Farnesoid X receptor: Acting through bile acids to treat metabolic disorders

Drugs of the Future

Volumn 35, Issue 8, 2010, Pages 635-641

  Zhang, Yanqiao ^a  

^a Northeastern Ohio Medical University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; AGN 34; BILE ACID; FARNESOID X RECEPTOR; LIPID; OBETICHOLIC ACID; TUROFEXORATE ISOPROPYL; UNCLASSIFIED DRUG; XL 335;

ANTIMICROBIAL ACTIVITY; ATHEROSCLEROSIS; BILE ACID METABOLISM; CHOLESTASIS; GALLSTONE FORMATION; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; HOMEOSTASIS AND REGULATION; HUMAN; LIPID METABOLISM; METABOLIC DISORDER; NONALCOHOLIC FATTY LIVER; PROTEIN FAMILY; REVIEW;

EID: 84952978609     PISSN: 03778282     EISSN: None     Source Type: Journal    
DOI: 10.1358/dof.2010.035.08.1520865     Document Type: Review

References (88)

1. Makishima, M., Okamoto, A.Y., Repa, J.J. et al. Identification of a nuclear receptor for bile acids. Science 1999, 284(5418): 1362-5.
2. Parks, D.J., Blanchard, S.G., Bledsoe, R.K. et al. Bile acids: Natural ligands for an orphan nuclear receptor. Science 1999, 284(5418): 1365-8.
3. Wang, H., Chen, J., Hollister, K., Sowers, L.C., Forman, B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999, 3(5): 543-53.
4. Staudinger, J.L., Goodwin, B., Jones, S.A. et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 2001, 98(6): 3369-74.
5. Xie, W., Radominska-Pandya, A., Shi, Y. et al. An essential role for nuclear receptors SXR/RXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci U S A 2001, 98(6): 3375-80.
6. Makishima, M., Lu, T.T., Xie, W. et al. Vitamin D receptor as an intestinal bile acid sensor. Science 2002, 296(5571): 1313-6.
7. Gupta, S., Stravitz, R.T., Dent, P., Hylemon, P.B. Down-regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. J Biol Chem 2001, 276(19): 15816-22.
8. Craven, P.A., Pfanstiel, J., DeRubertis, F.R. Role of activation of protein kinase C in the stimulation of colonic epithelial proliferation and reactive oxygen formation by bile acids. J Clin Invest 1987, 79(2): 532-41.
9. Pongracz, J., Clark, P., Neoptolemos, J.P., Lord, J.M. Expression of protein kinase C isoenzymes in colorectal cancer tissue and their differential activation by different bile acids. Int J Cancer 1995, 61(1): 35-9.
10. Stravitz, R.T., Rao, Y.P., Vlahcevic, Z.R., Gurley, E.C., Jarvis, W.D., Hylemon, P.B. Hepatocellular protein kinase C activation by bile acids: Implications for regulation of cholesterol 7 alpha-hydroxylase. Am J Physiol 1996, 271(2, Pt. 1): G293-303.
11. Rao, Y.P., Studer, E.J., Stravitz, R.T. et al. Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes. Hepatology 2002, 35(2): 307-14.
12. Qiao, L., Studer, E., Leach, K. et al. Deoxycholic acid (DCA) causes ligandin-dependent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: Inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell 2001, 12(9): 2629-45.
13. Maruyama, T., Miyamoto, Y., Nakamura, T. et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002, 298(5): 714-9.
14. Kawamata, Y., Fujii, R., Hosoya, M. et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003, 278(11): 9435-40.
15. Dent, P., Fang, Y., Gupta, S. et al. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology 2005, 42(6): 1291-9.
16. Watanabe, M., Houten, S.M., Mataki, C. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439(7075): 484-9.
17. Maloney, P.R., Parks, D.J., Haffner, C.D. et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Biol Chem 2000, 43(16): 2971-4.
18. Downes, M., Verdecia, M.A., Roecker, A.J. et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 2003, 11(4): 1079-92.
19. Dussault, I., Beard, R., Lin, M. et al. Identification of gene-selective modulators of the bile acid receptor FXR. J Biol Chem 2003, 278(9): 7027-33.
20. Pellicciari, R., Fiorucci, S., Camaioni, E. et al. 6alpha-ethyl- chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002, 45(17): 3569-72.
21. Flatt, B., Martin, R., Wang, T.L. et al. Discovery of XL335 (WAY-362450), a highly potent, selective, and orally active agonist of the farnesoid X receptor (FXR). J Med Chem 2009, 52(4): 904-7.
22. Forman, B.M., Goode, E., Chen, J. et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995, 81(5): 687-93.
23. Zhang, Y., Kast-Woelbern, H.R., Edwards, P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. J Biol Chem 2003, 278(1): 104-10.
24. Huber, R.M., Murphy, K., Miao, B. et al. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters. Gene 2002, 290(1-2): 35-43.
25. Seol, W., Choi, H.S., Moore, D.D. Isolation of proteins that interact specifically with the retinoid X receptor: Two novel orphan receptors. Mol Endocrinol 1995, 9(1): 72-85.
26. Cariou, B., van Harmelen, K., Duran-Sandoval, D. et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006, 281(16): 11039-49.
27. Rizzo, G., Disante, M., Mencarelli, A. et al. The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo. Mol Pharmacol 2006, 70(4): 1164-73.
28. Lee, F.Y., Lee, H., Hubbert, M.L., Edwards, P.A., Zhang, Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci 2006, 31(10): 572-80.
29. Zhang, Y., Yin, L., Anderson, J. et al. Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J Biol Chem 2010, 285(5): 3035-43.
30. Houten, S.M., Watanabe, M., Auwerx, J. Endocrine functions of bile acids. EMBO J 2006, 25(7): 1419-25.
31. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009, 89(1): 147-91.
32. Liu, Y., Binz, J., Numerick, M.J. et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 2003, 112(11): 1678-87.
33. Moschetta, A., Bookout, A.L., Mangelsdorf, D.J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 2004, 10(12): 1352-8.
34. Inagaki, T., Moschetta, A., Lee, Y.K. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006, 103(10): 3920-5.
35. Huang, W., Ma, K., Zhang, J. et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006, 312(5771): 233-6.
36. Chen, W.D., Wang, Y.D., Zhang, L. et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology 2010, 51(3): 953-62.
37. Maran, R.R., Thomas, A., Roth, M. et al. Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J Pharmacol Exp Ther 2009, 328(2): 469-77.
38. Modica, S., Murzilli, S., Salvatore, L., Schmidt, D.R, Moschetta A. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 2008, 68(23): 9589-94.
39. Yang, F., Huang, X., Yi, T., Yen, Y., Moore, D.D., Huang, W. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 2007, 67(3): 863-7.
40. Kim, I., Morimura, K., Shah, Y., Yang, Q., Ward, J.M., Gonzalez, F.J. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 2007, 28(5): 940-6.
41. Claudel, T., Staels, B., Kuipers, F. The farnesoid X receptor: A molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 2005, 25(10): 2020-30.
42. Zhang, Y., Edwards, P.A. FXR signaling in metabolic disease. FEBS Lett 2008, 582(1): 10-8.
43. Kalaany, N.Y., Mangelsdorf, D.J. LXRS and FXR: The yin and yang of cholesterol and fat metabolism. Annu Rev Physiol 2006, 68: 159-91.
44. Fiorucci, S., Rizzo, G., Donini, A., Distrutti, E., Santucci, L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med 2007, 13(7): 298-309.
45. Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J., Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008, 7(8): 678-93.
46. Ross, R. Atherosclerosis-An inflammatory disease. N Engl J Med 1999, 340(2): 115-26.
47. Libby, P., Ridker, P.M., Maseri, A. Inflammation and atherosclerosis. Circulation 2002, 105(9): 1135-43.
48. Lusis, A.J. Atherosclerosis. Nature 2000, 407(6801): 233-41.
49. Sinal, C.J., Tohkin, M., Miyata, M., Ward, J.M., Lambert, G., Gonzalez, F.J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000, 102(6): 731-44.
50. Zhang, Y., Wang, X., Vales, C. et al. FXR deficiency causes reduced atherosclerosis in Ldlr-/- mice. Arterioscler Thromb Vasc Biol 2006, 26(10): 2316-21.
51. Lambert, G., Amar, M.J., Guo, G., Brewer, H.B. Jr., Gonzalez, F.J., Sinal, C.J. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem 2003, 278(4): 2563-70.
52. Hanniman, E.A., Lambert, G., McCarthy, T.C., Sinal, C.J. Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice. J Lipid Res 2005, 46(12): 2595-604.
53. Guo, G.L., Santamarina-Fojo, S., Akiyama, T.E. et al. Effects of FXR in foam-cell formation and atherosclerosis development. Biochim Biophys Acta 2006, 1761(12): 1401-9.
54. Hartman, H.B., Gardell, S.J., Petucci, C.J., Wang, S., Krueger, J.A., Evans, M.J. Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice. J Lipid Res 2009, 50(6): 1090-100.
55. Mencarelli, A., Renga, B., Distrutti, E., Fiorucci, S. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol 2009, 296(2): H272-81.
56. Duez, H., Chao, Y.S., Hernandez, M. et al. Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice. J Biol Chem 2002, 277(50): 48051-7.
57. Li, A.C., Binder, C.J., Gutierrez, A. et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 2004, 114(11): 1564-76.
58. Tordjman, K., Bernal-Mizrachi, C., Zemany, L. et al. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J Clin Invest 2001, 107(8): 1025-34.
59. Zhang, Y., Lee, F.Y., Barrera, G. et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 2006, 103(4): 1006-11.
60. Ma, K., Saha, P.K., Chan, L., Moore, D.D. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 2006, 116(4): 1102-9.
61. Bilz, S., Samuel, V., Morino, K., Savage, D., Choi, C.S., Shulman, G.I. Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters. Am J Physiol Endocrinol Metab 2006, 290(4): E716-22.
62. Evans, M.J., Mahaney, P.E., Borges-Marcucci, L. et al. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am J Physiol Gastrointest Liver Physiol 2009, 296(3): G543-52.
63. Lundquist, J.T., Harnish, D.C., Kim, C.Y. et al. Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: Beneficial modulation of lipids in primates. J Med Chem 2010, 53(4): 1774-87.
64. Langhi, C., Le May, C., Kourimate, S. et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett 2008, 582(6): 949-55.
65. Angulo, P. Nonalcoholic fatty liver disease. N Engl J Med 2002, 346(16): 1221-31.
66. Day, C.P., James, O.F. Steatohepatitis: A tale of two "hits"? Gastroenterology 1998, 114(4): 842-5.
67. Farrell, G.C., Larter, C.Z. Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology 2006, 43(2, Suppl. 1): S99-112.
68. Petersen, K.F., Dufour, S., Befroy, D., Lehrke, M., Hendler, R.E., Shulman, G.I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005, 54(3): 603-8.
69. Yki-Jarvinen, H. Fat in the liver and insulin resistance. Ann Med 2005, 37(5): 347-56.
70. Anstee, Q.M., Goldin, R.D. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006, 87(1): 1-16.
71. Watanabe, M., Houten, S.M., Wang, L. et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004, 113(10): 1408-18.
72. Cipriani, S., Mencarelli, A., Palladino, G., Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 2010, 51(4): 771-84.
73. Zhang, S., Wang, J., Liu, Q., Harnish, D.C. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009, 51(2): 380-8.
74. Fiorucci, S., Rizzo, G., Antonelli, E. et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 2005, 314(2): 584-95.
75. Kong, B., Luyendyk, J.P., Tawfik, O., Guo, G.L. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 2009, 328(1): 116-22.
76. Cariou, B. The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis. Diabetes Metab 2008, 34(6, Pt. 2): 685-91.
77. Goodwin, B., Jones, S.A., Price, R.R. et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000, 6(3): 517-26.
78. Lu, T.T., Makishima, M., Repa, J.J. et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 2000, 6(3): 507-15.
79. Horton, J.D., Goldstein, J.L., Brown, M.S. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002, 109(9): 1125-31.
80. Zhang, Y., Castellani, L.W., Sinal, C.J., Gonzalez, F.J., Edwards, P.A. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 2004, 18(2): 157-69.
81. Boulias, K., Katrakili, N., Bamberg, K., Underhill, P., Greenfield, A., Talianidis, I. Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP. EMBO J 2005, 24(14): 2624-33.
82. Wang, L., Liu, J., Saha, P. et al. The orphan nuclear receptor SHP regulates PGC-1alpha expression and energy production in brown adipocytes. Cell Metab 2005, 2(4): 227-38.
83. Huang, J., Iqbal, J., Saha, P.K. et al. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 2007, 46(1): 147-57.
84. Nozawa, H. Xanthohumol, the chalcone from beer hops (Humulus lupulus L.), is the ligand for farnesoid X receptor and ameliorates lipid and glucose metabolism in KK-A(y) mice. Biochem Biophys Res Commun 2005, 336(3): 754-61.
85. Stayrook, K.R., Bramlett, K.S., Savkur, R.S. et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 2005, 146(3): 984-91.
86. Popescu, I.R., Helleboid-Chapman, A., Lucas, A. et al. The nuclear receptor FXR is expressed in pancreatic beta-cells and protects human islets from lipotoxicity. FEBS Lett 2010, 584(13): 2845-51.
87. Renga, B., Mencarelli, A., Vavassori, P., Brancaleone, V., Fiorucci, S. The bile acid sensor FXR regulates insulin transcription and secretion. Biochim Biophys Acta 2010, 1802(3): 363-72.
88. Chuang, J.C., Cha, J.Y., Garmey, J.C., Mirmira, R.G., Repa, J.J. Research resource: Nuclear hormone receptor expression in the endocrine pancreas. Mol Endocrinol 2008, 22(10): 2353-63.