FGF19

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Fibroblast growth factor 19
Protein FGF19 PDB 1pwa.png
PDB rendering based on 1pwa.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol FGF19
External IDs OMIM603891 MGI1096383 HomoloGene3754 GeneCards: FGF19 Gene
RNA expression pattern
PBB GE FGF19 gnf1h00068 at tn.png
More reference expression data
Orthologs
Species Human Mouse
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:
69.51 – 69.52 Mb
Chr 7:
144.9 – 144.9 Mb
PubMed search [1] [2]

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[edit]

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[edit]

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]

References[edit]

  1. ^ a b "Entrez Gene: FGF19 fibroblast growth factor 19". 
  2. ^ a b Jones SA (2012). "Physiology of FGF15/19". Adv. Exp. Med. Biol. 728: 171–82. doi:10.1007/978-1-4614-0887-1_11. PMID 22396169. 
  3. ^ a b c Potthoff MJ, Kliewer SA, Mangelsdorf DJ (February 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. 
  4. ^ 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 (Nov 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. 
  5. ^ Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N (Mar 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. 
  6. ^ Ladher RK, Anakwe KU, Gurney AL, Schoenwolf GC, Francis-West PH (December 2000). "Identification of synergistic signals initiating inner ear development". Science 290 (5498): 1965–7. doi:10.1126/science.290.5498.1965. PMID 11110663. 
  7. ^ Tamimi Y, Skarie JM, Footz T, Berry FB, Link BA, Walter MA (November 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. 
  8. ^ Miyata M, Hata T, Yamakawa H, Kagawa T, Yoshinari K, Yamazoe Y (October 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. 
  9. ^ Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (May 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. 
  10. ^ Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA (July 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. 
  11. ^ Lin BC, Wang M, Blackmore C, Desnoyers LR (September 2007). "Liver-specific activities of FGF19 require Klotho beta". J. Biol. Chem. 282 (37): 27277–84. doi:10.1074/jbc.M704244200. PMID 17627937. 
  12. ^ 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 (October 2007). "Co-receptor requirements for fibroblast growth factor-19 signaling". J. Biol. Chem. 282 (40): 29069–72. doi:10.1074/jbc.C700130200. PMID 17711860. 
  13. ^ 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 (May 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. 
  14. ^ Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA (May 2002). "Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity". Endocrinology 143 (5): 1741–7. doi:10.1210/en.143.5.1741. PMID 11956156. 
  15. ^ 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 (June 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. 
  16. ^ Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ (March 2011). "FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis". Science 331 (6024): 1621–4. doi:10.1126/science.1198363. PMC 3076083. PMID 21436455. 
  17. ^ Pai, R.; French, D; Ma, N; Hotzel, K; Plise, E; Salphati, L; Setchell, KDR; Ware, J; Lauriault, V; Schutt, L; Hartley, D; Dambach, D (19 January 2012). "Antibody-Mediated Inhibition of Fibroblast Growth Factor 19 Results in Increased Bile Acids Synthesis and Ileal Malabsorption of Bile Acids in Cynomolgus Monkeys". Toxicological Sciences 126 (2): 446–456. doi:10.1093/toxsci/kfs011. 
  18. ^ a b Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (November 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. 
  19. ^ Hofmann AF, Mangelsdorf DJ, Kliewer SA (November 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. 
  20. ^ Pattni SS, Brydon WG, Dew T, Johnston IM, Nolan JD, Srinivas M, Basumani P, Bardhan KD, Walters JR (October 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. 
  21. ^ Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL (April 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. 
  22. ^ Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, Schaap FG (February 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. 
  23. ^ 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". Dig. Dis. Sci. 58 (7): 1916–22. doi:10.1007/s10620-013-2609-x. PMID 23456506. 
  24. ^ 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. 
  25. ^ Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, Schaap FG (March 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. 
  26. ^ 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 (August 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. 

Further reading[edit]