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The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer

Abstract

Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apcmin/+ mice. Owing to altered gut microbiota and FXR signalling, changes in overall BA levels and specific BA metabolites probably contribute to enterohepatic tumorigenesis. Modulating intestinal FXR signalling and altering BA metabolites are potential strategies for gastrointestinal and liver cancer prevention and treatment. In this Review, studies on the role of FXR in metabolic diseases and gastrointestinal and liver cancer are discussed, and the potential for development of targeted drugs are summarized.

Key points

  • Farnesoid X receptor (FXR) signalling in liver and intestine modulates enterohepatic bile acid circulation and lipid and glucose metabolism.

  • Both activation of hepatic FXR and inhibition of intestinal FXR have beneficial effects on obesity-related metabolic diseases.

  • As a transcriptional factor, FXR directly regulates expression of tumour suppressors involved in gastrointestinal and liver cancers.

  • The protective role of FXR in hepatocellular carcinoma mainly depends on hepatic modulation of bile acid homeostasis.

  • Tissue-specific FXR agonists and antagonists should be explored as potentially clinical drugs for metabolic disease and cancer.

  • Gut microbiota-derived bile acid metabolism should be considered as a new drug target for development of therapeutic strategies.

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Fig. 1: Modulation of gut microbiota–bile acid–FXR axis to improve metabolic diseases.
Fig. 2: Fexaramine ameliorates insulin resistance mainly by activating TGR5 and upregulation of circulating FGF15/19.
Fig. 3: FXR silencing during colonic tumorigenesis.
Fig. 4: FXR influences the intestinal immune response and tumorigenesis.
Fig. 5: Loss function of tumour suppressors and imbalance of BA metabolism mainly account for HCC progression.

References

  1. 1.

    Russell, D. W. Fifty years of advances in bile acid synthesis and metabolism. J. Lipid Res. 50, S120–S125 (2009).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Chiang, J. Y. Bile acid metabolism and signaling. Compr. Physiol. 3, 1191–1212 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Wahlstrom, A., Sayin, S. I., Marschall, H. U. & Backhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).

    PubMed  Google Scholar 

  4. 4.

    Hofmann, A. F. & Hagey, L. R. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J. Lipid Res. 55, 1553–1595 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Dawson, P. A. Hepatic bile acid uptake in humans and mice: multiple pathways and expanding potential role for gut-liver signaling. Hepatology 66, 1384–1386 (2017).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Matsubara, T., Li, F. & Gonzalez, F. J. FXR signaling in the enterohepatic system. Mol. Cell Endocrinol. 368, 17–29 (2013).

    CAS  PubMed  Google Scholar 

  7. 7.

    Forman, B. M. et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687–693 (1995).

    CAS  PubMed  Google Scholar 

  8. 8.

    Makishima, M. et al. Identification of a nuclear receptor for bile acids. Science 284, 1362–1365 (1999).

    CAS  PubMed  Google Scholar 

  9. 9.

    Parks, D. J. et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365–1368 (1999).

    CAS  PubMed  Google Scholar 

  10. 10.

    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 3, 543–553 (1999).

    CAS  PubMed  Google Scholar 

  11. 11.

    Goodwin, B. et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6, 517–526 (2000).

    CAS  PubMed  Google Scholar 

  12. 12.

    Kong, B. et al. Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice. Hepatology 56, 1034–1043 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Denson, L. A. et al. The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121, 140–147 (2001).

    CAS  PubMed  Google Scholar 

  14. 14.

    Ananthanarayanan, M., Balasubramanian, N., Makishima, M., Mangelsdorf, D. J. & Suchy, F. J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem. 276, 28857–28865 (2001).

    CAS  PubMed  Google Scholar 

  15. 15.

    Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    CAS  Google Scholar 

  16. 16.

    Sun, L. et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat. Med. 24, 1919–1929 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Downes, M. et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol. Cell 11, 1079–1092 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Pellicciari, R. et al. 6α-Ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45, 3569–3572 (2002).

    CAS  PubMed  Google Scholar 

  19. 19.

    Jiang, C. et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6, 10166 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Gonzalez, F. J., Jiang, C. & Patterson, A. D. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Campbell, P. T. et al. Body mass index, waist circumference, diabetes, and risk of liver cancer for US adults. Cancer Res. 76, 6076–6083 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Chen, Y., Wang, X., Wang, J., Yan, Z. & Luo, J. Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur. J. Cancer 48, 2137–2145 (2012).

    PubMed  Google Scholar 

  23. 23.

    Bardou, M., Barkun, A. N. & Martel, M. Obesity and colorectal cancer. Gut 62, 933–947 (2013).

    CAS  PubMed  Google Scholar 

  24. 24.

    Cariou, B. et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039–11049 (2006).

    CAS  Google Scholar 

  25. 25.

    Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000).

    CAS  Google Scholar 

  26. 26.

    Prawitt, J. et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 60, 1861–1871 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Zhang, Y. et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006).

    CAS  Google Scholar 

  28. 28.

    Hirschfield, G. M. et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148, 751–761 e758 (2015).

    CAS  PubMed  Google Scholar 

  29. 29.

    Milona, A. et al. Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. Hepatology 52, 1341–1349 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Hoofnagle, J. H. FXR agonists as therapy for liver disease. Hepatology 72, 1–3 (2020).

    PubMed  Google Scholar 

  31. 31.

    Markham, A. & Keam, S. J. Obeticholic acid: first global approval. Drugs 76, 1221–1226 (2016).

    CAS  PubMed  Google Scholar 

  32. 32.

    Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    CAS  PubMed  Google Scholar 

  33. 33.

    Issa, D., Wattacheril, J. & Sanyal, A. J. Treatment options for nonalcoholic steatohepatitis–a safety evaluation. Expert Opin. Drug Saf. 16, 903–913 (2017).

    CAS  PubMed  Google Scholar 

  34. 34.

    Chapman, R. W. & Lynch, K. D. Obeticholic acid–a new therapy in PBC and NASH. Br. Med. Bull. 133, 95–104 (2020).

    CAS  PubMed  Google Scholar 

  35. 35.

    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. 51, 380–388 (2009).

    CAS  PubMed  Google Scholar 

  36. 36.

    Zhou, J. et al. SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis. Nat. Commun. 11, 240 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gonzalez, F. J. Nuclear receptor control of enterohepatic circulation. Compr. Physiol. 2, 2811–2828 (2012).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Xie, C. et al. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes 66, 613–626 (2017).

    CAS  PubMed  Google Scholar 

  39. 39.

    Chaurasia, B. & Summers, S. A. Ceramides - Lipotoxic inducers of metabolic disorders. Trends Endocrinol. Metab. 26, 538–550 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Kubota, K. et al. Improvements of mean body mass index and body weight in preobese and overweight Japanese adults with black Chinese tea (Pu-Erh) water extract. Nutr. Res. 31, 421–428 (2011).

    CAS  PubMed  Google Scholar 

  41. 41.

    Huang, F. et al. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat. Commun. 10, 4971 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Pathak, P. et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68, 1574–1588 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Pathak, P. et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J. Biol. Chem. 292, 11055–11069 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Chiang, J. Y. L. & Ferrell, J. M. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G554–G573 (2020).

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Trabelsi, M. S. et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6, 7629 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ducastel, S. et al. The nuclear receptor FXR inhibits glucagon-like peptide-1 secretion in response to microbiota-derived short-chain fatty acids. Sci. Rep. 10, 174 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Keum, N. & Giovannucci, E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat. Rev. Gastroenterol. Hepatol. 16, 713–732 (2019).

    PubMed  Google Scholar 

  49. 49.

    Fodde, R., Smits, R. & Clevers, H. APC, signal transduction and genetic instability in colorectal cancer. Nat. Rev. Cancer 1, 55–67 (2001).

    CAS  PubMed  Google Scholar 

  50. 50.

    Lax, S. et al. Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int. J. Cancer 130, 2232–2239 (2012).

    CAS  PubMed  Google Scholar 

  51. 51.

    Modica, S. et al. The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. Gastroenterology 138, 636–648.E12 (2010).

    CAS  PubMed  Google Scholar 

  52. 52.

    De Gottardi, A. et al. The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer. Dig. Dis. Sci. 49, 982–989 (2004).

    PubMed  Google Scholar 

  53. 53.

    Selmin, O. I. et al. Inactivation of adenomatous polyposis coli reduces bile acid/farnesoid X receptor expression through Fxr gene CpG methylation in mouse colon tumors and human colon cancer cells. J. Nutr. 146, 236–242 (2016).

    CAS  PubMed  Google Scholar 

  54. 54.

    Bailey, A. M. et al. FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G48–G58 (2014).

    CAS  PubMed  Google Scholar 

  55. 55.

    Modica, S. et al. Transcriptional regulation of the intestinal nuclear bile acid farnesoid X receptor (FXR) by the caudal-related homeobox 2 (CDX2). J. Biol. Chem. 289, 28421–28432 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Modica, S., Murzilli, S., Salvatore, L., Schmidt, D. R. & Moschetta, A. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res. 68, 9589–9594 (2008).

    CAS  PubMed  Google Scholar 

  57. 57.

    Maran, R. R. et al. Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. J. Pharmacol. Exp. Ther. 328, 469–477 (2009).

    CAS  PubMed  Google Scholar 

  58. 58.

    Peng, Z., Raufman, J. P. & Xie, G. Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis. PLoS ONE 7, e48461 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Qiao, P., Li, S., Zhang, H., Yao, L. & Wang, F. Farnesoid X receptor inhibits proliferation of human colorectal cancer cells via the miR135A1/CCNG2 signaling pathway. Oncol. Rep. 40, 2067–2078 (2018).

    CAS  PubMed  Google Scholar 

  60. 60.

    Yu, J. et al. Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis. Cell Death Dis. 11, 640 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lee, Y. J. et al. The role of nuclear receptor subfamily 1 group H member 4 (NR1H4) in colon cancer cell survival through the regulation of c-Myc stability. Mol. Cell 43, 459–468 (2020).

    CAS  Google Scholar 

  62. 62.

    Peng, Z., Chen, J., Drachenberg, C. B., Raufman, J. P. & Xie, G. Farnesoid X receptor represses matrix metalloproteinase 7 expression, revealing this regulatory axis as a promising therapeutic target in colon cancer. J. Biol. Chem. 294, 8529–8542 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E. & Fiorucci, S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183, 6251–6261 (2009).

    CAS  PubMed  Google Scholar 

  64. 64.

    Gadaleta, R. M. et al. Fibroblast growth factor 19 modulates intestinal microbiota and inflammation in presence of farnesoid X receptor. EBioMedicine 54, 102719 (2020).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Costarelli, V. et al. A prospective study of serum bile acid concentrations and colorectal cancer risk in post-menopausal women on the island of Guernsey. Br. J. Cancer 86, 1741–1744 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Cao, H. et al. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int. J. Cancer 140, 2545–2556 (2017).

    CAS  PubMed  Google Scholar 

  67. 67.

    Bernstein, H., Bernstein, C., Payne, C. M., Dvorakova, K. & Garewal, H. Bile acids as carcinogens in human gastrointestinal cancers. Mutat. Res. 589, 47–65 (2005).

    CAS  PubMed  Google Scholar 

  68. 68.

    Bernstein, C. et al. Carcinogenicity of deoxycholate, a secondary bile acid. Arch. Toxicol. 85, 863–871 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kuhn, T. et al. Prediagnostic plasma bile acid levels and colon cancer risk: a prospective study. J. Natl Cancer Inst. 112, 516–524 (2020).

    PubMed  Google Scholar 

  70. 70.

    Dermadi, D. et al. Western diet deregulates bile acid homeostasis, cell proliferation, and tumorigenesis in colon. Cancer Res. 77, 3352–3363 (2017).

    CAS  PubMed  Google Scholar 

  71. 71.

    Fu, T. et al. FXR regulates intestinal cancer stem cell proliferation. Cell 176, 1098–1112 e1018 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Lew, J. L. et al. The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. J. Biol. Chem. 279, 8856–8861 (2004).

    CAS  PubMed  Google Scholar 

  73. 73.

    Souris, J. S. et al. A novel mouse model of sporadic colon cancer induced by combination of conditional Apc genes and chemical carcinogen in the absence of Cre recombinase. Carcinogenesis 40, 1376–1386 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Hinoi, T. et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 67, 9721–9730 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Campbell, C. et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 581, 475–479 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kim, E. K., Cho, J. H., Kim, E. & Kim, Y. J. Ursodeoxycholic acid inhibits the proliferation of colon cancer cells by regulating oxidative stress and cancer stem-like cell growth. PLoS ONE 12, e0181183 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Khare, S. et al. Ursodeoxycholic acid suppresses Cox-2 expression in colon cancer: roles of Ras, p38, and CCAAT/enhancer-binding protein. Nutr. Cancer 60, 389–400 (2008).

    CAS  PubMed  Google Scholar 

  79. 79.

    Im, E. & Martinez, J. D. Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells. J. Nutr. 134, 483–486 (2004).

    CAS  PubMed  Google Scholar 

  80. 80.

    Shah, S. A., Volkov, Y., Arfin, Q., Abdel-Latif, M. M. & Kelleher, D. Ursodeoxycholic acid inhibits interleukin 1 beta [corrected] and deoxycholic acid-induced activation of NF-κB and AP-1 in human colon cancer cells. Int. J. Cancer 118, 532–539 (2006).

    CAS  PubMed  Google Scholar 

  81. 81.

    Liu, L., Fishman, M. L., Hicks, K. B., Kende, M. & Ruthel, G. Pectin/zein beads for potential colon-specific drug delivery: synthesis and in vitro evaluation. Drug Deliv. 13, 417–423 (2006).

    CAS  PubMed  Google Scholar 

  82. 82.

    Yan, F. et al. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J. Clin. Invest. 121, 2242–2253 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Amidon, S., Brown, J. E. & Dave, V. S. Colon-targeted oral drug delivery systems: design trends and approaches. AAPS PharmSciTech 16, 731–741 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    El-Serag, H. B. & Rudolph, K. L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557–2576 (2007).

    CAS  PubMed  Google Scholar 

  85. 85.

    Huang, X. F., Zhao, W. Y. & Huang, W. D. FXR and liver carcinogenesis. Acta Pharmacol. Sin. 36, 37–43 (2015).

    PubMed  Google Scholar 

  86. 86.

    Wolfe, A. et al. Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J. Pharmacol. Exp. Ther. 338, 12–21 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Su, H. et al. 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 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940–946 (2007).

    CAS  PubMed  Google Scholar 

  89. 89.

    Yang, F. et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 67, 863–867 (2007).

    CAS  PubMed  Google Scholar 

  90. 90.

    Takahashi, S. et al. Role of farnesoid X receptor and bile acids in hepatic tumor development. Hepatol. Commun. 2, 1567–1582 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Liu, X. et al. Farnesoid X receptor associates with beta-catenin and inhibits its activity in hepatocellular carcinoma. Oncotarget 6, 4226–4238 (2015).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Kong, B. et al. Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G295–G302 (2016).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Liang, Y., Yang, Z. & Zhong, R. Primary biliary cirrhosis and cancer risk: a systematic review and meta-analysis. Hepatology 56, 1409–1417 (2012).

    PubMed  Google Scholar 

  94. 94.

    Knisely, A. S. et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44, 478–486 (2006).

    CAS  PubMed  Google Scholar 

  95. 95.

    Cariello, M. et al. Long-term administration of nuclear bile acid receptor FXR agonist prevents spontaneous hepatocarcinogenesis in Abcb4(-/-) mice. Sci. Rep. 7, 11203 (2017).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Kimhofer, T., Fye, H., Taylor-Robinson, S., Thursz, M. & Holmes, E. Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review. Br. J. Cancer 112, 1141–1156 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Liao, M. et al. Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells. Mol. Cancer 10, 44 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Anakk, S. et al. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 5, 1060–1069 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    CAS  PubMed  Google Scholar 

  100. 100.

    Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360 (2018).

  101. 101.

    Kong, B. et al. Fibroblast growth factor 15-dependent and bile acid-independent promotion of liver regeneration in mice. Hepatology 68, 1961–1976 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Li, Q. et al. The ileal FGF15/19 to hepatic FGFR4 axis regulates liver regeneration after partial hepatectomy in mice. J. Physiol. Biochem. 74, 247–260 (2018).

    CAS  PubMed  Google Scholar 

  103. 103.

    Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Zweers, S. J. et al. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 55, 575–583 (2012).

    CAS  PubMed  Google Scholar 

  105. 105.

    Schaap, F. G., van der Gaag, N. A., Gouma, D. J. & Jansen, P. L. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 49, 1228–1235 (2009).

    CAS  PubMed  Google Scholar 

  106. 106.

    Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19, 347–358 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Ahn, S. M. et al. Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification. Hepatology 60, 1972–1982 (2014).

    CAS  PubMed  Google Scholar 

  108. 108.

    Zhao, H. et al. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β-catenin signaling cascade via FGFR4 activation. Oncotarget 7, 13575–13586 (2016).

    PubMed  Google Scholar 

  109. 109.

    Chen, J. et al. Fibroblast growth factor 19-mediated up-regulation of SYR-related high-mobility group Box 18 promotes hepatocellular carcinoma metastasis by transactivating fibroblast growth factor receptor 4 and Fms-related tyrosine kinase 4. Hepatology 71, 1712–1731 (2020).

    CAS  PubMed  Google Scholar 

  110. 110.

    Uriarte, I. et al. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int. J. Cancer 136, 2469–2475 (2015).

    CAS  PubMed  Google Scholar 

  111. 111.

    Zhou, M. et al. Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J. Hepatol. 66, 1182–1192 (2017).

    CAS  PubMed  Google Scholar 

  112. 112.

    Guo, F. et al. FXR induces SOCS3 and suppresses hepatocellular carcinoma. Oncotarget 6, 34606–34616 (2015).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Gao, B., Wang, H., Lafdil, F. & Feng, D. STAT proteins – key regulators of anti-viral responses, inflammation, and tumorigenesis in the liver. J. Hepatol. 57, 430–441 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Deuschle, U. et al. 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 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    He, J. et al. Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells. Mol. Cancer 14, 163 (2015).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Gadaleta, R. M. et al. Suppression of hepatic bile acid synthesis by a non-tumorigenic FGF19 analogue protects mice from fibrosis and hepatocarcinogenesis. Sci. Rep. 8, 17210 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Kang, H. J. et al. Characterization of hepatocellular carcinoma patients with FGF19 amplification assessed by fluorescence in situ hybridization: a large cohort study. Liver Cancer 8, 12–23 (2019).

    CAS  PubMed  Google Scholar 

  118. 118.

    Kim, R. D. et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 9, 1696–1707 (2019).

    CAS  PubMed  Google Scholar 

  119. 119.

    Attia, Y. M., Tawfiq, R. A., Ali, A. A. & Elmazar, M. M. The FXR agonist, obeticholic acid, suppresses HCC proliferation & metastasis: role of IL-6/STAT3 signalling pathway. Sci. Rep. 7, 12502 (2017).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Liu, T. et al. Mechanisms of MAFG dysregulation in cholestatic liver injury and development of liver cancer. Gastroenterology 155, 557–571.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Al-Dury, S. et al. Obeticholic acid may increase the risk of gallstone formation in susceptible patients. J. Hepatol. 71, 986–991 (2019).

    CAS  PubMed  Google Scholar 

  122. 122.

    Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582.e1 (2013).

    CAS  PubMed  Google Scholar 

  123. 123.

    Kanthan, R., Senger, J. L., Ahmed, S. & Kanthan, S. C. Gallbladder cancer in the 21st century. J. Oncol. 2015, 967472 (2015).

    PubMed  PubMed Central  Google Scholar 

  124. 124.

    Obama, K. et al. Genome-wide analysis of gene expression in human intrahepatic cholangiocarcinoma. Hepatology 41, 1339–1348 (2005).

    CAS  PubMed  Google Scholar 

  125. 125.

    Zhong, X. Y. et al. MicroRNA-421 functions as an oncogenic miRNA in biliary tract cancer through down-regulating farnesoid X receptor expression. Gene 493, 44–51 (2012).

    CAS  PubMed  Google Scholar 

  126. 126.

    Wang, W. et al. FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression. Oncotarget 7, 34617–34629 (2016).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Zuo, M. et al. RNA sequencing-based analysis of gallbladder cancer reveals the importance of the liver X receptor and lipid metabolism in gallbladder cancer. Oncotarget 7, 35302–35312 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

    Erice, O. et al. Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression. Biochim. Biophy. Acta Mol. Basis Dis. 1864, 1335–1344 (2018).

    CAS  Google Scholar 

  129. 129.

    Di Matteo, S. et al. The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma. PLoS ONE 14, e0210077 (2019).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Lozano, E. et al. Cocarcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development. Mol. Cancer Res. 12, 91–100 (2014).

    CAS  PubMed  Google Scholar 

  131. 131.

    Gege, C. et al. Ligands: current status and clinical applications. Handb. Exp. Pharmacol. 256, 167–205 (2019).

    CAS  PubMed  Google Scholar 

  132. 132.

    Yamada, S. et al. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget 9, 9925–9939 (2018).

    PubMed  PubMed Central  Google Scholar 

  133. 133.

    Wirbel, J. et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer. Nat. Med. 25, 679–689 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Chen, F. et al. Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter. J. Biol. Chem. 278, 19909–19916 (2003).

    CAS  PubMed  Google Scholar 

  135. 135.

    Frankenberg, T. et al. Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G912–G922 (2006).

    CAS  PubMed  Google Scholar 

  136. 136.

    Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).

    CAS  PubMed  Google Scholar 

  137. 137.

    Grober, J. et al. 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 (1999).

    CAS  PubMed  Google Scholar 

  138. 138.

    Zollner, G., Marschall, H. U., Wagner, M. & Trauner, M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol. Pharm. 3, 231–251 (2006).

    CAS  PubMed  Google Scholar 

  139. 139.

    Van Mil, S. W. et al. Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy. Gastroenterology 133, 507–516 (2007).

    PubMed  Google Scholar 

  140. 140.

    Yang, Z. X., Shen, W. & Sun, H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol. Int. 4, 741–748 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Takahashi, S. et al. Farnesoid X receptor protects against low-dose carbon tetrachloride-induced liver injury through the taurocholate-JNK pathway. Toxicol. Sci. 158, 334–346 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Fiorucci, S. et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127, 1497–1512 (2004).

    CAS  PubMed  Google Scholar 

  143. 143.

    Fiorucci, S. 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. 314, 584–595 (2009).

    Google Scholar 

  144. 144.

    Wu, W. B. et al. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem. Bioph Res. Co. 443, 68–73 (2014).

    CAS  Google Scholar 

  145. 145.

    Manley, S. et al. Farnesoid X receptor regulates forkhead Box O3a activation in ethanol-induced autophagy and hepatotoxicity. Redox Biol. 2, 991–1002 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Lu, W. et al. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach. Sci. Rep. 5, 8114 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Chen, W. D., Wang, Y. D., Meng, Z., Zhang, L. & Huang, W. Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim. Biophys. Acta 1812, 888–892 (2011).

    CAS  PubMed  Google Scholar 

  148. 148.

    Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463–472 (2011).

    CAS  PubMed  Google Scholar 

  149. 149.

    Jiang, C. T. et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J. Clin. Invest. 125, 386–402 (2015).

    PubMed  Google Scholar 

  150. 150.

    Inagaki, T. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl Acad. Sci. USA 103, 3920–3925 (2006).

    CAS  PubMed  Google Scholar 

  151. 151.

    Jiang, T. et al. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes 56, 2485–2493 (2007).

    CAS  PubMed  Google Scholar 

  152. 152.

    Gai, Z. et al. Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. Sci. Rep. 7, 9815 (2017).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Zhao, K. et al. Activation of FXR protects against renal fibrosis via suppressing Smad3 expression. Sci. Rep. 6, 37234 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Rizzo, G. et al. The farnesoid X receptor promotes adipocyte differentiation and regulates adipose cell function in vivo. Mol. Pharmacol. 70, 1164–1173 (2006).

    CAS  PubMed  Google Scholar 

  155. 155.

    Nijmeijer, R. M. et al. Impact of global Fxr deficiency on experimental acute pancreatitis and genetic variation in the FXR locus in human acute pancreatitis. PLoS ONE 9, e114393 (2014).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Popescu, I. R. et al. The nuclear receptor FXR is expressed in pancreatic β-cells and protects human islets from lipotoxicity. FEBS Lett. 584, 2845–2851 (2010).

    CAS  PubMed  Google Scholar 

  157. 157.

    Moris, D., Giaginis, C., Tsourouflis, G. & Theocharis, S. Farnesoid-X receptor (FXR) as a promising pharmaceutical target in atherosclerosis. Curr. Med. Chem. 24, 1147–1157 (2017).

    CAS  PubMed  Google Scholar 

  158. 158.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT04270682 (2020).

  159. 159.

    Liu, Y. P. et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J. Clin. Invest. 112, 1678–1687 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019).

    CAS  PubMed  Google Scholar 

  161. 161.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02855164 (2020).

  162. 162.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02516605 (2019).

  163. 163.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02913105 (2021).

  164. 164.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03804879 (2020)

  165. 165.

    Al-Khaifi, A., Rudling, M. & Angelin, B. An FXR agonist reduces bile acid synthesis independently of increases in FGF19 in healthy volunteers. Gastroenterology 155, 1012–1016 (2018).

    CAS  PubMed  Google Scholar 

  166. 166.

    US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01999101 (2016).

  167. 167.

    Patel, K. et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial. Hepatology 72, 58–71 (2020).

    CAS  PubMed  Google Scholar 

  168. 168.

    Floreani, A. & Mangini, C. Primary biliary cholangitis: old and novel therapy. Eur. J. Intern. Med. 47, 1–5 (2018).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are supported by the National Cancer Institute Intramural Research Program. J.C. was supported by a fellowship from the China Scholarship Council. We thank Y. Luo, S. Takahashi and T. Yan for reading the manuscript and providing feedback.

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Sun, L., Cai, J. & Gonzalez, F.J. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 18, 335–347 (2021). https://doi.org/10.1038/s41575-020-00404-2

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