Skip to main content

Physiology of FGF15/19

  • Chapter

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 728))

Abstract

This chapter will review the various biological actions of the mouse fibroblast growth factor 15 (Fgf15) and human fibroblast growth factor 19 (FGF19). Unlike other members of the fibroblast growth factor (FGF) family, the Fgf15 and FGF19 orthologs do not share a high degree of sequence identity. Fgf15 and FGF19 are members of an atypical subfamily of FGFs that function as hormones. Due to subtle changes in tertiary structure, these FGFs have low heparin binding affinity enabling them to diffuse away from their site of secretion and signal to distant cells. FGF signaling through the FGF receptors is also different for this sub-family, requiring klotho protein cofactors rather than heparin sulfate proteoglycan. Mouse Fgf15 and human FGF19 play key roles in enterohepatic signaling, regulation of liver bile acid biosynthesis, gallbladder motility and metabolic homeostasis.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biology 2001; 2(3): reviews3005.1-3005.12.

    Google Scholar 

  2. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends in Genetics 2004; 20(11):563–569.

    Article  PubMed  CAS  Google Scholar 

  3. Popovici C, Roubin R, Coulier F et al. An evolutionary history of the FGF superfamily. BioEssays 2005; 27:849–857.

    Article  PubMed  CAS  Google Scholar 

  4. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nature Reviews Drug Discovery 2009; 8:235–253.

    Article  PubMed  CAS  Google Scholar 

  5. Olsen SK, Garbi M, Zampieri N et al. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. JBC 2003; 278(36):34226–34236.

    Article  CAS  Google Scholar 

  6. Goldfarb M. Fibroblast growth factor homologous factors: evolution, structure and function. Cytokine Growth Factor Rev 2005; 16(2):215–220.

    Article  PubMed  CAS  Google Scholar 

  7. Goetz R, Beenken A, Ibrahimi OA et al. Molecular insights in the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007; 27:3417–3428.

    Article  PubMed  CAS  Google Scholar 

  8. Asada M, Shinomiya M, Suzuki M et al. Glycosaminoglycan affinity for the complete fibroblast growth factor family. BBA 2009; 1790:40–48.

    PubMed  CAS  Google Scholar 

  9. McWhirter JR, Goulding M, Weiner JA et al. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development 1997; 124:3221–3232.

    PubMed  CAS  Google Scholar 

  10. Iwata T, Hevner RF. Fibroblast growth factor signaling in development of the cerebral cortex. Develop. Growth Differ 2009; 51:299–323.

    Article  CAS  Google Scholar 

  11. Nishimura T, Utsunomiya Y, Hoshikawa M et al. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. BBA 1999; 1444:148–151.

    PubMed  CAS  Google Scholar 

  12. Xie M, Holcomb I, Deuel B et al. FGF-19, A novel fibroblast growth factor with unique specificity for FGFR4. Cytokine 1999; 11(10):729–735.

    Article  PubMed  CAS  Google Scholar 

  13. Zhang X, Ibrahimi OA, Olsen SK et al. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. JBC 2006; 281:15694–15700.

    Article  CAS  Google Scholar 

  14. Kurosu H, Ogawa Y, Miyoshi M et al. Regulation of Fibroblast growth factor-23 signaling by Klotho. JBC 2006; 281(10):6120–6123.

    Article  CAS  Google Scholar 

  15. Urakawa I, Yamazaki Y, Shimada T et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444:770–774.

    Article  PubMed  CAS  Google Scholar 

  16. Kurosu H, Kuro-o M. The klotho gene family and the endocrine fibroblast growth factors. Curr Opin Nephrol Hypertens 2008; 17:368–372.

    Article  PubMed  CAS  Google Scholar 

  17. Kuro-o M. Endocrine FGFs and klothos: emerging concepts. Trends Endocrin Metab 2008; 19(7):239–245.

    Article  CAS  Google Scholar 

  18. Wu X, Lemon B, Si X et al. C-terminal tail of FGF19 determines its specificity toward klotho coreceptors. JBC 2008; 283(48):33304–33309.

    Article  CAS  Google Scholar 

  19. Kurosu H, Kuro-o M. The klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endo 2009; 299:72–78.

    Article  CAS  Google Scholar 

  20. Kurosu H, Choi M, Ogawa Y et al. Tissue-specific expression of Klotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. JBC 2007; 282(37):26687–26695.

    Article  CAS  Google Scholar 

  21. Lin BC, Wang M, Blackmore C et al. Liver-specific activities of FGF19 require klotho beta. JBC 2007; 282(37):27277–27284.

    Article  CAS  Google Scholar 

  22. Wu X, Ge H, Gupte J et al. Co-receptor requirements for fibroblast growth factor-19 signaling. JBC 2007; 282(40):29069–29072.

    Article  CAS  Google Scholar 

  23. Katoh M, Katoh M. Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human. Int J Mol Med 2003; 12:45–50.

    PubMed  CAS  Google Scholar 

  24. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Developmental Dynamics 2008; 237:18–27.

    Article  PubMed  CAS  Google Scholar 

  25. Harmer NJ, Pellegrini L, Chirgadze D et al. The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry 2004; 43:629–640.

    Article  PubMed  CAS  Google Scholar 

  26. Holt JA, Luo G, Billin AN. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes and Dev 2003; 17:1581–1591.

    Article  PubMed  CAS  Google Scholar 

  27. Inagaki T, Choi M, Moschetta A et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metabolism 2005; 2:217–225.

    Article  PubMed  CAS  Google Scholar 

  28. Chiang JYL. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocrine Reviews 2002; 23(4): 443–463.

    Article  PubMed  CAS  Google Scholar 

  29. Kuipers F, Claudel T, Sturm E et al. The Farnesoid X Receptor (FXR) as modulator of bile acid metabolism. Reviews in Endocrine and Metabolic Disorders 2004; 5:319–326.

    Article  PubMed  CAS  Google Scholar 

  30. Forman BM, Goode E, Chen J et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995; 81:687–693.

    Article  PubMed  CAS  Google Scholar 

  31. Seol W, Choi HS, Moore DD. Isolation of proteins that interact specifically with the retinoid X receptor: Two novel orphan receptors. Mol Endocrinol 1995; 9:72–85.

    Article  PubMed  CAS  Google Scholar 

  32. Makishima M, Okamoto AY, Repa JJ et al. Identification of a nuclear receptor for bile acids. Science 1999; 284:1362–1365.

    Article  PubMed  CAS  Google Scholar 

  33. Parks DJ, Blanchard SG, Bledsoe RK et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284:1365–1368.

    Article  PubMed  CAS  Google Scholar 

  34. Wang H, Chen J, Hollister K et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999; 3:543–553.

    Article  PubMed  CAS  Google Scholar 

  35. Maloney PR, Parks DJ, Haffner CD et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 2000; 43:2971–2974.

    Article  PubMed  CAS  Google Scholar 

  36. Li J, Pircher PC, Schulman IG et al. Regulation of complement C3 expression by the bile acid receptor FXR. JBC 2005; 280:7427–7434.

    Article  CAS  Google Scholar 

  37. Song KH, Li T, Owsley E et al. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7-hydroxylase gene expression. Hepatology 2009; 49:297–305.

    Article  PubMed  CAS  Google Scholar 

  38. Kan M, Wu X, Wang F et al. Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. JBC 1999; 274(22):15947–15952.

    Article  CAS  Google Scholar 

  39. Yu C, Wang F, Kan M et al. Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4. JBC 2000; 275(20):15482–15489.

    Article  CAS  Google Scholar 

  40. Yu C, Wang F, Jin C et al. 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. JBC 2005; 280:17707–17714.

    Article  CAS  Google Scholar 

  41. Gilardi F, Mitro N, Godio C et al. The pharmacological exploitation of cholesterol 7-hydroxylase, the key enzyme in bile acid synthesis: from binding resins to chromatin remodeling to reduce plasma cholesterol. Pharmacol and Therapeutics 2007; 116449–472.

    Google Scholar 

  42. Hylemon PB, Zhou H, Pandak WM et al. Bile acids as regulatory molecules. J Lipid Res 2009; 50:1509–1520.

    Article  PubMed  CAS  Google Scholar 

  43. Goodwin B, Jones SA, Price RR et al. A regulatory cascade of the nuclear receptors FXR, SHP-1 and LRH-1 repress bile acid biosynthesis. Mol Cell 2000; 6:517–526.

    Article  PubMed  CAS  Google Scholar 

  44. Lu TT, Makishima M, Repa JJ et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 2000; 6:507–515.

    Article  PubMed  CAS  Google Scholar 

  45. Seol W, Choi HS, Moore DD. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 1996; 272:1336–1339.

    Article  PubMed  CAS  Google Scholar 

  46. Seol W, Chung M, Moore DD. Novel receptor interaction and repression domains in the orphan receptor SHP. Mol Cell Biology 1997; 17(12):7126–7131.

    CAS  Google Scholar 

  47. Becker-Andre M, Andre E, DeLamarter JF. Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem Biophys Res Commun 1993; 194:1371–1379.

    Article  PubMed  CAS  Google Scholar 

  48. Nita M, Du S, Brown C et al. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene. PNAS1999; 96:6660–6665.

    Article  Google Scholar 

  49. Cooper AD, Chen J, Botelho-Yetkinler MJ et al. Characterization of hepatic-specific regulatory elements in the promoter region of the human cholesterol 7-hydroxylase gene. JBC 1997; 272(6):3444–3452.

    Article  CAS  Google Scholar 

  50. Lee Y-K, Dell H, Dowhan DH et al. The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: Two mechanisms for repression. Mol Cell Bio 2000; 20(1):187–195.

    Article  CAS  Google Scholar 

  51. DeFabiani E, Nitro N, Anzulovich AC et al. The negative effects of bile acids and tumor necrosis factor-on the transcription of cholesterol 7-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4: a novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. JBC 2001; 276:30708–30716.

    Article  CAS  Google Scholar 

  52. Stroup D, Chiang JYL. HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7-hydroxyase gene (CYP7A1). J Lipid Res 2000; 41:1–11.

    PubMed  CAS  Google Scholar 

  53. Shin DJ, Obsorne TF. FGF15/FGFR4 Integrates growth factor signaling with hepatic bile acid metabolism and insulin action. JBC 2009; 284(17):1110–11120.

    Google Scholar 

  54. Schaap FG, van der Gaag NA, Gouma KJ et al. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 2009; 49:1228–1235.

    Article  PubMed  CAS  Google Scholar 

  55. Pandak WM, Heuman DM, Redford K et al. Hormonal regulation of cholesterol 7-hydroxylase specific activity, mRNA levels and transcriptional activity in vivo in the rat. J Lipid Res 1997; 38:2483–2491.

    PubMed  CAS  Google Scholar 

  56. Dueland S, Reichen J, Everson GT et al. Regulation of cholesterol and bile acid homeostasis in bile-obstructed rats. Biochem J 1991; 280:373–377.

    PubMed  CAS  Google Scholar 

  57. Gustafsson J. Effect of biliary obstruction on 26-hydroxylation of C27-steroids in bile acid synthesis. J Lipid Res 1978; 19:237–243.

    PubMed  CAS  Google Scholar 

  58. Kim I, Ahn SH, Inagaki T et al. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 2007; 48:2664–2672.

    Article  PubMed  CAS  Google Scholar 

  59. Ito S, Fujimori T, Furuya A et al. Impaired negative feedback suppression of bile acid synthesis in mice lacking Klotho. J Clinical Invest 2005; 115(8):2202–2208.

    Article  CAS  Google Scholar 

  60. Lundåsen T, Gälman C, Angelin B et al. Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med 2006; 260:530–536.

    Article  PubMed  Google Scholar 

  61. Choi M, Moschetta A, Bookout AL et al. Identification of a hormonal basis for gallbladder filling. Nature Med 2006; 12(11):1253–1255.

    Article  PubMed  CAS  Google Scholar 

  62. Portincasa P, Di Ciaula A, Wang HH et al. Coordinate regulation of gallbladder motor function in the gut-liver axis. Hepatology 2008; 47:2112–2126.

    Article  PubMed  CAS  Google Scholar 

  63. Thaysen EH, Pedersen L Diarrhoea associated with idiopathic bile acid malabsorption. Fact or fantasy? Dan Med Bull 1973; 20:174–177.

    PubMed  CAS  Google Scholar 

  64. Thaysen EH, Pedersen L. Idiopathic bile acid catharsis. Gut 1976; 17:965–970.

    Article  PubMed  CAS  Google Scholar 

  65. Sauter GH, Moussavian AC, Meyer G et al. Bowel habits and bile acid malabsorption in the months after cholecystectomy. Am J Gastroenterol 2002; 97:1732–1735.

    Article  PubMed  Google Scholar 

  66. Dawson PA, Haywood J, Craddock AL et al. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. JBC 2003; 278:33920–33927.

    Article  CAS  Google Scholar 

  67. Jung D, Inagaki T, Gerard RD et al. FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption. J Lipid Res 2007; 48(12):2693–2700.

    Article  PubMed  CAS  Google Scholar 

  68. Walters JRF, Tasleem AM, Omer OS et al. A new mechanism for bile acid diarrhea: effective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 2009; 7(11):1189–94 2009.

    Article  PubMed  CAS  Google Scholar 

  69. Hofmann AF, Mangelsdorf DJ, Kliewer SA. Chronic diarrhea due to excessive bile acid synthesis and not defective ileal transport: a new syndrome of defective fibroblast growth factor 19 release. Clin Gastroenterol Hepatol 2009; 7(11): 1151–1154.

    Article  PubMed  CAS  Google Scholar 

  70. Miyata M, Yakamatsu Y, Kuribayashi H et al. Administration of ampicillin elevates hepatic primary bile acid synthesis through suppression of ileal FGF15 expression. JPET, doi:10.1124/jpet/109.160093

    Google Scholar 

  71. Tomlinson E, Fu L, John L et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 2002; 143(5):1741–1747.

    Article  PubMed  CAS  Google Scholar 

  72. Fu L, John LM, Adams SH et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145(6):2594–2603.

    Article  PubMed  CAS  Google Scholar 

  73. Fleury C, Neverova M, Collins S et al. Uncoupling protein-1: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 1997; 15:269–272.

    Article  PubMed  CAS  Google Scholar 

  74. Pinkney JH, Boss O, Bray GA et al. Physiological relationships of uncoupling protein-2 gene expression in human adipose tissue in vivo. J Clin Endocrinol Metab 2000; 85:2312–2317.

    Article  PubMed  CAS  Google Scholar 

  75. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA et al. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001; 291:2613–2616.

    Article  PubMed  CAS  Google Scholar 

  76. Li T, Kong X, Owsley E et al. Insulin regulation of cholesterol 7-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c. JBC 2006; 281(39):28745–28754.

    Article  CAS  Google Scholar 

  77. Li T, Ma H, Chiang JY. TGF1, TNF and insulin signaling crosstalk in regulation of the rat cholesterol 7-hydroxylase gene expression. J Lipid Res 2008; 49(9):1981–1989.

    Article  PubMed  CAS  Google Scholar 

  78. Huang X, Yang C, Luo Y et al. FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet-induced fatty liver. Diabetes 2007; 56:2501–2510.

    Article  PubMed  CAS  Google Scholar 

  79. Nicholes K, Guillet S, Tomlinson E et al. A mouse model of hepatocellular carcinoma. Ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathology 2002; 160(6):2295–2307.

    Article  CAS  Google Scholar 

  80. Pai R, Dunlap D, Qing J et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating-catenin signaling. Cancer Res 2008; 68(13):5086–5095.

    Article  PubMed  CAS  Google Scholar 

  81. Desnoyers LR, Pai R, Ferrando RE et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 2008; 27:85–97.

    Article  PubMed  CAS  Google Scholar 

  82. Lopez-Serra L, Ballestar E, Ropero S et al. Unmasking of epigenetically silenced candidate tumor suppressor genes by removal of methyl-CpG-binding domain proteins. Oncogene 2008; 27:3556–3566.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Jones, S.A. (2012). Physiology of FGF15/19. In: Kuro-o, M. (eds) Endocrine FGFs and Klothos. Advances in Experimental Medicine and Biology, vol 728. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0887-1_11

Download citation

Publish with us

Policies and ethics