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词条 FGF19
释义

  1. Functions

  2. Clinical significance

  3. References

  4. Further reading

{{Infobox_gene}}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]

Clinical significance

Patients with chronic diarrhea due to bile acid malabsorption have been shown to have reduced fasting FGF19.[18] 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.[18][19] 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.[20]

FGF19 is also found in the liver of patients with cholestasis.[21] It can be synthesised in the gall-bladder and secreted into bile.[22] FGF19 is expressed in around half of hepatocellular carcinomas and was associated with larger size, early recurrence and poor prognosis.[23]

Patients with the metabolic syndrome, non-alcoholic fatty liver disease and insulin resistance have reduced levels of FGF19.[24][25] FGF19 increases to normal values in obese patients who undergo Roux-en-Y gastric bypass bariatric surgery.[26]

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References

1. ^1 {{cite web | title = Entrez Gene: FGF19 fibroblast growth factor 19| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9965| accessdate = }}
2. ^1 {{cite journal | vauthors = Jones SA | title = Physiology of FGF15/19 | journal = Adv. Exp. Med. Biol. | volume = 728 | issue = | pages = 171–82 | year = 2012 | pmid = 22396169 | doi = 10.1007/978-1-4614-0887-1_11 }}
3. ^1 2 {{cite journal | vauthors = Potthoff MJ, Kliewer SA, Mangelsdorf DJ | title = Endocrine fibroblast growth factors 15/19 and 21: from feast to famine | journal = Genes Dev. | volume = 26 | issue = 4 | pages = 312–24 | year = 2012 | pmid = 22302876 | pmc = 3289879 | doi = 10.1101/gad.184788.111 }}
4. ^{{cite journal | vauthors = 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 | title = FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4 | journal = Cytokine | volume = 11 | issue = 10 | pages = 729–35 | year = 1999 | pmid = 10525310 | pmc = | doi = 10.1006/cyto.1999.0485 }}
5. ^{{cite journal | vauthors = Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N | title = Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain | journal = Biochim. Biophys. Acta | volume = 1444 | issue = 1 | pages = 148–51 | year = 1999 | pmid = 9931477 | pmc = | doi = 10.1016/S0167-4781(98)00255-3 }}
6. ^{{cite journal | vauthors = Ladher RK, Anakwe KU, Gurney AL, Schoenwolf GC, Francis-West PH | title = Identification of synergistic signals initiating inner ear development | journal = Science | volume = 290 | issue = 5498 | pages = 1965–7 | year = 2000 | pmid = 11110663 | doi = 10.1126/science.290.5498.1965 }}
7. ^{{cite journal | vauthors = Tamimi Y, Skarie JM, Footz T, Berry FB, Link BA, Walter MA | title = FGF19 is a target for FOXC1 regulation in ciliary body-derived cells | journal = Hum. Mol. Genet. | volume = 15 | issue = 21 | pages = 3229–40 | year = 2006 | pmid = 17000708 | doi = 10.1093/hmg/ddl400 }}
8. ^{{cite journal | vauthors = Miyata M, Hata T, Yamakawa H, Kagawa T, Yoshinari K, Yamazoe Y | title = Involvement of multiple elements in FXR-mediated transcriptional activation of FGF19 | journal = J. Steroid Biochem. Mol. Biol. | volume = 132 | issue = 1-2 | pages = 41–7 | year = 2012 | pmid = 22561792 | doi = 10.1016/j.jsbmb.2012.04.008 }}
9. ^{{cite journal | vauthors = Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR | title = Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids | journal = Am. J. Physiol. Gastrointest. Liver Physiol. | volume = 304 | issue = 10 | pages = G940–8 | year = 2013 | pmid = 23518683 | pmc = 3652069 | doi = 10.1152/ajpgi.00398.2012 }}
10. ^{{cite journal | vauthors = Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA | title = Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis | journal = Genes Dev. | volume = 17 | issue = 13 | pages = 1581–91 | year = 2003 | pmid = 12815072 | pmc = 196131 | doi = 10.1101/gad.1083503 }}
11. ^{{cite journal | vauthors = Lin BC, Wang M, Blackmore C, Desnoyers LR | title = Liver-specific activities of FGF19 require Klotho beta | journal = J. Biol. Chem. | volume = 282 | issue = 37 | pages = 27277–84 | year = 2007 | pmid = 17627937 | doi = 10.1074/jbc.M704244200 }}
12. ^{{cite journal | vauthors = 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 | title = Co-receptor requirements for fibroblast growth factor-19 signaling | journal = J. Biol. Chem. | volume = 282 | issue = 40 | pages = 29069–72 | year = 2007 | pmid = 17711860 | doi = 10.1074/jbc.C700130200 }}
13. ^{{cite journal | vauthors = 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 | title = Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members | journal = Mol. Cell. Biol. | volume = 27 | issue = 9 | pages = 3417–28 | year = 2007 | pmid = 17339340 | pmc = 1899957 | doi = 10.1128/MCB.02249-06 }}
14. ^{{cite journal | vauthors = Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA | title = Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity | journal = Endocrinology | volume = 143 | issue = 5 | pages = 1741–7 | year = 2002 | pmid = 11956156 | doi = 10.1210/en.143.5.1741 }}
15. ^{{cite journal | vauthors = 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 | title = Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes | journal = Endocrinology | volume = 145 | issue = 6 | pages = 2594–603 | year = 2004 | pmid = 14976145 | doi = 10.1210/en.2003-1671 }}
16. ^{{cite journal | vauthors = Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ | title = FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis | journal = Science | volume = 331 | issue = 6024 | pages = 1621–4 | year = 2011 | pmid = 21436455 | pmc = 3076083 | doi = 10.1126/science.1198363 }}
17. ^{{cite journal | vauthors = Pai R, French D, Ma N, Hotzel K, Plise E, Salphati L, Setchell KD, Ware J, Lauriault V, Schutt L, Hartley D, Dambach D | title = Antibody-mediated inhibition of fibroblast growth factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys | journal = Toxicol. Sci. | volume = 126 | issue = 2 | pages = 446–456 | year = 2012 | pmid = 22268002 | doi = 10.1093/toxsci/kfs011 }}
18. ^1 {{cite journal | vauthors = Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW | title = A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis | journal = Clin. Gastroenterol. Hepatol. | volume = 7 | issue = 11 | pages = 1189–94 | year = 2009 | pmid = 19426836 | doi = 10.1016/j.cgh.2009.04.024 }}
19. ^{{cite journal | vauthors = Hofmann AF, Mangelsdorf DJ, Kliewer SA | title = Chronic diarrhea due to excessive bile acid synthesis and not defective ileal transport: a new syndrome of defective fibroblast growth factor 19 release | journal = Clin. Gastroenterol. Hepatol. | volume = 7 | issue = 11 | pages = 1151–4 | year = 2009 | pmid = 19665580 | pmc = 2850200 | doi = 10.1016/j.cgh.2009.07.026 }}
20. ^{{cite journal | vauthors = Pattni SS, Brydon WG, Dew T, Johnston IM, Nolan JD, Srinivas M, Basumani P, Bardhan KD, Walters JR | title = Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention | journal = Aliment. Pharmacol. Ther. | volume = 38 | issue = 8 | pages = 967–76 | year = 2013 | pmid = 23981126 | doi = 10.1111/apt.12466 }}
21. ^{{cite journal | vauthors = Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL | title = High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis | journal = Hepatology | volume = 49 | issue = 4 | pages = 1228–35 | year = 2009 | pmid = 19185005 | doi = 10.1002/hep.22771 }}
22. ^{{cite journal | vauthors = Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, Schaap FG | title = The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract | journal = Hepatology | volume = 55 | issue = 2 | pages = 575–83 | year = 2012 | pmid = 21953282 | doi = 10.1002/hep.24702 }}
23. ^{{cite journal | vauthors = Hyeon J, Ahn S, Lee JJ, Song DH, Park CK | title = Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma | journal = Dig. Dis. Sci. | volume = 58 | issue = 7 | pages = 1916–22 | year = 2013 | pmid = 23456506 | doi = 10.1007/s10620-013-2609-x }}
24. ^{{cite journal | vauthors = Stejskal D, Karpísek M, Hanulová Z, Stejskal P | title = Fibroblast growth factor-19: development, analytical characterization and clinical evaluation of a new ELISA test | journal = Scand. J. Clin. Lab. Invest. | volume = 68 | issue = 6 | pages = 501–7 | year = 2008 | pmid = 18609104 | doi = 10.1080/00365510701854967 }}
25. ^{{cite journal | vauthors = Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG | title = The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance | journal = Am. J. Physiol. Gastrointest. Liver Physiol. | volume = 298 | issue = 3 | pages = G440–5 | year = 2010 | pmid = 20093562 | doi = 10.1152/ajpgi.00322.2009 }}
26. ^{{cite journal | vauthors = 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 | title = The role of bile after Roux-en-Y gastric bypass in promoting weight loss and improving glycaemic control | journal = Endocrinology | volume = 153 | issue = 8 | pages = 3613–9 | year = 2012 | pmid = 22673227 | pmc = 3404349 | doi = 10.1210/en.2011-2145 }}

Further reading

{{refbegin|35em}}
  • {{cite journal | vauthors = Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM | title = A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice | journal = Am. J. Pathol. | volume = 160 | issue = 6 | pages = 2295–307 | year = 2002 | pmid = 12057932 | pmc = 1850847 | doi = 10.1016/S0002-9440(10)61177-7 }}
  • {{cite journal | vauthors = Katoh M, Katoh M | title = Evolutionary conservation of CCND1-ORAOV1-FGF19-FGF4 locus from zebrafish to human | journal = Int. J. Mol. Med. | volume = 12 | issue = 1 | pages = 45–50 | year = 2003 | pmid = 12792807 | doi = 10.3892/ijmm.12.1.45 }}
  • {{cite journal | vauthors = Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL | title = 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 | journal = Biochemistry | volume = 43 | issue = 3 | pages = 629–40 | year = 2004 | pmid = 14730967 | doi = 10.1021/bi035320k }}
{{refend}}{{PDB Gallery|geneid=9965}}{{Growth factors}}{{Growth factor receptor modulators}}

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