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W2034198983 abstract "FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation. FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation. IntroductionFGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors (FGFs). 3The abbreviations used are: FGFfibroblast growth factorPBSphosphate-buffered salineBrdUbromodeoxyuridineFGFRFGF receptorERKextracellular signal-regulated kinase. Unlike other FGFs, all three have been shown to function as endocrine hormones in the regulation of various metabolic processes (1.Fukumoto S. Endocr. J. 2008; 55: 23-31Crossref PubMed Scopus (103) Google Scholar). FGF23 originates in bone and regulates phosphate homeostasis in kidney (2.Fukumoto S. Yamashita T. Bone. 2007; 40: 1190-1195Crossref PubMed Scopus (113) Google Scholar), FGF21 is expressed predominantly in liver and signals in adipose tissue (3.Ogawa Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. Eliseenkova A.V. Mohammadi M. Kuro-o M. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 7432-7437Crossref PubMed Scopus (464) Google Scholar), and FGF19 is secreted from ileum and functions as an enterohepatic signal for the regulation of bile acid metabolism (4.Inagaki 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 (1283) Google Scholar).FGF19 and FGF21 have similar effects on regulating glucose, lipid, and energy metabolism. Both FGF19 and FGF21 transgenic mice are resistant to diet-induced obesity, have decreased body fat mass and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (5.Tomlinson E. Fu L. John L. Hultgren B. Huang X. Renz M. Stephan J.P. Tsai S.P. Powell-Braxton L. French D. Stewart T.A. Endocrinology. 2002; 143: 1741-1747Crossref PubMed Scopus (287) Google Scholar, 6.Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. Vandlen R. Simmons L. Foster J. Stephan J.P. Tsai S.P. Stewart T.A. Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (424) Google Scholar, 7.Kharitonenkov 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. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1581) Google Scholar, 8.Xu J. Lloyd D.J. Hale C. Stanislaus S. Chen M. Sivits G. Vonderfecht S. Hecht R. Li Y.S. Lindberg R.A. Chen J.L. Jung D.Y. Zhang Z. Ko H.J. Kim J.K. Véniant M.M. Diabetes. 2009; 58: 250-259Crossref PubMed Scopus (853) Google Scholar). Administration of recombinant FGF19 or FGF21 protein to diabetic mice resulted in the reduction of serum glucose and insulin levels, improved glucose tolerance, and reduced liver steatosis and body weight (7.Kharitonenkov 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. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1581) Google Scholar, 8.Xu J. Lloyd D.J. Hale C. Stanislaus S. Chen M. Sivits G. Vonderfecht S. Hecht R. Li Y.S. Lindberg R.A. Chen J.L. Jung D.Y. Zhang Z. Ko H.J. Kim J.K. Véniant M.M. Diabetes. 2009; 58: 250-259Crossref PubMed Scopus (853) Google Scholar). In addition, FGF21 improved glucose, insulin, and lipid profiles and reduced body weight in diabetic rhesus monkeys (9.Kharitonenkov A. Wroblewski V.J. Koester A. Chen Y.F. Clutinger C.K. Tigno X.T. Hansen B.C. Shanafelt A.B. Etgen G.J. Endocrinology. 2007; 148: 774-781Crossref PubMed Scopus (609) Google Scholar). Taken together, these observations suggest the potential utility of FGF19 and FGF21 for the treatment of diabetes and obesity (1.Fukumoto S. Endocr. J. 2008; 55: 23-31Crossref PubMed Scopus (103) Google Scholar).Because of the sequence and structural homology between FGF19 and FGF21 with the other FGFs, most of which have well established roles in cell proliferation and mitogenesis, whether FGF19 and FGF21 could induce cell proliferation have also been investigated. In the case of FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In addition, increases in the proliferation of pericentral hepatocytes, as measured by enhanced BrdU labeling, was observed both in FGF19 transgenic animals and wild-type mice administered recombinant FGF19 (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Because constitutive hepatocellular proliferation may be a prerequisite for transformation (11.Fausto N. Sem. Liver Dis. 1999; 19: 243-252Crossref PubMed Scopus (97) Google Scholar), it is interesting to note that cell lineage analysis of FGF19-induced tumors suggests that dysplastic and neoplastic hepatocytes originated adjacent to central veins, where increased proliferation was localized as determined by BrdU labeling (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). These results suggest that FGF19 induced hepatocyte proliferation may ultimately lead to HCC formation (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). FGFR4 has been proposed to play a role in the observed induction of hepatocyte proliferation and carcinogenesis by FGF19 (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar); however, contradicting evidence proposing a protective role for FGFR4 in suppressing hepatoma progression has also been proposed (12.Huang X. Yang C. Jin C. Luo Y. Wang F. McKeehan W.L. Mol. Carcinogenesis. 2009; 48: 553-562Crossref PubMed Scopus (34) Google Scholar). Therefore, the mechanism for FGF19 induced hepatocyte mitogenesis has not been elucidated, and the receptor responsible for this activity remains unclear.Receptor utilization for this subfamily has been elucidated recently. Both FGF19 and FGF21 utilize β-Klotho, a single transmembrane protein, as a co-receptor in addition to FGFRs for signaling (13.Kurosu H. Kuro-O M. Mol. Cell. Endocrinol. 2009; 299: 72-78Crossref PubMed Scopus (149) Google Scholar). Potential differences in FGFR utilization between FGF19 and FGF21 have been reported (14.Kurosu H. Choi M. Ogawa Y. Dickson A.S. Goetz R. Eliseenkova A.V. Mohammadi M. Rosenblatt K.P. Kliewer S.A. Kuro-o M. J. Biol. Chem. 2007; 282: 26687-26695Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar, 15.Wu X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. Tang J. Lindberg R. Li Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 14379-14384Crossref PubMed Scopus (71) Google Scholar, 16.Wu X. Li Y. Aging. 2009; 1: 1023-1027Crossref PubMed Scopus (23) Google Scholar). However, whether FGF21 causes hepatocyte proliferation and whether the reported differences in receptor specificity between FGF19 and FGF21 contribute to mitogenicity are not clear.In this report, we show that, in contrast to FGF19, FGF21 does not increase hepatocyte proliferation in vivo. In addition, using a series of novel FGF19 and FGF21 truncation and chimeric molecules, we have identified a region on FGF19 that is responsible for FGFR4 activation and propose that FGFR4 activation is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation.DISCUSSIONBoth FGF19 and FGF21 are novel hormones that regulate glucose, lipid, and energy homeostasis (5.Tomlinson E. Fu L. John L. Hultgren B. Huang X. Renz M. Stephan J.P. Tsai S.P. Powell-Braxton L. French D. Stewart T.A. Endocrinology. 2002; 143: 1741-1747Crossref PubMed Scopus (287) Google Scholar, 6.Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. Vandlen R. Simmons L. Foster J. Stephan J.P. Tsai S.P. Stewart T.A. Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (424) Google Scholar, 7.Kharitonenkov 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. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1581) Google Scholar, 8.Xu J. Lloyd D.J. Hale C. Stanislaus S. Chen M. Sivits G. Vonderfecht S. Hecht R. Li Y.S. Lindberg R.A. Chen J.L. Jung D.Y. Zhang Z. Ko H.J. Kim J.K. Véniant M.M. Diabetes. 2009; 58: 250-259Crossref PubMed Scopus (853) Google Scholar). FGF19 is also able to induce hepatocyte proliferation and cause formation of liver tumors in mice; however, the mechanism has not been determined previously (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In this report, using BrdU labeling as a measure for in vivo mitotic activity, we show that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation when compared directly with FGF19. These experiments suggest functional differentiation between FGF19 and FGF21. Given that increased hepatocyte proliferation is believed to be a prerequisite for neoplastic transformation (11.Fausto N. Sem. Liver Dis. 1999; 19: 243-252Crossref PubMed Scopus (97) Google Scholar), these results may suggest that FGF21 would not cause HCC in rodents.To better understand the mechanism leading to the proliferative activity observed with FGF19, we initially focused our attention on the differences in receptor specificity observed between FGF19 and FGF21. Both FGF19 and FGF21 activate FGFR1c, 2c and 3c, however, only FGF19 activates FGFR4 in vitro as measured by ERK phosphorylation (Fig. 2). Because FGFR4 is the predominant FGF receptor expressed in the liver, we hypothesized that the unique specificity of FGF19 toward FGFR4 might be responsible for its involvement in liver tumorigenesis. The first direct evidence supporting this hypothesis was derived from experiments with FGF19dCTD, a C-terminally truncated variant of FGF19 protein. The inability of FGF19dCTD to bind β-Klotho explains its lack of activity at FGFRs 1c, 2c, and 3c (Fig. 3) (15.Wu X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. Tang J. Lindberg R. Li Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 14379-14384Crossref PubMed Scopus (71) Google Scholar). However, FGF19dCTD retained its ability to activate FGFR4 in a β-Klotho-independent manner. Therefore, this variant is an FGFR4 specific activator. When tested in vivo for its effect on hepatocyte proliferation, FGF19dCTD increased BrdU incorporation in pericentral hepatocytes similar to FGF19, suggesting activation of FGFR4 alone is sufficient to promote hepatocyte proliferation.To provide further evidence supporting this hypothesis and to identify region(s) in FGF19 responsible for FGFR4 activation, we generated chimeric proteins between FGF19 and FGF21 and tested their activity in signaling and proliferation assays (Fig. 4). These analyses showed an absolute correlation between the ability to activate FGFR4, measured by ERK phosphorylation in vitro, and increased pericentral hepatocyte proliferation measured by BrdU labeling in liver in vivo. This provides further evidence for the hypothesis that liver FGFR4 activation and hepatocyte proliferation are linked. In addition, this study identified a 5 amino acid region (residues 38–42) on FGF19 that is important and potentially sufficient for FGFR4 activation. This was further supported by experiments with FGF21/1938–42 in which only these 5 amino acids from FGF19 were substituted into FGF21. The substitution of these 5 amino acids was sufficient to confer a gain-of-function phenotype on FGF21 with respect to both FGFR4 activation and increased hepatocyte proliferation (Fig. 5).Taken together: 1) the lack of increased hepatocyte proliferation by FGF21 treatment in direct comparison with FGF19; 2) the ability of FGF19dCTD, an FGFR4 specific activator, to increase pericentral hepatocyte BrdU incorporation; 3) the absolute correlation among FGF19/FGF21 chimeric molecules in their ability to induce FGFR4 activation and to increase pericentral hepatocyte BrdU staining; and finally 4) the ability of just 5 residues from FGF19 to confer FGFR4 activation and increased BrdU labeling in pericentral hepatocytes, these observations provide compelling evidence that FGFR4 activation in hepatocytes leads to increased proliferation which may cause HCC. IntroductionFGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors (FGFs). 3The abbreviations used are: FGFfibroblast growth factorPBSphosphate-buffered salineBrdUbromodeoxyuridineFGFRFGF receptorERKextracellular signal-regulated kinase. Unlike other FGFs, all three have been shown to function as endocrine hormones in the regulation of various metabolic processes (1.Fukumoto S. Endocr. J. 2008; 55: 23-31Crossref PubMed Scopus (103) Google Scholar). FGF23 originates in bone and regulates phosphate homeostasis in kidney (2.Fukumoto S. Yamashita T. Bone. 2007; 40: 1190-1195Crossref PubMed Scopus (113) Google Scholar), FGF21 is expressed predominantly in liver and signals in adipose tissue (3.Ogawa Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. Eliseenkova A.V. Mohammadi M. Kuro-o M. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 7432-7437Crossref PubMed Scopus (464) Google Scholar), and FGF19 is secreted from ileum and functions as an enterohepatic signal for the regulation of bile acid metabolism (4.Inagaki 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 (1283) Google Scholar).FGF19 and FGF21 have similar effects on regulating glucose, lipid, and energy metabolism. Both FGF19 and FGF21 transgenic mice are resistant to diet-induced obesity, have decreased body fat mass and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (5.Tomlinson E. Fu L. John L. Hultgren B. Huang X. Renz M. Stephan J.P. Tsai S.P. Powell-Braxton L. French D. Stewart T.A. Endocrinology. 2002; 143: 1741-1747Crossref PubMed Scopus (287) Google Scholar, 6.Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. Vandlen R. Simmons L. Foster J. Stephan J.P. Tsai S.P. Stewart T.A. Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (424) Google Scholar, 7.Kharitonenkov 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. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1581) Google Scholar, 8.Xu J. Lloyd D.J. Hale C. Stanislaus S. Chen M. Sivits G. Vonderfecht S. Hecht R. Li Y.S. Lindberg R.A. Chen J.L. Jung D.Y. Zhang Z. Ko H.J. Kim J.K. Véniant M.M. Diabetes. 2009; 58: 250-259Crossref PubMed Scopus (853) Google Scholar). Administration of recombinant FGF19 or FGF21 protein to diabetic mice resulted in the reduction of serum glucose and insulin levels, improved glucose tolerance, and reduced liver steatosis and body weight (7.Kharitonenkov 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. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1581) Google Scholar, 8.Xu J. Lloyd D.J. Hale C. Stanislaus S. Chen M. Sivits G. Vonderfecht S. Hecht R. Li Y.S. Lindberg R.A. Chen J.L. Jung D.Y. Zhang Z. Ko H.J. Kim J.K. Véniant M.M. Diabetes. 2009; 58: 250-259Crossref PubMed Scopus (853) Google Scholar). In addition, FGF21 improved glucose, insulin, and lipid profiles and reduced body weight in diabetic rhesus monkeys (9.Kharitonenkov A. Wroblewski V.J. Koester A. Chen Y.F. Clutinger C.K. Tigno X.T. Hansen B.C. Shanafelt A.B. Etgen G.J. Endocrinology. 2007; 148: 774-781Crossref PubMed Scopus (609) Google Scholar). Taken together, these observations suggest the potential utility of FGF19 and FGF21 for the treatment of diabetes and obesity (1.Fukumoto S. Endocr. J. 2008; 55: 23-31Crossref PubMed Scopus (103) Google Scholar).Because of the sequence and structural homology between FGF19 and FGF21 with the other FGFs, most of which have well established roles in cell proliferation and mitogenesis, whether FGF19 and FGF21 could induce cell proliferation have also been investigated. In the case of FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In addition, increases in the proliferation of pericentral hepatocytes, as measured by enhanced BrdU labeling, was observed both in FGF19 transgenic animals and wild-type mice administered recombinant FGF19 (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Because constitutive hepatocellular proliferation may be a prerequisite for transformation (11.Fausto N. Sem. Liver Dis. 1999; 19: 243-252Crossref PubMed Scopus (97) Google Scholar), it is interesting to note that cell lineage analysis of FGF19-induced tumors suggests that dysplastic and neoplastic hepatocytes originated adjacent to central veins, where increased proliferation was localized as determined by BrdU labeling (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). These results suggest that FGF19 induced hepatocyte proliferation may ultimately lead to HCC formation (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). FGFR4 has been proposed to play a role in the observed induction of hepatocyte proliferation and carcinogenesis by FGF19 (10.Nicholes K. Guillet S. Tomlinson E. Hillan K. Wright B. Frantz G.D. Pham T.A. Dillard-Telm L. Tsai S.P. Stephan J.P. Stinson J. Stewart T. French D.M. Am. J. Pathol. 2002; 160: 2295-2307Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar); however, contradicting evidence proposing a protective role for FGFR4 in suppressing hepatoma progression has also been proposed (12.Huang X. Yang C. Jin C. Luo Y. Wang F. McKeehan W.L. Mol. Carcinogenesis. 2009; 48: 553-562Crossref PubMed Scopus (34) Google Scholar). Therefore, the mechanism for FGF19 induced hepatocyte mitogenesis has not been elucidated, and the receptor responsible for this activity remains unclear.Receptor utilization for this subfamily has been elucidated recently. Both FGF19 and FGF21 utilize β-Klotho, a single transmembrane protein, as a co-receptor in addition to FGFRs for signaling (13.Kurosu H. Kuro-O M. Mol. Cell. Endocrinol. 2009; 299: 72-78Crossref PubMed Scopus (149) Google Scholar). Potential differences in FGFR utilization between FGF19 and FGF21 have been reported (14.Kurosu H. Choi M. Ogawa Y. Dickson A.S. Goetz R. Eliseenkova A.V. Mohammadi M. Rosenblatt K.P. Kliewer S.A. Kuro-o M. J. Biol. Chem. 2007; 282: 26687-26695Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar, 15.Wu X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. Tang J. Lindberg R. Li Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 14379-14384Crossref PubMed Scopus (71) Google Scholar, 16.Wu X. Li Y. Aging. 2009; 1: 1023-1027Crossref PubMed Scopus (23) Google Scholar). However, whether FGF21 causes hepatocyte proliferation and whether the reported differences in receptor specificity between FGF19 and FGF21 contribute to mitogenicity are not clear.In this report, we show that, in contrast to FGF19, FGF21 does not increase hepatocyte proliferation in vivo. In addition, using a series of novel FGF19 and FGF21 truncation and chimeric molecules, we have identified a region on FGF19 that is responsible for FGFR4 activation and propose that FGFR4 activation is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation." @default.
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W2034198983 title "FGF19-induced Hepatocyte Proliferation Is Mediated through FGFR4 Activation" @default.
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