Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21

Abstract

The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21. The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particular FGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21. The FGF19 2The abbreviations used are:FGFfibroblast growth factorFGFRFGF receptorERKextracellular signal-regulated kinaseTBSTris-buffered salinesiRNAsmall interfering RNARTreverse transcription subfamily of ligands, which consists of FGF15 (the mouse ortholog of human FGF19), FGF19, FGF21, and FGF23, has emerged as a novel group of endocrine factors that regulate diverse metabolic processes in adulthood (1Itoh N. Ornitz D.M. Trends Genet. 2004; 20: 563-569Abstract Full Text Full Text PDF PubMed Scopus (879) Google Scholar). FGF15/19 expression is induced upon feeding in intestinal epithelial cells in response to bile acid released into the intestinal lumen. FGF15/19 then acts on hepatocytes to reduce bile acid synthesis through suppressing transcription of CYP7A1, which encodes the rate-limiting enzyme for bile acid synthesis (2Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar). FGF15/19 also acts on the gall bladder and stimulates its filling with bile. Thus, FGF15/19 functions as an essential component in a postprandial negative feedback loop for bile acid synthesis and release (2Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar, 3Choi M. Moschetta A. Bookout A.L. Peng L. Umetani M. Holmstrom S.R. Suino-Powell K. Xu H.E. Richardson J.A. Gerard R.D. Mangelsdorf D.J. Kliewer S.A. Nat. Med. 2006; 12: 1253-1255Crossref PubMed Scopus (243) Google Scholar). Conversely, FGF21 expression is induced upon fasting in the liver (4Inagaki T. Dutchak P. Zhao G. Ding X. Gautron L. Parameswara V. Li Y. Goetz R. Mohammadi M. Esser V. Elmquist J.K. Gerard R.D. Burgess S.C. Hammer R.E. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2007; 5: 415-425Abstract Full Text Full Text PDF PubMed Scopus (1207) Google Scholar, 5Badman M.K. Pissios P. Kennedy A.R. Koukos G. Flier J.S. Maratos-Flier E. Cell Metab. 2007; 5: 426-437Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar). FGF21 secreted from the liver then acts on adipose tissues to induce metabolic adaptation to fasting. Specifically, FGF21 stimulates lipolysis in adipocytes to release fatty acids, which in turn converted to ketones in the liver. FGF21 was originally identified as a hormone that stimulates glucose uptake in adipocytes (6Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. Gromada J. Brozinick J.T. Hawkins E.D. Wroblewski V.J. Li D.S. Mehrbod F. Jaskunas S.R. Shanafelt A.B. J. Clin. Investig. 2005; 115: 1627-1635Crossref PubMed Scopus (1648) Google Scholar). However, unlike insulin, FGF21 reduces fat storage because it stimulates lipolysis (4Inagaki T. Dutchak P. Zhao G. Ding X. Gautron L. Parameswara V. Li Y. Goetz R. Mohammadi M. Esser V. Elmquist J.K. Gerard R.D. Burgess S.C. Hammer R.E. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2007; 5: 415-425Abstract Full Text Full Text PDF PubMed Scopus (1207) Google Scholar, 5Badman M.K. Pissios P. Kennedy A.R. Koukos G. Flier J.S. Maratos-Flier E. Cell Metab. 2007; 5: 426-437Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar). The FGF23 gene was identified as the gene mutated in patients with autosomal dominant hypophosphatemic rickets (7White K.E. Evans W.E. O'Rlordan J.L.H. Speer M.C. Econs M.J. Lorenz-Deplereux B. Grabowski M. Meitinger T. Storm T.M. Nat. Genet. 2000; 26: 345-348Crossref PubMed Scopus (1297) Google Scholar). Autosomal dominant hypophosphatemic rickets patients carry a missense mutation in the FGF23 gene that confers resistance to proteolytic inactivation of FGF23 protein, resulting in increased blood FGF23 levels. Because of its inhibitory activity on phosphate reabsorption and vitamin D biosynthesis in the kidney, high FGF23 blood levels in autosomal dominant hypophosphatemic rickets patients result in phosphate wasting and defects in bone mineralization (8Quarles L.D. Am. J. Physiol. 2003; 285: E1-E9Crossref PubMed Scopus (287) Google Scholar, 9Schiavi S.C. Kumar R. 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Eliseen-kova A.V. Xu C. Neubert T. Zhang F. Linhardt R.J. Yu X. White K.E. Inagaki T. Kliewer S.A. Yamamoto M. Kurosu H. Ogawa Y. Kuro-o M. Lanske B. Razzaque M.S. Mohammadi M. Mol. Cell. Biol. 2007; 27: 3417-3428Crossref PubMed Scopus (434) Google Scholar, 13Harmer N.J. Pellegrini L. Chirgadze D. Fernandez-Recio J. Blundell T.L. Biochemistry. 2004; 43: 629-640Crossref PubMed Scopus (106) Google Scholar). The weak heparin binding affinity of the FGF19 family members enables them to avoid being captured in extracellular matrices and thus to function as endocrine factors. On the other hand, this weak heparin binding activity reduces the capacity of heparin/heparan sulfate to promotes direct interaction between FGFs and FGFRs (14Mohammadi M. Olsen S.K. Ibrahimi O.A. Cytokine Growth Factor Rev. 2005; 16: 107-137Crossref PubMed Scopus (563) Google Scholar). Indeed, attempts to demonstrate a direct interaction between FGFRs and the FGF19 family proteins in vitro have failed. 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Yamazaki Y. Hasegawa H. Y. Fujita T. Fukumoto S. K. Yamashita T. J. Clin. Investig. 2004; PubMed Scopus Google Scholar, M.S. D. T. R. Lanske B. J. 2006; 20: PubMed Scopus Google Scholar). we that βKlotho, a Klotho family protein, functions as a cofactor necessary for FGF21 binding to FGFRs and activation of FGF signaling Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). βKlotho acid with Klotho and is in adipose and S. S. N. S. S. T. Y. 2000; PubMed Scopus Google Scholar). βKlotho also with FGFRs and the affinity of FGF21 for the FGFRs in a to FGF23, and FGFRs Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). in βKlotho expression have phenotypes with mice in FGF15 FGFR4 increased bile acid synthesis and increased expression of CYP7A1 and which in bile acid synthesis (2Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar, S. T. A. J. Y. Y. J. Clin. Investig. 2005; 115: PubMed Scopus Google Scholar, C. F. M. C. Jones M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the that and βKlotho are essential in the negative of bile acid synthesis. this we and that FGF19, like its subfamily FGF21, requires βKlotho to stably bind to FGFRs and FGF The between FGF19 and FGF21 activities in their receptor binding and the tissue-specific of their cognate These into the by which the FGF19 subfamily of ligands metabolic activities in target for βKlotho and FGFRs with a their by of as (15Kurosu H. Ogawa Y. Miyoshi M. Yamamoto M. Nandi A. Rosenblatt K.P. Baum M.G. Schiavi S. Hu M.C. Moe O.W. Kuro-o M. J. Biol. Chem. 2006; 281: 6120-6123Abstract Full Text Full Text PDF PubMed Scopus (1077) Google Scholar, Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). Cell and of the mouse and of Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). cells cells and cells in and of expression was to the and for cells and to the of FGF19, FGF21, and FGF19, FGF21, and FGF23 in in and by and as S.R. J. Mohammadi M. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). human growth gene to I. Yamazaki Y. Shimada T. Iijima K. Hasegawa H. Okawa K. Fujita T. Fukumoto S. Yamashita T. Nature. 2006; 444: 770-774Crossref PubMed Scopus (1474) Google Scholar, I. M. A. C. G. 2005; PubMed Scopus Google was from human and into the cells with the the and in of and on with for and with saline of the was a in the signal was as from the cells and to from that response to was with human βKlotho and and in the and of the and with FGF21 and to the protein as that response to FGF21 was used for FGF19 of FGF on and then for with human FGF19, FGF21, FGF23 The cells in in a for and and for analysis protein kinase and as (15Kurosu H. Ogawa Y. Miyoshi M. Yamamoto M. Nandi A. Rosenblatt K.P. Baum M.G. Schiavi S. Hu M.C. Moe O.W. Kuro-o M. J. Biol. Chem. 2006; 281: 6120-6123Abstract Full Text Full Text PDF PubMed Scopus (1077) Google Scholar, Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). The signal was an analysis mice of FGF19 FGF21 by into the fat and and the The tissues in in the and to of the by the and of The of FGF19 from cells with FGFR with FGFR and βKlotho and with for The with Tris-buffered saline and then with FGF19 for the with (15Kurosu H. Ogawa Y. Miyoshi M. Yamamoto M. Nandi A. Rosenblatt K.P. Baum M.G. Schiavi S. Hu M.C. Moe O.W. Kuro-o M. J. Biol. Chem. 2006; 281: 6120-6123Abstract Full Text Full Text PDF PubMed Scopus (1077) Google by with the proteins with and to analysis βKlotho D FGF19 D of βKlotho by RNA adipocytes with by as and then used for analysis and for glucose uptake Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). cells by as the cells with in with cells of and with a gene and the cells for the cells and used for analysis and adipocytes with with FGF19 FGF21 in with fatty for and to the glucose uptake as Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). RNA was the of CYP7A1 and cells with with FGF19, FGF21, for RNA of RNA was with of and then into the to the The used to gene expression in of of and of in a of of the in on an and levels by the as the and adipose in of and The for the of and then for to The of liver and adipose with of protein protein with of for respectively. The of liver and adipose with of protein with and with for The with and with proteins with and to analysis D and D FGF19 βKlotho to FGF FGF21 and FGF23, FGF19 to FGF signaling in cells as by of and expression of Klotho in cells a response to FGF23 but not to FGF19 FGF21. Conversely, expression of βKlotho to both FGF21 and FGF19 but not FGF23 Because activation of FGF signaling with FGF23 activity and expression of the growth gene in cells I. Yamazaki Y. Shimada T. Iijima K. Hasegawa H. Okawa K. Fujita T. Fukumoto S. Yamashita T. Nature. 2006; 444: 770-774Crossref PubMed Scopus (1474) Google we FGF19 and FGF21 also increase activity in with the in FGF19 and FGF21 the only in cells in a it of βKlotho expression These observations that FGF19 requires βKlotho to FGF We have that βKlotho and Klotho binding affinity of FGF21 and FGF23, to their cognate FGFRs (15Kurosu H. Ogawa Y. Miyoshi M. Yamamoto M. Nandi A. Rosenblatt K.P. Baum M.G. Schiavi S. Hu M.C. Moe O.W. Kuro-o M. J. Biol. Chem. 2006; 281: 6120-6123Abstract Full Text Full Text PDF PubMed Scopus (1077) Google Scholar, Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). We βKlotho also binding of FGF19 to its cognate βKlotho to and FGFR4 to and and not with of FGFRs Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). the of βKlotho, FGF19 not bind to and FGFR4 and bound to and the of βKlotho, binding of FGF21 to and FGFR4 was binding to and was only increased These observations are of for FGF21 Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google and that FGF19 also requires βKlotho for binding to and FGFR4 and for activation of FGF to Both FGF19 and adipocytes express βKlotho and to FGF21 Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google we FGF19 also activates FGF signaling in these of and induced by FGF19 was with that induced by FGF21 We of and and by βKlotho expression and that βKlotho is required for both FGF19 and FGF21 to FGF signaling in of levels of mouse that adipocytes express These observations that activation of FGF signaling by FGF19 and FGF21 in these cells is through the Because FGF21 glucose uptake in adipocytes of (6Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. Gromada J. Brozinick J.T. Hawkins E.D. Wroblewski V.J. Li D.S. Mehrbod F. Jaskunas S.R. Shanafelt A.B. J. Clin. Investig. 2005; 115: 1627-1635Crossref PubMed Scopus (1648) Google Scholar, Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google we FGF19 activity upon Indeed, FGF19 increased glucose uptake which was with that induced by FGF21 These activities of FGF19 and FGF21 are also on βKlotho because by βKlotho expression to FGF19 but the also βKlotho we FGF19 and FGF21 FGF signaling in these The of for and in cells to that in adipocytes we of and by βKlotho expression and that βKlotho is required for FGF19 to FGF signaling in hepatocytes as as in However, in to hepatocytes are to FGF21 in of of and of levels of demonstrated that hepatocytes express FGFR4 that FGF19 can FGF signaling through the βKlotho-FGFR4 efficiently FGF21, the that FGF21 is of binding to the βKlotho-FGFR4 in vitro Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google Scholar). Because FGF19 transcription of CYP7A1 that encodes the rate-limiting enzyme of bile acid synthesis in hepatocytes J.A. Luo G. J. M. Kliewer S.A. Goodwin B. Jones S.A. 2003; PubMed Scopus Google we the of FGF19 to CYP7A1 expression also on βKlotho. FGF19, but not FGF21, the of CYP7A1 and increased that of an receptor that CYP7A1 expression (2Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar, S. M. K. S. T. B. M. Cell. 2: Full Text Full Text PDF PubMed Scopus Google Scholar, L. D. Y. S. P. R.A. M. Cell. 2: Full Text Full Text PDF PubMed Scopus Google Scholar). these activities of FGF19 are on βKlotho because by of βKlotho expression FGF19 and FGF21 through FGFR which FGFR are for activation of FGF signaling by FGF19 and FGF21, we expression of βKlotho and FGFR in the and which FGFR to FGF19 FGF21. cells are for this because not to FGF19 and FGF21 when with the βKlotho expression We cells with expression for βKlotho and of the FGFR and then the with FGF19 FGF21. Both FGF19 and FGF21 FGF signaling in cells βKlotho and but not in cells expressing cells βKlotho and FGFR4 to FGF19 but to FGF21 which is of the response to FGF19 and FGF21 in hepatocytes We conclude that FGF21 can bind to but signal through the βKlotho-FGFR4 These observations the that FGF21 functions as an for the βKlotho-FGFR4 the of and in FGF19 signaling to of the FGF19 cells demonstrate that the expression of βKlotho in combination with particular FGFR determines the to FGF19 and FGF21. this in we which FGFR are in target organs for FGF19 and FGF21. of levels that adipose and liver express and we βKlotho bound to and FGFR4 in these tissues. βKlotho was with and FGFR4 from of adipose and we FGF19 FGF21 into mice and the of activation of FGF signaling in adipose kidney, and liver. FGF19 FGF signaling in liver and in adipose as by of FGF21, however, FGF signaling in adipose but not in liver These the and and this we have identified factors that the tissue-specific activity of FGF19 and FGF19, like FGF21, requires βKlotho for binding to FGFRs and activation of FGF only FGF19 signals efficiently through and adipocytes express βKlotho and hepatocytes express βKlotho and FGFR4. These both FGF19 and FGF21 increase glucose uptake in adipocytes FGF19 but not FGF21 expression of CYP7A1 in hepatocytes and FGF21 for of FGF15 (the mouse ortholog of and to expression of CYP7A1 in mice (2Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. Luo G. Jones S.A. Goodwin B. Richardson J.A. Gerard R.D. Repa J.J. Mangelsdorf D.J. Kliewer S.A. Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (1364) Google Scholar). The capacity of FGF19 to FGF signaling through FGFR4 and other FGFRs of in the of gall bladder filling by βKlotho and FGFRs are in the gall with expression being the M. Moschetta A. Bookout A.L. Peng L. Umetani M. Holmstrom S.R. Suino-Powell K. Xu H.E. Richardson J.A. Gerard R.D. Mangelsdorf D.J. Kliewer S.A. Nat. Med. 2006; 12: 1253-1255Crossref PubMed Scopus (243) Google Scholar). of FGF19 an increase in gall bladder not only in mice but also in mice in FGFR4 expression M. Moschetta A. Bookout A.L. Peng L. Umetani M. Holmstrom S.R. Suino-Powell K. Xu H.E. Richardson J.A. Gerard R.D. Mangelsdorf D.J. Kliewer S.A. Nat. Med. 2006; 12: 1253-1255Crossref PubMed Scopus (243) Google that gall bladder filling induced by FGF19 can through other FGF19 has to on liver and gall the that FGF19 can signal through the has the that FGF19 also on Indeed, E. L. L. B. X. M. L. D. PubMed Scopus (287) Google and (6Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. Gromada J. Brozinick J.T. Hawkins E.D. Wroblewski V.J. Li D.S. Mehrbod F. Jaskunas S.R. Shanafelt A.B. J. Clin. Investig. 2005; 115: 1627-1635Crossref PubMed Scopus (1648) Google mice phenotypes adipose which fat and resistance to induced by a high fat activity of FGF19 by that high levels of FGF19 on adipocytes through the in mice and to induced by FGF21. not FGF15/19 to the of function to of FGF signaling in response to FGF19 in adipose was that in liver adipocytes and hepatocytes in to FGF19 and for this is that FGF19 the bound to hepatocytes extracellular matrices the through the liver and not adipose tissues a high the affinity of the FGF19 subfamily members to heparin/heparan sulfate is the other FGF family FGF19 a affinity to heparin FGF21 and FGF23 (12Goetz R. Beenken A. Ibrahimi O.A. Kalinina J. Olsen S.K. Eliseen-kova A.V. Xu C. Neubert T. Zhang F. Linhardt R.J. Yu X. White K.E. Inagaki T. Kliewer S.A. Yamamoto M. Kurosu H. Ogawa Y. Kuro-o M. Lanske B. Razzaque M.S. Mohammadi M. Mol. Cell. Biol. 2007; 27: 3417-3428Crossref PubMed Scopus (434) Google Scholar, X. Ibrahimi O.A. Olsen S.K. H. Mohammadi M. Ornitz D.M. J. Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google and by extracellular matrices in the liver to this is the of FGF15/19 to the of function because FGF19 is secreted from the and the liver the being to adipose through Thus, the of FGF19 to bind to heparin/heparan sulfate to the of metabolic activity of FGF19 to the liver and gall factors and induced by FGF19 FGF21 is that induced by it is that FGFRs as because an in the interaction between βKlotho, and the and βKlotho βKlotho by is only of in adipocytes not that the of FGFRs not bind to βKlotho and by the that FGFR has a affinity to βKlotho Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. A.V. Mohammadi M. Kuro-o M. S. A. 2007; PubMed Scopus Google that not only the of βKlotho and FGFRs but also the of FGFR the of on the and thus to that signals through efficiently the other FGFR The between and of and is in cells and and in cells and cells with a response to with the other FGFRs is to have a affinity to to the other FGFR D.M. Xu J. J.S. F. G. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These factors to the of and in activation of FGF signaling in The FGF19 subfamily members function as hormones that on target organs to On the other hand, tissues express FGFR that function as receptors for these have that tissue-specific expression of Klotho and βKlotho, in combination with FGFR the target organs of the FGF19 subfamily FGF19, FGF21, and FGF23 in the of metabolic processes bile acid, glucose, fatty acids, and vitamin D and thus in the diverse human metabolic and bone These FGFs and their Klotho gene family members for in metabolic We O. and L. for with with