Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury.
Hepatic injury and regeneration of the liver are associated with activation of hepatic stellate cells (HSC). Fibroblast growth factors (FGFs) and their receptors are important regulators of repair in various tissues. HSC express FGFR3IIIc as well as FGFGR4 and different spliced FGFR1IIIc and FGFR2IIIc isoforms which differ in the presence or absence of the acid box and of the first Ig-like domain. Expression of FGF9, known to be capable to activate the HSC FGFR2/3-isoforms, was increased in HSC in liver slice cultures after exposition to carbon tetrachloride, as an acute liver injury model. FGF9 significantly stimulated 3-H thymidine incorporation of hepatocytes, but failed to induce DNA synthesis in HSC despite the fact that FGF9 induced a sustained activation of extracellular signal-related kinases (ERK) 1/2. FGF9 induced an increased phosphorylation of Tyr436 of the fibroblast growth factor receptor substrate (FRS) 2, while phosphorylation of Tyr196 which is required for efficient Grb2 recruitment remained unchanged. Our findings suggest that HSC FGF9 provide a paracrine mitogenic signal to hepatocytes during acute liver injury, while the autocrine FGF9 signaling appears to be not sufficient to induce cell proliferation.
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany.
Marianne
M
Antoine
Werner
W
Wirz
Carmen G
CG
Tag
Axel M
AM
Gressner
Meltem
M
Marvituna
Mathias
M
Wycislo
Claus
C
Hellerbrand
Paul
P
Kiefer
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D002522:Chlorocebus aethiops; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000235:genetics* / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008934:Mitogens / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D051525:Fibroblast Growth Factor 9; D008934:Mitogens; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3