Nuclear bile acid receptor FXR as pharmacological target: Are we there yet?

FEBS Letters

Volumn 580, Issue 23, 2006, Pages 5492-5499

  Modica, Salvatore ^a,b   Moschetta, Antonio ^a,b  

^a Consorzio Mario Negri Sud ^*  (Italy)

^b UNIVERSITY OF BARI   (Italy)

Author keywords

Cholesterol; Farnesoid X receptor; Gallstones; Hypertriglyceridemia; Metabolic syndrome

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY] PHENYL]VINYL]BENZOIC ACID; 3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; BILE ACID; FARNESOID X RECEPTOR; TAUROURSODEOXYCHOLIC ACID; UNCLASSIFIED DRUG;

CELL PROLIFERATION; CHOLELITHIASIS; DRUG EFFECT; GENE EXPRESSION; GENETIC TRANSCRIPTION; GLUCONEOGENESIS; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; GLYCOGEN SYNTHESIS; HUMAN; HYPERTRIGLYCERIDEMIA; INSULIN SENSITIVITY; LIPID METABOLISM; LIVER REGENERATION; LIVER RESECTION; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; SHORT SURVEY; STATISTICAL SIGNIFICANCE;

ANIMALS; BILE ACIDS AND SALTS; GLUCOSE; HUMANS; INTESTINES; LIPID METABOLISM; LIVER DISEASES; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

BACTERIA (MICROORGANISMS);

EID: 33749344968     PISSN: 00145793     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.febslet.2006.07.082     Document Type: Short Survey

References (72)

1. Blumberg B., and Evans R.M. Orphan nuclear receptors - new ligands and new possibilities. Genes Dev. 12 (1998) 3149-3155
2. Kliewer S.A., Lehmann J.M., and Willson T.M. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284 (1999) 757-760
3. Mangelsdorf D.J., and Evans R.M. The RXR heterodimers and orphan receptors. Cell 83 (1995) 841-850
4. Chawla A., Repa J.J., Evans R.M., and Mangelsdorf D.J. Nuclear receptors and lipid physiology: opening the X-files. Science 294 (2001) 1866-1870
5. Shulman A.I., and Mangelsdorf D.J. Retinoid x receptor heterodimers in the metabolic syndrome. N. Engl. J. Med. 353 (2005) 604-615
6. Mangelsdorf D.J., Thummel C., Beato M., Herrlich P., Schutz G., Umesono K., Blumberg B., Kastner P., Mark M., and Chambon P. The nuclear receptor superfamily: the second decade. Cell 83 (1995) 835-839
7. McKenna N.J., and O'Malley B.W. Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108 (2002) 465-474
8. Forman B.M., Goode E., Chen J., Oro A.E., Bradley D.J., Perlmann T., Noonan D.J., Burka L.T., McMorris T., Lamph W.W., Evans R.M., and Weinberger C. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81 (1995) 687-693
9. Makishima M., Okamoto A.Y., Repa J.J., Tu H., Learned R.M., Luk A., Hull M.V., Lustig K.D., Mangelsdorf D.J., and Shan B. Identification of a nuclear receptor for bile acids. Science 284 (1999) 1362-1365
10. Parks D.J., Blanchard S.G., Bledsoe R.K., Chandra G., Consler T.G., Kliewer S.A., Stimmel J.B., Willson T.M., Zavacki A.M., Moore D.D., and Lehmann J.M. Bile acids: natural ligands for an orphan nuclear receptor. Science 284 (1999) 1365-1368
11. Wang H., Chen J., Hollister K., Sowers L.C., and Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3 (1999) 543-553
12. Hofmann A.F. The continuing importance of bile acids in liver and intestinal disease. Arch. Intern. Med 159 (1999) 2647-2658
13. Angelin B., Einarsson K., Hellstrom K., and Leijd B. Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J. Lipid Res. 19 (1978) 1017-1024
14. Beil U., Crouse J.R., Einarsson K., and Grundy S.M. Effects of interruption of the enterohepatic circulation of bile acids on the transport of very low density-lipoprotein triglycerides. Metabolism 31 (1982) 438-444
15. Buchwald H., Varco R.L., Matts J.P., Long J.M., Fitch L.L., Campbell G.S., Pearce M.B., Yellin A.E., Edmiston W.A., and Smink Jr. R.D. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N. Engl. J. Med. 323 (1990) 946-955
16. Crouse III J.R. Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. Am. J. Med. 83 (1987) 243-248
17. Kuriyama M., Tokimura Y., Fujiyama J., Utatsu Y., and Osame M. Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use. J. Neurol. Sci. 125 (1994) 22-28
18. Shepherd J., Packard C.J., Morgan H.G., Third J.L., Stewart J.M., and Lawrie T.D. The effects of cholestyramine on high density lipoprotein metabolism. Atherosclerosis 33 (1979) 433-444
19. Bateson M.C., Maclean D., Evans J.R., and Bouchier I.A. Chenodeoxycholic acid therapy for hypertriglyceridaemia in men. Br. J. Clin. Pharmacol. 5 (1978) 249-254
20. Leiss O., and von Bergmann K. Different effects of chenodeoxycholic acid and ursodeoxycholic acid on serum lipoprotein concentrations in patients with radiolucent gallstones. Scand. J. Gastroenterol. 17 (1982) 587-592
21. Claudel T., Sturm E., Duez H., Torra I.P., Sirvent A., Kosykh V., Fruchart J.C., Dallongeville J., Hum D.W., Kuipers F., and Staels B. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J. Clin. Invest. 109 (2002) 961-971
22. Sinal C.J., Tohkin M., Miyata M., Ward J.M., Lambert G., and Gonzalez F.J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102 (2000) 731-744
23. Kok T., Hulzebos C.V., Wolters H., Havinga R., Agellon L.B., Stellaard F., Shan B., Schwarz M., and Kuipers F. 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 (2003) 41930-41937
24. Lu T.T., Makishima M., Repa J.J., Schoonjans K., Kerr T.A., Auwerx J., and Mangelsdorf D.J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6 (2000) 507-515
25. Goodwin B., Jones S.A., Price R.R., Watson M.A., McKee D.D., Moore L.B., Galardi C., Wilson J.G., Lewis M.C., Roth M.E., Maloney P.R., Willson T.M., and Kliewer S.A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6 (2000) 517-526
26. Kerr T.A., Saeki S., Schneider M., Schaefer K., Berdy S., Redder T., Shan B., Russell D.W., and Schwarz M. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell 2 (2002) 713-720
27. Inagaki T., Choi M., Moschetta A., Peng L., Cummins C.L., McDonald J.G., Luo G., Jones S.A., Goodwin B., Richardson J.A., Gerard R.D., Repa J.J., Mangelsdorf D.J., and Kliewer S.A. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2 (2005) 217-225
28. Nagano M., Kuroki S., Mizuta A., Furukawa M., Noshiro M., Chijiiwa K., and Tanaka M. Regulation of bile acid synthesis under reconstructed enterohepatic circulation in rats. Steroids 69 (2004) 701-709
29. Holt J.A., Luo G., Billin A.N., Bisi J., McNeill Y.Y., Kozarsky K.F., Donahee M., Wang d.Y., Mansfield T.A., Kliewer S.A., Goodwin B., and Jones S.A. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17 (2003) 1581-1591
30. Yu C., Wang F., Jin C., Huang X., and McKeehan W.L. Independent repression of bile acid synthesis and activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblast growth factor receptor 4 (FGFR4) and bile acids. J. Biol. Chem. 280 (2005) 17707-17714
31. Ratliff E.P., Gutierrez A., and Davis R.A. Transgenic expression of CYP7a1 in LDL receptor deficient mice blocks diet-induced hypercholesterolemia. J. Lipid Res. (2006)
32. Urizar N.L., Liverman A.B., Dodds D.T., Silva F.V., Ordentlich P., Yan Y., Gonzalez F.J., Heyman R.A., Mangelsdorf D.J., and Moore D.D. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 296 (2002) 1703-1706
33. Lambert G., Amar M.J., Guo G., Brewer Jr. H.B., Gonzalez F.J., and Sinal C.J. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J. Biol. Chem. 278 (2003) 2563-2570
34. Brown M.S., and Goldstein J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89 (1997) 331-340
35. Horton J.D., Goldstein J.L., and Brown M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109 (2002) 1125-1131
36. Watanabe M., Houten S.M., Wang L., Moschetta A., Mangelsdorf D.J., Heyman R.A., Moore D.D., and Auwerx J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113 (2004) 1408-1418
37. Cariou B., van Harmelen K., Duran-Sandoval D., van Dijk T.H., Grefhorst A., Abdelkarim M., Caron S., Torpier G., Fruchart J.C., Gonzalez F.J., Kuipers F., and Staels B. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281 (2006) 11039-11049
38. Moller D.E. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414 (2001) 821-827
39. Borgius L.J., Steffensen K.R., Gustafsson J.A., and Treuter E. Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J. Biol. Chem. 277 (2002) 49761-49766
40. Yamagata K., Daitoku H., Shimamoto Y., Matsuzaki H., Hirota K., Ishida J., and Fukamizu A. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J. Biol. Chem. 279 (2004) 23158-23165
41. Zhang Y., Lee F.Y., Barrera G., Lee H., Vales C., Gonzalez F.J., Willson T.M., and Edwards P.A. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. USA 103 (2006) 1006-1011
42. Duran-Sandoval D., Mautino G., Martin G., Percevault F., Barbier O., Fruchart J.C., Kuipers F., and Staels B. Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes 53 (2004) 890-898
43. Ma K., Saha P.K., Chan L., and Moore D.D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116 (2006) 1102-1109
44. Seppala-Lindroos A., Vehkavaara S., Hakkinen A.M., Goto T., Westerbacka J., Sovijarvi A., Halavaara J., and Yki-Jarvinen H. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J. Clin. Endocrinol. Metab. 87 (2002) 3023-3028
45. Cariou B., van Harmelen K., Duran-Sandoval D., van Dijk T., Grefhorst A., Bouchaert E., Fruchart J.C., Gonzalez F.J., Kuipers F., and Staels B. Transient impairment of the adaptive response to fasting in FXR-deficient mice. FEBS Lett. 579 (2005) 4076-4080
46. Yu L., Hammer R.E., Li-Hawkins J., Von Bergmann K., Lutjohann D., Cohen J.C., and Hobbs H.H. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA 99 (2002) 16237-16242
47. Gerloff T., Stieger B., Hagenbuch B., Madon J., Landmann L., Roth J., Hofmann A.F., and Meier P.J. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273 (1998) 10046-10050
48. Smit J.J., Schinkel A.H., Oude Elferink R.P., Groen A.K., Wagenaar E., van Deemter L., Mol C.A., Ottenhoff R., van der Lugt N.M., and van Roon M.A. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75 (1993) 451-462
49. Figge A., Lammert F., Paigen B., Henkel A., Matern S., Korstanje R., Shneider B.L., Chen F., Stoltenberg E., Spatz K., Hoda F., Cohen D.E., and Green R.M. Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J. Biol. Chem. 279 (2004) 2790-2799
50. Smith A.J., De Vree J.M., Ottenhoff R., Oude Elferink R.P., Schinkel A.H., and Borst P. Hepatocyte-specific expression of the human MDR3 P-glycoprotein gene restores the biliary phosphatidylcholine excretion absent in Mdr2 (-/-) mice. Hepatology 28 (1998) 530-536
51. Yu L., Li-Hawkins J., Hammer R.E., Berge K.E., Horton J.D., Cohen J.C., and Hobbs H.H. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J. Clin. Invest. 110 (2002) 671-680
52. Ananthanarayanan M., Balasubramanian N., Makishima M., Mangelsdorf D.J., and Suchy F.J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem. 276 (2001) 28857-28865
53. Huang L., Zhao A., Lew J.L., Zhang T., Hrywna Y., Thompson J.R., de P.N., Royo I., Blevins R.A., Pelaez F., Wright S.D., and Cui J. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J. Biol. Chem. 278 (2003) 51085-51090
54. Liu Y., Binz J., Numerick M.J., Dennis S., Luo G., Desai B., MacKenzie K.I., Mansfield T.A., Kliewer S.A., Goodwin B., and Jones S.A. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J. Clin. Invest 112 (2003) 1678-1687
55. Repa J.J., Berge K.E., Pomajzl C., Richardson J.A., Hobbs H., and Mangelsdorf D.J. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277 (2002) 18793-18800
56. Velardi A.L., Groen A.K., Elferink R.P., van der M.R., Palasciano G., and Tytgat G.N. Cell type-dependent effect of phospholipid and cholesterol on bile salt cytotoxicity. Gastroenterology 101 (1991) 457-464
57. Moschetta A., vanBerge-Henegouwen G.P., Portincasa P., Palasciano G., Groen A.K., and van Erpecum K.J. Sphingomyelin exhibits greatly enhanced protection compared with egg yolk phosphatidylcholine against detergent bile salts. J. Lipid Res. 41 (2000) 916-924
58. Moschetta A., Bookout A.L., and Mangelsdorf D.J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med. 10 (2004) 1352-1358
59. Tepperman J., Caldwell F.T., and Tepperman H.M. Induction of gallstones in mice by feeding a cholesterol-cholic acid containing diet. Am. J. Physiol. 206 (1964) 628-634
60. Barbier O., Torra I.P., Sirvent A., Claudel T., Blanquart C., Duran-Sandoval D., Kuipers F., Kosykh V., Fruchart J.C., and Staels B. FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity. Gastroenterology 124 (2003) 1926-1940
61. Jung D., Mangelsdorf D.J., and Meyer U.A. PXR is a target of FXR. J. Biol. Chem. 281 (2006) 19081-19091
62. Pawlikowska L., Groen A., Eppens E.F., Kunne C., Ottenhoff R., Looije N., Knisely A.S., Killeen N.P., Bull L.N., Elferink R.P., and Freimer N.B. A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Hum. Mol. Genet. 13 (2004) 881-892
63. Barone M., Francavilla A., Polimeno L., Ierardi E., Romanelli D., Berloco P., Di Leo A., and Panella C. Modulation of rat hepatocyte proliferation by bile salts: in vitro and in vivo studies. Hepatology 23 (1996) 1159-1166
64. Ueda J., Chijiiwa K., Nakano K., Zhao G., and Tanaka M. Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E-associated kinase activity. Surgery 131 (2002) 564-573
65. Huang W., Ma K., Zhang J., Qatanani M., Cuvillier J., Liu J., Dong B., Huang X., and Moore D.D. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312 (2006) 233-236
66. Thaysen E.H., and Pedersen L. Idiopathic bile acid catharsis. Gut 17 (1976) 965-970
67. Landrier J.F., Eloranta J.J., Vavricka S.R., and Kullak-Ublick G.A. The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes. Am. J. Physiol. Gastrointest. Liver Physiol. 290 (2006) G476-G485
68. Dawson P.A., Hubbert M., Haywood J., Craddock A.L., Zerangue N., Christian W.V., and Ballatori N. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J. Biol. Chem. 280 (2005) 6960-6968
69. Berg R.D. Bacterial translocation from the gastrointestinal tract. Trends Microbiol. 3 (1995) 149-154
70. Lorenzo-Zuniga V., Bartoli R., Planas R., Hofmann A.F., Vinado B., Hagey L.R., Hernandez J.M., Mane J., Alvarez M.A., Ausina V., and Gassull M.A. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37 (2003) 551-557
71. Inagaki T., Moschetta A., Lee Y.K., Peng L., Zhao G., Downes M., Yu R.T., Shelton J.M., Richardson J.A., Repa J.J., Mangelsdorf D.J., and Kliewer S.A. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. USA 103 (2006) 3920-3925
72. Dussault I., Beard R., Lin M., Hollister K., Chen J., Xiao J.H., Chandraratna R., and Forman B.M. Identification of gene-selective modulators of the bile acid receptor FXR. J. Biol. Chem. 278 (2003) 7027-7033