Endocrine FGFs: Evolution, physiology, pathophysiology, and pharmacotherapy

Frontiers in Endocrinology

Volumn 6, Issue , 2015, Pages

  Itoh, Nobuyuki ^a   Ohta, Hiroya ^b   Konishi, Morichika ^b  

^a KYOTO UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b KOBE PHARMACEUTICAL UNIVERSITY   (Japan)

Author keywords

Biomarker; Disease; Endocrine; FGF; Klotho; Metabolism; Mutation; Polymorphism

Indexed keywords

EID: 84962366018     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2015.00154     Document Type: Review

References (97)

1. Ornitz DM, Itoh N. The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol (2005) 4:215–66. doi:10.1002/wdev.176
2. McWhirter JR, Goulding M, Weiner JA, Chun J, Murre C. A novel fibroblast growth factor gene expressed in the developing nervous system is a downstream target of the chimeric homeodomain oncoprotein E2A-Pbx1. Development (1997) 124:3221–32.
3. Nishimura T, Utsunomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta (1999) 1444:148–51. doi:10.1016/S0167-4781(98)00255-3
4. Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine (1999) 11:729–35. doi:10.1006/cyto.1999.0485
5. Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Dev Dyn (2008) 237:18–27. doi:10.1002/dvdy.21388
6. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta (2000) 1492:203–6. doi:10.1016/S0167-4781(00)00067-1
7. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest (2005) 115:1627–35. doi:10.1172/JCI23606
8. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab (2007) 25:415–25. doi:10.1016/j. cmet.2007.05.003
9. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab (2007) 5:426–37. doi:10.1016/j.cmet.2007.05.002
10. Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun (2000) 277:494–8. doi:10.1006/bbrc.2000.3696
11. Consortium ADHR. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet (2000) 26:345–8. doi:10.1038/81664
12. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A (2001) 98:6500–5. doi:10.1073/pnas.101545198
13. Kuro-o M. Klotho and βKlotho. Adv Exp Med Biol (2012) 728:25–40. doi:10.1007/978-1-4614-0887-1_2
14. Beenken A, Mohammadi M. The structural biology of the FGF19 subfamily. Adv Exp Med Biol (2012) 728:1–24. doi:10.1007/978-1-4614-0887-1_1
15. Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R. FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem (2010) 285:5165–70. doi:10.1074/jbc.M109.068783
16. Itoh N. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease. Cell Tissue Res (2010) 342:1–11. doi:10.1007/s00441-010-1024-2
17. Oulion S, Bertrand S, Escriva H. Evolution of the FGF gene family. Int J Evol Biol (2012) 2012:298147. doi:10.1155/2012/298147
18. Zhang G, Li C, Li Q, Li B, Larkin DM, Lee C, et al. Comparative genomics reveals insights into avian genome evolution and adaptation. Science (2014) 346:1311–20. doi:10.1126/science.1251385
19. Vincentz JW, McWhirter JR, Murre C, Baldini A, Furuta Y. Fgf15 is required for proper morphogenesis of the mouse cardiac outflow tract. Genesis (2005) 41:192–201. doi:10.1002/gene.20114
20. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab (2005) 2:217–25. doi:10.1016/j.cmet.2005.09.001
21. Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, et al. Identification of a hormonal basis for gallbladder filling. Nat Med (2006) 12:1253–5. doi:10.1038/nm1501
22. Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science (2011) 331:1621–4. doi:10.1126/science.1198363
23. Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HC, Carotti S, et al. Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut (2013) 62:899–910. doi:10.1136/gutjnl-2012-302945
24. Kong B, Huang J, Zhu Y, Li G, Williams J, Shen S, et al. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol (2014) 306:G893–902. doi:10.1152/ajpgi.00337.2013
25. Uriarte I, Latasa MU, Carotti S, Fernandez-Barrena MG, Garcia-Irigoyen O, Elizalde M, et al. Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development. Int J Cancer (2015) 136:2469–75. doi:10.1002/ijc.29287
26. Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Curr Opin Investig Drugs (2009) 10:359–64.
27. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol (2010) 24:2050–64. doi:10.1210/me.2010-0142
28. Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology (2009) 150:4625–33. doi:10.1210/en.2009-0119
29. Badman MK, Koester A, Flier JS, Kharitonenkov A, Maratos-Flier E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology (2009) 150:4931–40. doi:10.1210/en.2009-0532
30. Murata Y, Nishio K, Mochiyama T, Konishi M, Shimada M, Ohta H, et al. Fgf21 impairs adipocyte insulin sensitivity in mice fed a low-carbohydrate, high-fat ketogenic diet. PLoS One (2013) 8:e69330. doi:10.1371/journal.pone.0069330
31. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab (2013) 17:779–89. doi:10.1016/j.cmet.2013.04.005
32. HollandWL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab (2013) 17:790–7. doi:10.1016/j.cmet.2013.03.019
33. Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes (2013) 62:1453–63. doi:10.2337/db12-1116
34. So WY, Cheng Q, Xu A, Lam KS, Leung PS. Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice. Cell Death Dis (2015) 6:e1707. doi:10.1038/cddis.2015.80
35. Kim SH, Kim KH, Kim HK, Kim MJ, Back SH, Konishi M, et al. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress. Diabetologia (2015) 58:809–18. doi:10.1007/s00125-014-3475-6
36. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias LA, et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun (2013) 4:2019. doi:10.1038/ncomms3019
37. Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M, et al. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res (2015) 106:19–31. doi:10.1093/cvr/cvu263
38. Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW, Kharitonenkov A, et al. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology (2009) 137:1795–804. doi:10.1053/j. gastro.2009.07.064
39. Yan X, Chen J, Zhang C, Zhou S, Zhang Z, Chen J, et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J Cell Mol Med (2015) 19:1557–68. doi:10.1111/jcmm.12530
40. Yan X, Chen J, Zhang C, Zeng J, Zhou S, Zhang Z, et al. Fibroblast growth factor 21 deletion aggravates diabetes-induced pathogenic changes in the aorta in type 1 diabetic mice. Cardiovasc Diabetol (2015) 14:77. doi:10.1186/s12933-015-0241-0
41. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest (2004) 113:561–8. doi:10.1172/JCI200419081
42. Lysaght AC, Yuan Q, Fan Y, Kalwani N, Caruso P, Cunnane M, et al. FGF23 deficiency leads to mixed hearing loss and middle ear malformation in mice. PLoS One (2014) 9:e107681. doi:10.1371/journal.pone.0107681
43. Schaap FG, van der Gaag NA, Gouma DJ, Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology (2009) 49:1228–35. doi:10.1002/hep.22771
44. Topaz O, Shurman DL, Bergman R, Indelman M, Ratajczak P, Mizrachi M, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet (2004) 36:579–81. doi:10.1038/ng1358
45. Chefetz I, Heller R, Galli-Tsinopoulou A, Richard G, Wollnik B, Indelman MA, et al. Novel homozygous missense mutation in FGF23 causes familial tumoral calcinosis associated with disseminated visceral calcification. Hum Genet (2005) 118:261–6. doi:10.1007/s00439-005-0026-8
46. Garringer HJ, Malekpour M, Esteghamat F, Mortazavi SM, Davis SI, Farrow EG, et al. Molecular genetic and biochemical analyses of FGF23 mutations in familial tumoral calcinosis. Am J Physiol Endocrinol Metab (2008) 295:E929–37. doi:10.1152/ajpendo.90456.2008
47. White KE, Carn G, Lorenz-Depiereux B, Benet-Pages A, Strom TM, Econs MJ. Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23. Kidney Int (2001) 60:2079–86. doi:10.1046/j.1523-1755.2001.00064.x
48. Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F, Tanaka T, et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet (2013) 22:1895–902. doi:10.1093/hmg/ddt032
49. Zhang M, Zeng L, Wang YJ, An ZM, Ying BW. Associations of fibroblast growth factor 21 gene 3′ untranslated region single-nucleotide polymorphisms with metabolic syndrome, obesity, and diabetes in a Han Chinese population. DNA Cell Biol (2012) 31:547–52. doi:10.1089/dna.2011.1302
50. Falcini F, Rigante D, Masi L, Covino M, Franceschelli F, Leoncini G, et al. Fibroblast growth factor 23 (FGF23) gene polymorphism in children with Kawasaki syndrome (KS) and susceptibility to cardiac abnormalities. Ital J Pediatr (2013) 39:69. doi:10.1186/1824-7288-39-69
51. Kim HJ, Kim KH, Lee J, Oh JJ, Cheong HS, Wong EL, et al. Single nucleotide polymorphisms in fibroblast growth factor 23 gene, FGF23, are associated with prostate cancer risk. BJU Int (2014) 114:303–10. doi:10.1111/bju.12396
52. Reiche M, Bachmann A, Lössner U, Blüher M, Stumvoll M, Fasshauer M. Fibroblast growth factor 19 serum levels: relation to renal function and metabolic parameters. Horm Metab Res (2010) 42:178–81. doi:10.1055/s-0029-1243249
53. Li M, Qureshi AR, Ellis E, Axelsson J. Impaired postprandial fibroblast growth factor (FGF)-19 response in patients with stage 5 chronic kidney diseases is ameliorated following antioxidative therapy. Nephrol Dial Transplant (2013) 28(Suppl 4):iv212–9. doi:10.1093/ndt/gft337
54. Hao Y, Zhou J, Zhou M, Ma X, Lu Z, Gao M, et al. Serum levels of fibroblast growth factor 19 are inversely associated with coronary artery disease in Chinese individuals. PLoS One (2013) 8:e72345. doi:10.1371/journal. pone.0072345
55. Mutanen A, Lohi J, Heikkilä P, Jalanko H, Pakarinen MP. Loss of ileum decreases serum fibroblast growth factor 19 in relation to liver inflammation and fibrosis in pediatric onset intestinal failure. J Hepatol (2015) 62:1391–7. doi:10.1016/j.jhep.2015.01.004
56. Roesch SL, Styer AM, Wood GC, Kosak Z, Seiler J, Benotti P, et al. Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes. PLoS One (2015) 10:e0116928. doi:10.1371/journal.pone.0116928
57. Pattni SS, Brydon WG, Dew T, Johnston IM, Nolan JD, Srinivas M. Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention. Aliment Pharmacol Ther (2013) 38:967–76. doi:10.1111/apt.12466
58. Nolan JD, Johnston IM, Pattni SS, Dew T, Orchard TR, Walters JR. Diarrhea in Crohn’s disease: investigating the role of the ileal hormone fibroblast growth factor 19. J Crohns Colitis (2015) 9:125–31. doi:10.1093/ecco-jcc/jju022
59. Renner O, Harsch S, Matysik S, Lütjohann D, Schmitz G, Stange EF. Upregulation of hepatic bile acid synthesis via fibroblast growth factor 19 is defective in gallstone disease but functional in overweight individuals. United European Gastroenterol J (2014) 2:216–25. doi:10.1177/2050640614527938
60. Nagamatsu H, Teishima J, Goto K, Shikuma H, Kitano H, Shoji K, et al. FGF19 promotes progression of prostate cancer. Prostate (2015) 75:1092–101. doi:10.1002/pros.22994
61. Hindricks J, Ebert T, Bachmann A, Kralisch S, Lössner U, Kratzsch J, et al. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol (Oxf) (2014) 80:918–24. doi:10.1111/cen.12380
62. Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One (2010) 5:e15534. doi:10.1371/journal. pone.0015534
63. Chow WS, Xu A, Woo YC, Tso AW, Cheung SC, Fong CH, et al. Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol (2013) 33:2454–9. doi:10.1161/ATVBAHA.113.301599
64. Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, et al. Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine (2013) 62:322–6. doi:10.1016/j.cyto.2013.02.019
65. Salehi MH, Kamalidehghan B, Houshmand M, Aryani O, Sadeghizadeh M, Mossalaeie MM. Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich ataxia). Mol Biol Rep (2013) 40:6495–9. doi:10.1007/s11033-013-2767-0
66. Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology (2013) 81:1819–26. doi:10.1212/01.wnl.0000436068.43384.ef
67. Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) (2009) 71:369–75. doi:10.1111/j.1365-2265.2008.03502.x
68. Lin Y, Xiao YC, Zhu H, Xu QY, Qi L, Wang YB, et al. Serum fibroblast growth factor 21 levels are correlated with the severity of diabetic retinopathy. J Diabetes Res (2014) 2014:929756. doi:10.1155/2014/929756
69. Korwutthikulrangsri M, Mahachoklertwattana P, Chanprasertyothin S, Pongratanakul S, Poomthavorn P. Serum fibroblast growth factor 21 in overweight and obese Thai children and adolescents: its relation to glucose metabolism and its change after glucose loading. Clin Endocrinol (Oxf) (2015). doi:10.1111/cen.12808
70. Reinehr T, Karges B, Meissner T, Wiegand S, Fritsch M, Holl RW, et al. Fibroblast growth factor 21 and fetuin-A in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab (2015) 100:3004–10. doi:10.1210/jc.2015-2192
71. Dostálová I, Kaválková P, Haluzíková D, Lacinová Z, Mráz M, Papezová H, et al. Plasma concentrations of fibroblast growth factors 19 and 21 in patients with anorexia nervosa. J Clin Endocrinol Metab (2008) 93:3627–32. doi:10.1210/jc.2008-0746
72. Durovcová V, Marek J, Hána V, Matoulek M, Zikán V, Haluzíková D, et al. Plasma concentrations of fibroblast growth factors 21 and 19 in patients with Cushing’s syndrome. Physiol Res (2010) 59:415–22.
73. Hanssen MJ, Broeders E, Samms RJ, Vosselman MJ, van der Lans AA, Cheng CC, et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep (2015) 5:10275. doi:10.1038/srep10275
74. Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol (2010) 53:934–40. doi:10.1016/j. jhep.2010.05.018
75. Alisi A, Ceccarelli S, Panera N, Prono F, Petrini S, De Stefanis C, et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS One (2013) 8:e67160. doi:10.1371/journal.pone.0067160
76. Kukla M, Berdowska A, Stygar D, Gabriel A, Mazur W, Łogiewa-Bazger B, et al. Serum FGF21 and RBP4 levels in patients with chronic hepatitis C. Scand J Gastroenterol (2012) 47:1037–47. doi:10.3109/00365521.2012.694901
77. Gariani K, Drifte G, Dunn-Siegrist I, Pugin J, Jornayvaz FR. Increased FGF21 plasma levels in humans with sepsis and SIRS. Endocr Connect (2013) 2:146–53. doi:10.1530/EC-13-0040
78. Hulejová H, Andrés Cerezo L, Kuklová M, Pecha O, Vondráček T, Pavelka K, et al. Novel adipokine fibroblast growth factor 21 is increased in rheumatoid arthritis. Physiol Res (2012) 61:489–94.
79. Ozeki M, Fujita S, Kizawa S, Morita H, Sohmiya K, Hoshiga M, et al. Association of serum levels of FGF23 and α-Klotho with glomerular filtration rate and proteinuria among cardiac patients. BMC Nephrol (2014) 15:147. doi:10.1186/1471-2369-15-147
80. Portale AA, Wolf M, Jüppner H, Messinger S, Kumar J, Wesseling-Perry K, et al. Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol (2014) 9:344–53. doi:10.2215/CJN.05840513
81. Taal MW, Thurston V, McIntyre NJ, Fluck RJ, McIntyre CW. The impact of vitamin D status on the relative increase in fibroblast growth factor 23 and parathyroid hormone in chronic kidney disease. Kidney Int (2014) 86:407–13. doi:10.1038/ki.2013.537
82. di Giuseppe R, Buijsse B, Hirche F, Wirth J, Arregui M, Westphal S, et al. Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitamin D3, and risk of heart failure: a prospective, case-cohort study. J Clin Endocrinol Metab (2014) 99:947–55. doi:10.1210/jc.2013-2963
83. Isakova T, Houston J, Santacruz L, Schiavenato E, Somarriba G, Harmon WG, et al. Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. Pediatr Nephrol (2013) 28:2035–42. doi:10.1007/s00467-013-2515-7
84. Xiao Y, Peng C, Huang W, Zhang J, Xia M, Zhang Y, et al. Circulating fibroblast growth factor 23 is associated with angiographic severity and extent of coronary artery disease. PLoS One (2013) 8:e72545. doi:10.1371/journal. pone.0072545
85. di Giuseppe R, Kühn T, Hirche F, Buijsse B, Dierkes J, Fritsche A, et al. Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study. Eur J Epidemiol (2015) 30:131–41. doi:10.1007/s10654-014-9982-4
86. Jovanovich A, Ix JH, Gottdiener J, McFann K, Katz R, Kestenbaum B, et al. Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. Atherosclerosis (2013) 231:114–9. doi:10.1016/j.atherosclerosis.2013.09.002
87. Wright CB, Dong C, Stark M, Silverberg S, Rundek T, Elkind MS, et al. Plasma FGF23 and the risk of stroke: the Northern Manhattan study (NOMAS). Neurology (2014) 82:1700–6. doi:10.1212/WNL.0000000000000410
88. Panwar B, Jenny NS, Howard VJ, Wadley VG, Muntner P, Kissela BM, et al. Fibroblast growth factor 23 and risk of incident stroke in community-living adults. Stroke (2015) 46:322–8. doi:10.1161/STROKEAHA.114.007489
89. Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med (2014) 6:247ra100. doi:10.1126/scitranslmed.3009098
90. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology (2007) 148:774–81. doi:10.1210/en.2006-1168
91. Adams AC, Halstead CA, Hansen BC, Irizarry AR, Martin JA, Myers SR, et al. LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS One (2013) 8:e65763. doi:10.1371/journal. pone.0065763
92. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab (2013) 18:333–40. doi:10.1016/j.cmet.2013.08.005
93. Véniant MM, Komorowski R, Chen P, Stanislaus S, Winters K, Hager T, et al. Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology (2012) 153:4192–203. doi:10.1210/en.2012-1211
94. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, et al. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol (2015). doi:10.1111/bcp.12676
95. Smith R, Duguay A, Bakker A, Li P, Weiszmann J, Thomas MR, et al. FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/β-Klotho bispecific protein. PLoS One (2013) 8:e61432. doi:10.1371/journal.pone.0061432
96. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest (2014) 124:1587–97. doi:10.1172/JCI72829
97. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab (2015) 100:2565–73. doi:10.1210/jc.2015-1551