Biology:FGF19

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.[1] It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor in chronic bile acid diarrhea and in certain metabolic disorders.[2][3]

Functions

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes including embryonic development cell growth, morphogenesis, tissue repair, tumor growth and invasion. This growth factor is a high affinity, heparin dependent ligand for FGFR4.[4] Expression of this gene was detected only in fetal but not adult brain tissue.[5] Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development.[1][6][7]

The orthologous protein in mouse is FGF15, which shares about 50% amino acid identity and has similar functions. Together they are often referred to as FGF15/19.[2][3]

FGF19 has important roles as a hormone produced in the ileum in response to bile acid absorption.[3] Bile acids bind to the farnesoid X receptor (FXR), stimulating FGF19 transcription. Several FXR / bile acid response elements have been identified in the FGF19 gene.[8] Human FGF19 transcripts have been shown to be stimulated approximately 300-fold by physiological concentrations of bile acids including chenodeoxycholic acid, glycochenodeoxycholic acid and obeticholic acid in explants of ileal mucosa.[9]

FGF19 regulates new bile acid synthesis, acting through the FGFR4/Klotho-β receptor complexes in the liver to inhibit CYP7A1.[10][11][12][13]

FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models.[14][15][16]

When FGF19 was inhibited by specific anti-FGF19 antibodies in monkeys, severe diarrhea was the result. There was also evidence of liver toxicity. Increases in bile acid synthesis, serum and fecal total bile acids, and specific bile acid transporters were found.[17]

Role as a cancer promoter

FGF19 is frequently amplified in human cancers.[18] Amplification of the FGF19 genomic locus was found in liver cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, and esophageal cancer, among others.[19][20][21][22][23] Targeting FGF19 inhibits tumor growth in colon cancer cells and hepatocellar carcinoma.[24][25] Increase in FGF19 correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.[26][27][28]

Clinical significance

Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19.[29] Surgical resection of the ileum (as often occurs in Crohn's disease) will reduce bile acid absorption and remove the stimulus for FGF19 production.

In primary bile acid diarrhea, absorption of bile acids is usually normal, but defective FGF19 production can produce excessive bile acid synthesis, as shown by increased levels of 7α-hydroxy-4-cholesten-3-one, and excessive bile acid fecal loss, indicated by reduced SeHCAT retention.[29][30] This was confirmed in a prospective study of patients with chronic diarrhea, where the predictive value for FGF19 in diagnosis of primary bile acid diarrhea and response to bile acid sequestrants was demonstrated.[31]

FGF19 is also found in the liver of patients with cholestasis.[32] It can be synthesised in the gall-bladder and secreted into bile.[33] FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.[34]

Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19.[35][36] FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass and other types of bariatric surgery.[37][38]

References

  1. ↑ 1.0 1.1 "Entrez Gene: FGF19 fibroblast growth factor 19". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9965. 
  2. ↑ 2.0 2.1 "Physiology of FGF15/19". Endocrine FGFS and Klothos. Advances in Experimental Medicine and Biology. 728. 2012. pp. 171–82. doi:10.1007/978-1-4614-0887-1_11. ISBN 978-1-4614-0886-4. 
  3. ↑ 3.0 3.1 3.2 "Endocrine fibroblast growth factors 15/19 and 21: from feast to famine". Genes Dev. 26 (4): 312–24. 2012. doi:10.1101/gad.184788.111. PMID 22302876. 
  4. ↑ "FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4". Cytokine 11 (10): 729–35. 1999. doi:10.1006/cyto.1999.0485. PMID 10525310. 
  5. ↑ "Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain". Biochim. Biophys. Acta 1444 (1): 148–51. 1999. doi:10.1016/S0167-4781(98)00255-3. PMID 9931477. 
  6. ↑ "Identification of synergistic signals initiating inner ear development". Science 290 (5498): 1965–7. 2000. doi:10.1126/science.290.5498.1965. PMID 11110663. Bibcode: 2000Sci...290.1965L. 
  7. ↑ "FGF19 is a target for FOXC1 regulation in ciliary body-derived cells". Hum. Mol. Genet. 15 (21): 3229–40. 2006. doi:10.1093/hmg/ddl400. PMID 17000708. 
  8. ↑ "Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19". J. Steroid Biochem. Mol. Biol. 132 (1–2): 41–7. 2012. doi:10.1016/j.jsbmb.2012.04.008. PMID 22561792. 
  9. ↑ "Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids". Am. J. Physiol. Gastrointest. Liver Physiol. 304 (10): G940–8. 2013. doi:10.1152/ajpgi.00398.2012. PMID 23518683. 
  10. ↑ "Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis". Genes Dev. 17 (13): 1581–91. 2003. doi:10.1101/gad.1083503. PMID 12815072. 
  11. ↑ "Liver-specific activities of FGF19 require Klotho beta". J. Biol. Chem. 282 (37): 27277–84. 2007. doi:10.1074/jbc.M704244200. PMID 17627937. 
  12. ↑ "Co-receptor requirements for fibroblast growth factor-19 signaling". J. Biol. Chem. 282 (40): 29069–72. 2007. doi:10.1074/jbc.C700130200. PMID 17711860. 
  13. ↑ "Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members". Mol. Cell. Biol. 27 (9): 3417–28. 2007. doi:10.1128/MCB.02249-06. PMID 17339340. 
  14. ↑ "Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity". Endocrinology 143 (5): 1741–7. 2002. doi:10.1210/endo.143.5.8850. PMID 11956156. 
  15. ↑ "Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes". Endocrinology 145 (6): 2594–603. 2004. doi:10.1210/en.2003-1671. PMID 14976145. 
  16. ↑ "FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis". Science 331 (6024): 1621–4. 2011. doi:10.1126/science.1198363. PMID 21436455. Bibcode: 2011Sci...331.1621K. 
  17. ↑ "Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys". Toxicol. Sci. 126 (2): 446–456. 2012. doi:10.1093/toxsci/kfs011. PMID 22268002. 
  18. ↑ "Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression". Frontiers in Cell and Developmental Biology 8: 95. 2020. doi:10.3389/fcell.2020.00095. PMID 32154250. 
  19. ↑ "Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening". Cancer Cell 19 (3): 347–58. March 2011. doi:10.1016/j.ccr.2011.01.040. PMID 21397858. 
  20. ↑ "Quantitative Proteomic Verification of Membrane Proteins as Potential Therapeutic Targets Located in the 11q13 Amplicon in Cancers". Journal of Proteome Research 14 (9): 3670–9. September 2015. doi:10.1021/acs.jproteome.5b00508. PMID 26151158. 
  21. ↑ "FGF19 promotes progression of prostate cancer". The Prostate 75 (10): 1092–101. July 2015. doi:10.1002/pros.22994. PMID 25854696. 
  22. ↑ "Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival". Oncotarget 7 (36): 57633–57650. September 2016. doi:10.18632/oncotarget.9328. PMID 27192118. 
  23. ↑ "FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas". Thoracic Cancer 8 (6): 655–665. November 2017. doi:10.1111/1759-7714.12504. PMID 28906590. 
  24. ↑ "Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models". Oncogene 27 (1): 85–97. January 2008. doi:10.1038/sj.onc.1210623. PMID 17599042. 
  25. ↑ "Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models". PLOS ONE 7 (5): e36713. 2012. doi:10.1371/journal.pone.0036713. PMID 22615798. Bibcode: 2012PLoSO...736713F. 
  26. ↑ "Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma". BMC Cancer 12: 56. February 2012. doi:10.1186/1471-2407-12-56. PMID 22309595. 
  27. ↑ "FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation". Oncotarget 7 (12): 13575–86. March 2016. doi:10.18632/oncotarget.6185. PMID 26498355. 
  28. ↑ "Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma". Digestive Diseases and Sciences 58 (7): 1916–22. July 2013. doi:10.1007/s10620-013-2609-x. PMID 23456506. 
  29. ↑ 29.0 29.1 "A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis". Clin. Gastroenterol. Hepatol. 7 (11): 1189–94. 2009. doi:10.1016/j.cgh.2009.04.024. PMID 19426836. https://zenodo.org/record/851309. 
  30. ↑ "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. 7 (11): 1151–4. 2009. doi:10.1016/j.cgh.2009.07.026. PMID 19665580. 
  31. ↑ "Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention". Aliment. Pharmacol. Ther. 38 (8): 967–76. 2013. doi:10.1111/apt.12466. PMID 23981126. 
  32. ↑ "High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis". Hepatology 49 (4): 1228–35. 2009. doi:10.1002/hep.22771. PMID 19185005. 
  33. ↑ "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 (2): 575–83. 2012. doi:10.1002/hep.24702. PMID 21953282. 
  34. ↑ "Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma". Dig. Dis. Sci. 58 (7): 1916–22. 2013. doi:10.1007/s10620-013-2609-x. PMID 23456506. 
  35. ↑ "Fibroblast growth factor-19: development, analytical characterization and clinical evaluation of a new ELISA test". Scand. J. Clin. Lab. Invest. 68 (6): 501–7. 2008. doi:10.1080/00365510701854967. PMID 18609104. 
  36. ↑ "The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance". Am. J. Physiol. Gastrointest. Liver Physiol. 298 (3): G440–5. 2010. doi:10.1152/ajpgi.00322.2009. PMID 20093562. 
  37. ↑ "The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control". Endocrinology 153 (8): 3613–9. 2012. doi:10.1210/en.2011-2145. PMID 22673227. 
  38. ↑ "Effect of bariatric surgery on circulating FGF-19: A systematic review and meta-analysis". Obesity Reviews 21 (8): e13038. August 2020. doi:10.1111/obr.13038. PMID 32329176. 

Further reading



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