FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation.
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.
Wu
Xinle
X
Amgen, Inc., South San Francisco, California 94080, USA.
Ge
Hongfei
H
Lemon
Bryan
B
Vonderfecht
Steven
S
Weiszmann
Jennifer
J
Hecht
Randy
R
Gupte
Jamila
J
Hager
Todd
T
Wang
Zhulun
Z
Lindberg
Richard
R
Li
Yang
Y
D041721:3T3-L1 Cells; D000595:Amino Acid Sequence; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
C117476:FGF19 protein, human; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4