Bile Acid Receptors and Liver Cancer

Current Pathobiology Reports

Volumn 1, Issue 1, 2013, Pages 29-35

  Wang, Xichun ^a   Fu, Xianghui ^a   Van Ness, Carl ^a   Meng, Zhipeng ^a   Ma, Xiaoxiao ^a   Huang, Wendong ^a  

^a CITY OF HOPE NATIONAL MEDICAL CENTER   (United States)

Author keywords

Bile acids; FXR; Inflammation; Liver cancer; Metabolism; TGR5

Indexed keywords

EID: 84885477828     PISSN: None     EISSN: 2167485X     Source Type: Journal    
DOI: 10.1007/s40139-012-0003-6     Document Type: Review

References (75)

1. Jenkins G, Hardie LJ, Royal Society of Chemistry (2008) Bile acids: toxicology and bioactivity. Royal Society of Chemistry, Cambridge
2. Halilbasic E, Claudel T, Trauner M (2012) Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol. doi:10.1016/j.jhep.2012.08.002
3. Liao M, Zhao J, Wang T, Duan J, Zhang Y, et al (2011) Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells. Mol Cancer 10:44
4. Tinkle CL, Haas-Kogan D (2012) Hepatocellular carcinoma: natural history, current management, and emerging tools. Biologics 6:207–219
5. Baptissart M, Vega A, Maqdasy S, Caira F, Baron S, et al (2012) Bile acids: from digestion to cancers. Biochimie. [Epub ahead of print]
6. Raufman JP, Cheng K, Zimniak P (2003) Activation of muscarinic receptor signaling by bile acids: physiological and medical implications. Dig Dis Sci 48:1431–1444
7. Jansen PLM (2007) Endogenous bile acids as carcinogens. J Hepatol 47:434–435
8. •• Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, et al (2006) Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44:478–486. The first indication of a link between BAs and human HCC.
9. Scheimann AO, Strautnieks SS, Knisely AS, Byrne JA, Thompson RJ, et al (2007) Mutations in bile salt export pump (ABCB11) in two children with progressive familial intrahepatic cholestasis and cholangiocarcinoma. J Pediatr 150:556–559
10. Cameron RG, Imaida K, Tsuda H, Ito N (1982) Promotive effects of steroids and bile acids on hepatocarcinogenesis initiated by diethylnitrosamine. Cancer Res 42:2426–2428
11. Tsuda H, Masui T, Imaida K, Fukushima S, Ito N (1984) Promotive effect of primary and secondary bile acids on the induction of gamma-glutamyl transpeptidase-positive liver cell foci as a possible endogenous factor for hepatocarcinogenesis in rats. Gann 75:871–875
12. Kitazawa S (1993) Studies on initiating activity of secondary bile acids for rat hepatocarcinogenesis. Hokkaido Igaku Zasshi 68:110–120
13. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, et al (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466
14. •• Yang F, Huang X, Yi T, Yen Y, Moore DD, et al (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863–867. The first evidence that, in the absence of FXR, HCC develops spontaneously in mice.
15. Yerushalmi B, Dahl R, Devereaux MW, Gumpricht E, Sokol RJ (2001) Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology 33:616–626
16. Gupta S, Natarajan R, Payne SG, Studer EJ, Spiegel S, et al (2004) Deoxycholic acid activates the c-Jun N-terminal kinase pathway via FAS receptor activation in primary hepatocytes. Role of acidic sphingomyelinase-mediated ceramide generation in FAS receptor activation. J Biol Chem 279:5821–5828
17. Jean-Louis S, Akare S, Ali MA, Mash EA, Jr., Meuillet E, et al (2006) Deoxycholic acid induces intracellular signaling through membrane perturbations. J Biol Chem 281:14948–14960
18. Dent P, Fang Y, Gupta S, Studer E, Mitchell C, et al (2005) Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology 42:1291–1299
19. Wang YD, Chen WD, Huang W (2008) FXR, a target for different diseases. Histol Histopathol 23:621–627
20. Chen WD, Wang YD, Meng Z, Zhang L, Huang W (2011) Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim Biophys Acta 1812:888–892
21. •• Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719. The first publication to identify TGR5 as a BA membrane receptor.
22. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, et al (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435–9440
23. • Maruyama T, Tanaka K, Suzuki J, Miyoshi H, Harada N, et al (2006) Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice. J Endocrinol 191:197–205. TGR5 knockout mice were generated.
24. • Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, et al (2006) Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 398:423–430. TGR5 knockout mice and cholestreol gallstone formation.
25. Chen X, Lou G, Meng Z, Huang W (2011) TGR5: a novel target for weight maintenance and glucose metabolism. Exp Diabetes Res 2011:853501
26. Fiorucci S, Mencarelli A, Palladino G, Cipriani S (2009) Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci 30:570–580
27. Keitel V, Häussinger D (2012) Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol 36:412–419
28. •• Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, et al (1995) Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81:687–693.First paper to clone FXR gene.
29. Cai SY, Xiong L, Wray CG, Ballatori N, Boyer JL (2007) The farnesoid X receptor FXRalpha/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution. Am J Physiol Regul Integr Comp Physiol 293:R1400–1409
30. Meng Z, Wang Y, Wang L, Jin W, Liu N, et al (2010) FXR regulates liver repair after CCl4-induced toxic injury. Mol Endocrinol 24:886–897
31. Meng Z, Liu N, Fu X, Wang X, Wang YD, et al (2011) Insufficient bile acid signaling impairs liver repair in CYP27(−/−) mice. J Hepatol 55:885–895
32. • Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, et al (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233–236. Identification of an unexpected role of FXR in liver regeneration.
33. Zhang LS, Huang XF, Meng ZP, Dong BN, Shiah S, et al (2009) Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol 23:137–145
34. • Kim I, Morimura K, Shah Y, Yang Q, Ward JM, et al (2007) Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28:940–946. First evidence of FXR in suppressing HCC.
35. Zhu Y, Li F, Guo GL (2011) Tissue-specific function of farnesoid X receptor in liver and intestine. Pharmacol Res 63:259–265
36. Zhang L, Wang YD, Chen WD, Wang X, Lou G, et al (2012) Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine. Hepatology. doi:10.1002/hep.25905. FXR couples BA regulation to liver regeneration/repair. Both liver- and intestine-FXR are activated after liver resection or injury, which contribute to promoting liver regeneration/repair.
37. Ueno Y, Moriyama M, Uchida T, Arakawa Y (2001) Irregular regeneration of hepatocytes is an important factor in the hepatocarcinogenesis of liver disease. Hepatology 33:357–362
38. Wolfe A, Thomas A, Edwards G, Jaseja R, Guo GL, et al (2011) Increased activation of the Wnt/beta-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther 338:12–21
39. Zhang YQ, Ge XM, Heemstra LA, Chen WD, Xu JS, et al (2012) Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 26:272–280
40. Schoenborn JR, Wilson CB (2007) Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96:41–101
41. Meng Z, Wang X, Gan Y, Zhang Y, Zhou H, et al (2012) Deletion of IFNγ enhances hepatocarcinogenesis in FXR knockout mice. J Hepatol 57:1004–1012
42. •• Wang Y-D, Chen W-D, Yu D, Forman BM, Huang W (2011) The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology 54:1421–1432. TGR5 suppresses hepatic inflammation by antagonizing NF-κB activities. This may be also the mechanism by which TGR5 suppresses immune response.
43. •• Wang YD, Chen WD, Wang M, Yu D, Forman BM, et al (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643. First evidence that FXR suppress hepatic inflammatory response by antagonizing NF-κB activities.
44. Xu Z, Huang G, Gong W, Zhao Y, Zhou P, et al (2012) Activation of Farnesoid X Receptor Increases the Expression of Cytokine Inducible SH2-Containing Protein in HepG2 Cells. J Interferon Cytokine Res 32:517–523
45. Wang YD, Yang F, Chen WD, Huang X, Lai L, et al (2008) Farnesoid X receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo. Mol Endocrinol 22:1622–1632
46. Nomoto M, Miyata M, Yin S, Kurata Y, Shimada M, et al (2009) Bile Acid-Induced Elevated Oxidative Stress in the Absence of Farnesoid X Receptor. Biol Pharm Bull 32:172–178
47. Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, et al (2009) Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 175:2392–2405
48. • He N, Park K, Zhang Y, Huang J, Lu S, et al (2008) Epigenetic inhibition of nuclear receptor small heterodimer partner is associated with and regulates hepatocellular carcinoma growth. Gastroenterology 134:793–802. The role of Shp in suppressing HCC is demonstrated. This paper also examines the expression of Shp in human HCC samples.
49. Deuschle U, Schuler J, Schulz A, Schluter T, Kinzel O, et al (2012) FXR Controls the tumor suppressor NDRG2 and FXR agonists reduce liver tumor growth and metastasis in an Orthotopic mouse xenograft model. PLoS One 7:e43044
50. Su H, Ma C, Liu J, Li N, Gao M, et al (2012) Downregulation of nuclear receptor FXR is associated with multiple malignant clinicopathological characteristics in human hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol. 303:G1245–G1253
51. Fujino T, Takeuchi A, Maruko-Ohtake A, Ohtake Y, Satoh J, et al (2012) Critical role of farnesoid X receptor (FXR) for hepatocellular carcinoma cell proliferation. J Biochem. [Epub ahead of print]
52. Takahara Y, Takahashi M, Zhang QW, Wagatsuma H, Mori M, et al (2008) Serial changes in expression of functionally clustered genes in progression of liver fibrosis in hepatitis C patients. World J Gastroenterol 14:2010–2022
53. Liu N, Meng Z, Lou G, Zhou W, Wang X, et al (2012) Hepatocarcinogenesis in FXR−/− mice mimics human HCC progression that operates through HNF1alpha regulation of FXR expression. Mol Endocrinol 26:775–785
54. Zhang Y, Gong W, Dai SS, Huang G, Shen XD, et al (2012) Downregulation of human Farnesoid X receptor by miR-421 promotes proliferation and migration of hepatocellular carcinoma cells. Mol Cancer Res 10:516–522
55. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Gorg B, et al (2007) The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45:695–704
56. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, et al (2009) The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50:861–870
57. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, et al (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev 57:279–288
58. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, et al (2006) Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484–489
59. Houten SM, Watanabe M, Auwerx J (2006) Endocrine functions of bile acids. EMBO J 25:1419–1425
60. Thomas C, Auwerx J, Schoonjans K (2008) Bile acids and the membrane bile acid receptor TGR5–connecting nutrition and metabolism. Thyroid 18:167–174
61. Sato H, Genet C, Strehle A, Thomas C, Lobstein A, et al (2007) Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem Biophys Res Commun 362:793–798
62. Katsuma S, Hirasawa A, Tsujimoto G (2005) Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun 329:386–390
63. • Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, et al (2009) TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167–177.TGR5 participates in regulating glucose homeostasis.
64. Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M (2010) Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 28:220–224
65. Martin R, Carvalho-Tavares J, Hernandez M, Arnes M, Ruiz-Gutierrez V, et al (2010) Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: a potential therapeutic role. Biochem Pharmacol 79:198–208
66. Schmidt SV, Nino-Castro AC, Schultze JL (2012) Regulatory dendritic cells: there is more than just immune activation. Front Immunol 3:274
67. Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, et al (2012) Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology 136:153–162
68. •• Chen W-D, Yu D, Forman BM, Huang W, Wang Y-D (2012) The deficiency of G-protein-coupled bile acid receptor gpbar1 (TGR5) enhances chemically-induced liver carcinogenesis. Hepatology. doi:10.1002/hep.26019. First evidence that TGR5 may suppress HCC development.
69. He G, Karin M (2011) NF-kappaB and STAT3: key players in liver inflammation and cancer. Cell Res 21:159–168
70. Fiorucci S, Mencarelli A, Distrutti E, Zampella A (2012) Farnesoid X receptor: from medicinal chemistry to clinical applications. Future Med Chem 4:877–891
71. Hollman DAA, Milona A, van Erpecum KJ, van Mil SWC (2012) Anti-inflammatory and metabolic actions of FXR: Insights into molecular mechanisms. Biochimica Biophysica Acta 1821:1443–1452
72. Fu J, Si P, Zheng M, Chen L, Shen X, et al (2012) Discovery of new non-steroidal FXR ligands via a virtual screening workflow based on Phase shape and induced fit docking. Bioorg Med Chem Lett 22:6848–6853
73. Fiorucci S, Distrutti E, Bifulco G, D’Auria MV, Zampella A (2012) Marine sponge steroids as nuclear receptor ligands. Trends Pharmacol Sci 33:591–601
74. Ono E, Inoue J, Hashidume T, Shimizu M, Sato R (2011) Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet. Biochem Biophys Res Commun 410:677–681
75. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, et al (2011) The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PloS One 6:e25637