs},26 αA-crystallin {Hs},27 fibrinogen {Hs},28 kininogen {Hs},18 syndecan-1 {Hs},4 VPAC1 {Hs},29 OSTα and OSTβ {Hs}30–32; repressed: CYP7A1 {Hs, Rn, Mm},14,15 ABAT {Hs, Mm},33,34 NTCP {Rn, Mm},35 APOAI {Hs},36,37 ApoCIII {Hs, Mm},36 hepatic lipase {Hs},38 SREBP-1c {Mm},39 VLDLR {Hs, Mm}40
Mutant phenotype Elevated serum bile acids, cholesterol and triglycerides; increased hepatic cholesterol and triglycerides; proatherogenic serum lipoprotein profile; reduced bile acid pools and reduced fecal bile acid secretion {Mm} [knockout]41,42
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; Q-PCR, quantitative polymerase chain reaction; BAR, bile acid receptor; SHP, small heterodimer partner; BSEP, bile salt export pump; IBABP, ileal bile acid-binding protein; BACS, bile acid-CoA synthetase; PLTP, phospholipid transfer protein; OST, organic solute transporter; ABAT, apical bile acid transporter; NTCP, sodium/taurocholate cotransporting polypeptide; APOAI, apolipoprotein A-I; VLDLR, very-low-density lipoprotein receptor

  • ↵1. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, et al. (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81: 687-693

  • ↵2. Seol W, Choi HS, and Moore DD (1995) Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9: 72-85

  • ↵3. Deng R, Yang D, Yang J, and Yan B (2006) Oxysterol 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 317: 317-325

  • ↵4. Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, et al. (2003) A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11: 1079-1092

  • ↵5. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, and Shan B (1999) Identification of a nuclear receptor for bile acids. Science (Wash DC) 284: 1362-1365

  • ↵6. Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, Moore LB, Wilson JG, Lewis MC, et al. (2000) Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43: 2971-2974

  • ↵7. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, et al. (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science (Wash DC) 284: 1365-1368

  • ↵8. Wang H, Chen J, Hollister K, Sowers LC, and Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3: 543-553

  • ↵9. Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, Gonzalez FJ, Heyman RA, Mangelsdorf DJ, and Moore DD (2002) A natural product that lowers cholesterol as an antagonist ligand for FXR. Science (Wash DC) 296: 1703-1706

  • ↵10. Huber RM, Murphy K, Miao B, Link JR, Cunningham MR, Rupar MJ, Gunyuzlu PL, Haws TF, Kassam A, Powell F, et al. (2002) Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 290: 35-43

  • ↵11. Zhang Y, Kast-Woelbern HR, and Edwards PA (2003) Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 278: 104-110

  • ↵12. Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang da Y, Mansfield TA, Kliewer SA, et al. (2003) Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 17: 1581-1591

  • ↵13. Li J, Pircher PC, Schulman IG, and Westin SK (2005) Regulation of complement c3 expression by the bile acid receptor FXR. J Biol Chem 280: 7427-7434

  • ↵14. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, et al. (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6: 517-526

  • ↵15. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, and Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507-515

  • ↵16. Ananthanarayanan M, Li S, Balasubramaniyan N, Suchy FJ, and Walsh MJ (2004) Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1. J Biol Chem 279: 54348-54357

  • ↵17. Grober J, Zaghini I, Fujii H, Jones SA, Kliewer SA, Willson TM, Ono T, and Besnard P (1999) Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene: involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274: 29749-29754

  • ↵18. Cui J, Huang L, Zhao A, Lew JL, Yu J, Sahoo S, Meinke PT, Royo I, Pelaez F, and Wright SD (2003) Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 278: 10214-10220

  • ↵19. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, et al. (2005) Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217-225

  • ↵20. Jaye MC, Krawiec JA, Campobasso N, Smallwood A, Qiu C, Lu Q, Kerrigan JJ, De Los Frailes Alvaro M, Laffitte B, Liu WS, et al. (2005) Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure. J Med Chem 48: 5419-5422

  • ↵21. Mak PA, Kast-Woelbern HR, Anisfeld AM, and Edwards PA (2002) Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors. J Lipid Res 43: 2037-2041

  • ↵22. Jung D, Podvinec M, Meyer UA, Mangelsdorf DJ, Fried M, Meier PJ, and Kullak-Ublick GA (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology 122: 1954-1966

  • ↵23. Pircher PC, Kitto JL, Petrowski ML, Tangirala RK, Bischoff ED, Schulman IG, and Westin SK (2003) Farnesoid X receptor regulates bile acid-amino acid conjugation. J Biol Chem 278: 27703-27711

  • ↵24. Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reue K, Gonzalez FJ, Willson TM, and Edwards PA (2001) Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 15: 1720-1728

  • ↵25. Savkur RS, Thomas JS, Bramlett KS, Gao Y, Michael LF, and Burris TP (2005) Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor γ coactivator-1α. J Pharmacol Exp Ther 312: 170-178

  • ↵26. Pineda Torra I, Freedman LP, and Garabedian MJ (2004) Identification of DRIP205 as a coactivator for the farnesoid X receptor. J Biol Chem 279: 36184-36191

  • ↵27. Lee FY, Kast-Woelbern HR, Chang J, Luo G, Jones SA, Fishbein MC, and Edwards PA (2005) α -Crystallin is a target gene of the farnesoid X-activated receptor in human livers. J Biol Chem 280: 31792-31800

  • ↵28. Anisfeld AM, Kast-Woelbern HR, Lee H, Zhang Y, Lee FY, and Edwards PA (2005) Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling. J Lipid Res 46: 458-468

  • ↵29. Chignard N, Mergey M, Barbu V, Finzi L, Tiret E, Paul A, and Housset C (2005) VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium. Hepatology 42: 549-557

  • ↵30. Frankenberg T, Rao A, Chen F, Haywood J, Shneider BL, and Dawson PA (2006) Regulation of the mouse organic solute transporter α -β, Ostα -Ostβ, by bile acids. Am J Physiol 290: G912-G922

  • ↵31. Landrier JF, Eloranta JJ, Vavricka SR, and Kullak-Ublick GA (2006) The nuclear receptor for bile acids, FXR, transactivates the human organic solute transporter-α and -β genes. Am J Physiol 290: G476-G485

  • ↵32. Zollner G, Wagner M, Moustafa T, Fickert P, Silbert D, Gumhold J, Fuchsbichler A, Halilbasic E, Denk H, Marschall HU, et al. (2006) Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter α /β in the adaptive response to bile acids. Am J Physiol 290: G923-G932

  • ↵33. Dussault I, Beard R, Lin M, Hollister K, Chen J, Xiao JH, Chandraratna R, and Forman BM (2003) Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 278: 7027-7033

  • ↵34. Neimark E, Chen F, Li X, and Shneider BL (2004) Bile acid-induced negative feedback regulation of the human ileal bile acid transporter. Hepatology 40: 149-156

  • ↵35. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, and Karpen SJ (2001) The orphan nuclear receptor, SHP, mediates bile acid-induced inhibition of the rat bile acid transporter, NTCP. Gastroenterology 121: 140-147

  • ↵36. Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, Fruchart JC, Gonzalez FJ, and Staels B (2003) Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 125: 544-555

  • ↵37. Srivastava RA, Srivastava N, and Averna M (2000) Dietary cholic acid lowers plasma levels of mouse and human apolipoprotein A-I primarily via a transcriptional mechanism. Eur J Biochem 267: 4272-4280

  • ↵38. Sirvent A, Verhoeven AJ, Jansen H, Kosykh V, Darteil RJ, Hum DW, Fruchart JC, and Staels B (2004) Farnesoid X receptor represses hepatic lipase gene expression. J Lipid Res 45: 2110-2115

  • ↵39. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, and Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Investig 113: 1408-1418

  • ↵40. Sirvent A, Claudel T, Martin G, Brozek J, Kosykh V, Darteil R, Hum DW, Fruchart JC, and Staels B (2004) The farnesoid X receptor induces very low density lipoprotein receptor gene expression. FEBS Lett 566: 173-177

  • ↵41. Kok T, Hulzebos CV, Wolters H, Havinga R, Agellon LB, Stellaard F, Shan B, Schwarz M, and Kuipers F (2003) Enterohepatic circulation of bile salts in farnesoid X receptor-deficient mice: efficient intestinal bile salt absorption in the absence of ileal bile acid-binding protein. J Biol Chem 278: 41930-41937

  • ↵42. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, and Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731-744