Wikipedia

FGF19

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]

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

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.
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  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.
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  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.
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  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.
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Further reading

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