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FGF19

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FGF19
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFGF19, fibroblast growth factor 19
External IDsOMIM: 603891; MGI: 1096383; HomoloGene: 3754; GeneCards: FGF19; OMA:FGF19 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9965

14170

Ensembl

ENSG00000162344

ENSMUSG00000031073

UniProt

O95750

O35622

RefSeq (mRNA)

NM_005117

NM_008003

RefSeq (protein)

NP_005108

NP_032029

Location (UCSC)Chr 11: 69.7 – 69.7 MbChr 7: 144.9 – 144.9 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fibroblast growth factor 19 is a protein that in humans is encoded by the FGF19 gene.[5] 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.[6][7]

Functions

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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.[8] Expression of this gene was detected only in fetal but not adult brain tissue.[9] Synergistic interaction of the chick homolog and Wnt-8c has been shown to be required for initiation of inner ear development.[5][10][11]

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.[6][7]

FGF19 has important roles as a hormone produced in the ileum in response to bile acid absorption.[7] 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.[12] 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.[13]

FGF19 regulates new bile acid synthesis, acting through the FGFR4/Klotho-β receptor complexes in the liver to inhibit CYP7A1.[14][15][16][17]

FGF19 also has metabolic effects, affecting glucose and lipid metabolism when used in experimental mouse models.[18][19][20]

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.[21]

Role as a cancer promoter

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FGF19 is frequently amplified in human cancers.[22] Amplification of the FGF19 genomic locus was found in liver cancer, breast cancer, lung cancer, prostate cancer, bladder cancer, and esophageal cancer, among others.[23][24][25][26][27] Targeting FGF19 inhibits tumor growth in colon cancer cells and hepatocellar carcinoma.[28][29] Increase in FGF19 correlates with tumor progression and poorer prognosis of hepatocellular carcinoma.[30][31][32]

Clinical significance

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Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19.[33] 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.[33][34] 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.[35]

FGF19 is also found in the liver of patients with cholestasis.[36] It can be synthesised in the gall-bladder and secreted into bile.[37] FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.[38]

Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19.[39][40] FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass and other types of bariatric surgery.[41][42]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000162344 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031073 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: FGF19 fibroblast growth factor 19".
  6. ^ a b Jones SA (2012). "Physiology of FGF15/19". Endocrine FGFS and Klothos. Advances in Experimental Medicine and Biology. Vol. 728. pp. 171–82. doi:10.1007/978-1-4614-0887-1_11. ISBN 978-1-4614-0886-4. PMID 22396169.
  7. ^ a b c Potthoff MJ, Kliewer SA, Mangelsdorf DJ (2012). "Endocrine fibroblast growth factors 15/19 and 21: from feast to famine". Genes Dev. 26 (4): 312–24. doi:10.1101/gad.184788.111. PMC 3289879. PMID 22302876.
  8. ^ Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, Foster J, Liang J, Brush J, Gu Q, Hillan K, Goddard A, Gurney AL (1999). "FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4". Cytokine. 11 (10): 729–35. doi:10.1006/cyto.1999.0485. PMID 10525310.
  9. ^ Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N (1999). "Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain". Biochim. Biophys. Acta. 1444 (1): 148–51. doi:10.1016/S0167-4781(98)00255-3. PMID 9931477.
  10. ^ Ladher RK, Anakwe KU, Gurney AL, Schoenwolf GC, Francis-West PH (2000). "Identification of synergistic signals initiating inner ear development". Science. 290 (5498): 1965–7. Bibcode:2000Sci...290.1965L. doi:10.1126/science.290.5498.1965. PMID 11110663.
  11. ^ Tamimi Y, Skarie JM, Footz T, Berry FB, Link BA, Walter MA (2006). "FGF19 is a target for FOXC1 regulation in ciliary body-derived cells". Hum. Mol. Genet. 15 (21): 3229–40. doi:10.1093/hmg/ddl400. PMID 17000708.
  12. ^ Miyata M, Hata T, Yamakawa H, Kagawa T, Yoshinari K, Yamazoe Y (2012). "Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19". J. Steroid Biochem. Mol. Biol. 132 (1–2): 41–7. doi:10.1016/j.jsbmb.2012.04.008. PMID 22561792. S2CID 25039514.
  13. ^ Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (2013). "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. doi:10.1152/ajpgi.00398.2012. PMC 3652069. PMID 23518683.
  14. ^ Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (2003). "Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis". Genes Dev. 17 (13): 1581–91. doi:10.1101/gad.1083503. PMC 196131. PMID 12815072.
  15. ^ Lin BC, Wang M, Blackmore C, Desnoyers LR (2007). "Liver-specific activities of FGF19 require Klotho beta". J. Biol. Chem. 282 (37): 27277–84. doi:10.1074/jbc.M704244200. PMID 17627937.
  16. ^ Wu X, Ge H, Gupte J, Weiszmann J, Shimamoto G, Stevens J, Hawkins N, Lemon B, Shen W, Xu J, Veniant MM, Li YS, Lindberg R, Chen JL, Tian H, Li Y (2007). "Co-receptor requirements for fibroblast growth factor-19 signaling". J. Biol. Chem. 282 (40): 29069–72. doi:10.1074/jbc.C700130200. PMID 17711860.
  17. ^ Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M (2007). "Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members". Mol. Cell. Biol. 27 (9): 3417–28. doi:10.1128/MCB.02249-06. PMC 1899957. PMID 17339340.
  18. ^ Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA (2002). "Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity". Endocrinology. 143 (5): 1741–7. doi:10.1210/endo.143.5.8850. PMID 11956156.
  19. ^ Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, Williams PM, Soriano R, Corpuz R, Moffat B, Vandlen R, Simmons L, Foster J, Stephan JP, Tsai SP, Stewart TA (2004). "Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes". Endocrinology. 145 (6): 2594–603. doi:10.1210/en.2003-1671. PMID 14976145.
  20. ^ Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ (2011). "FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis". Science. 331 (6024): 1621–4. Bibcode:2011Sci...331.1621K. doi:10.1126/science.1198363. PMC 3076083. PMID 21436455.
  21. ^ Pai R, French D, Ma N, Hotzel K, Plise E, Salphati L, Setchell KD, Ware J, Lauriault V, Schutt L, Hartley D, Dambach D (2012). "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. doi:10.1093/toxsci/kfs011. PMID 22268002.
  22. ^ Liu Y, Cao M, Cai Y, Li X, Zhao C, Cui R (2020). "Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression". Frontiers in Cell and Developmental Biology. 8: 95. doi:10.3389/fcell.2020.00095. PMC 7044267. PMID 32154250.
  23. ^ Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, et al. (March 2011). "Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening". Cancer Cell. 19 (3): 347–58. doi:10.1016/j.ccr.2011.01.040. PMC 3061399. PMID 21397858.
  24. ^ Hoover H, Li J, Marchese J, Rothwell C, Borawoski J, Jeffery DA, et al. (September 2015). "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. doi:10.1021/acs.jproteome.5b00508. PMID 26151158.
  25. ^ Nagamatsu H, Teishima J, Goto K, Shikuma H, Kitano H, Shoji K, et al. (July 2015). "FGF19 promotes progression of prostate cancer". The Prostate. 75 (10): 1092–101. doi:10.1002/pros.22994. PMID 25854696. S2CID 41522150.
  26. ^ Tiong KH, Tan BS, Choo HL, Chung FF, Hii LW, Tan SH, et al. (September 2016). "Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival". Oncotarget. 7 (36): 57633–57650. doi:10.18632/oncotarget.9328. PMC 5295378. PMID 27192118.
  27. ^ Zhang X, Kong M, Zhang Z, Xu S, Yan F, Wei L, Zhou J (November 2017). "FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas". Thoracic Cancer. 8 (6): 655–665. doi:10.1111/1759-7714.12504. PMC 5668513. PMID 28906590.
  28. ^ Desnoyers LR, Pai R, Ferrando RE, Hötzel K, Le T, Ross J, et al. (January 2008). "Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models". Oncogene. 27 (1): 85–97. doi:10.1038/sj.onc.1210623. PMID 17599042.
  29. ^ French DM, Lin BC, Wang M, Adams C, Shek T, Hötzel K, et al. (2012). "Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models". PLOS ONE. 7 (5): e36713. Bibcode:2012PLoSO...736713F. doi:10.1371/journal.pone.0036713. PMC 3352934. PMID 22615798.
  30. ^ Miura S, Mitsuhashi N, Shimizu H, Kimura F, Yoshidome H, Otsuka M, et al. (February 2012). "Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma". BMC Cancer. 12: 56. doi:10.1186/1471-2407-12-56. PMC 3293719. PMID 22309595.
  31. ^ Zhao H, Lv F, Liang G, Huang X, Wu G, Zhang W, et al. (March 2016). "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. doi:10.18632/oncotarget.6185. PMC 4924662. PMID 26498355.
  32. ^ Hyeon J, Ahn S, Lee JJ, Song DH, Park CK (July 2013). "Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma". Digestive Diseases and Sciences. 58 (7): 1916–22. doi:10.1007/s10620-013-2609-x. PMID 23456506. S2CID 11804579.
  33. ^ a b Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (2009). "A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis". Clin. Gastroenterol. Hepatol. 7 (11): 1189–94. doi:10.1016/j.cgh.2009.04.024. PMID 19426836.
  34. ^ Hofmann AF, Mangelsdorf DJ, Kliewer SA (2009). "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. doi:10.1016/j.cgh.2009.07.026. PMC 2850200. PMID 19665580.
  35. ^ Pattni SS, Brydon WG, Dew T, Johnston IM, Nolan JD, Srinivas M, Basumani P, Bardhan KD, Walters JR (2013). "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. doi:10.1111/apt.12466. PMID 23981126. S2CID 6386339.
  36. ^ Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL (2009). "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. doi:10.1002/hep.22771. PMID 19185005. S2CID 5306097.
  37. ^ Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, Schaap FG (2012). "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. doi:10.1002/hep.24702. PMID 21953282. S2CID 25030572.
  38. ^ Hyeon J, Ahn S, Lee JJ, Song DH, Park CK (2013). "Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma". Dig. Dis. Sci. 58 (7): 1916–22. doi:10.1007/s10620-013-2609-x. PMID 23456506. S2CID 11804579.
  39. ^ Stejskal D, Karpísek M, Hanulová Z, Stejskal P (2008). "Fibroblast growth factor-19: development, analytical characterization and clinical evaluation of a new ELISA test". Scand. J. Clin. Lab. Invest. 68 (6): 501–7. doi:10.1080/00365510701854967. PMID 18609104. S2CID 80519.
  40. ^ Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG (2010). "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. doi:10.1152/ajpgi.00322.2009. PMID 20093562. S2CID 24667851.
  41. ^ Pournaras DJ, Glicksman C, Vincent RP, Kuganolipava S, Alaghband-Zadeh J, Mahon D, Bekker JH, Ghatei MA, Bloom SR, Walters JR, Welbourn R, le Roux CW (2012). "The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control". Endocrinology. 153 (8): 3613–9. doi:10.1210/en.2011-2145. PMC 3404349. PMID 22673227.
  42. ^ Ryan PM, Hayward NE, Sless RT, Garwood P, Rahmani J (August 2020). "Effect of bariatric surgery on circulating FGF-19: A systematic review and meta-analysis". Obesity Reviews. 21 (8): e13038. doi:10.1111/obr.13038. PMID 32329176. S2CID 216110704.

Further reading

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