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TY  - THES
AU  - Stojanov, Sabrina
TI  - Die Bedeutung von Fetuin-A für Proliferation und Fibrogenese im Knockout-Modell
CY  - Aachen
PB  - Publikationsserver der RWTH Aachen University
M1  - RWTH-CONV-113460
SP  - V, 79 S. : graph. Darst.
PY  - 2009
N1  - Aachen, Techn. Hochsch., Diss., 2009
AB  - The human cirrhosis of the liver is a progressive illness with serious clinical results, like portal hypertension and terminal functional loss of the organ. At the end stands the liver transplant or the exitus letalis, not to forget the strongly raised prevalence for the hepatocellular carcinoma. For these reasons it is essential to develop new therapy concepts with views of forecast improvement or even healing. With a knockout model of the mouse we examined the effect of fetuin-A for physiological proliferation and pathological fibrogenesis of the liver. The rational was, that fetuin-A as a TGF-beta antagonist possibly adjusts the effects on proliferation and fibrogenesis of this growth factor and therefore the loss of the fetuin-A availability in the knockout model leads to a more progressive liver damage or disturbed repair. We bred two mouse groups, on the one hand the wild type and on the other hand the knockout type with which the encoding gene had been switched off for fetuin-A by gene targeting. In the first test part we used a fibrosis model to study the in vivo effect against the background of already existing in vitro data of the fetuin-A antagonism towards TGF-beta, a central mediator of the fibrogenesis. On the one hand we observed that with the wild type animals it came to a fetuin-A induction in spite of acute phase reaction. Because fetuin-A is, as everybody knows, a negative acute phase protein, the values would have had to sink, actually. We assume a possibly raised fetuin-A release within cell destruction. Also human patients with acute hepatitis possessed a light increase of the fetuin-A concentration. Furthermore differing fibrosis grades arose during the investigations with the same course of disease and TGF-beta induction. At the beginning the fetuin-A deficient mice showed a diminished cell proliferation and against our expectations towards the wild type animals temporarily a light decreased fibrosis development. When using the wound healing model of the partial hepatectomia the fetuin-A knockout mice showed a clear delay in the early regeneration phase. The typical peak of the hepatocyte proliferation after 24 hours was missing in this model. Apoptosis, acute phase reaction and TGF-beta induction also were similar in both mice groups. The inhibitory impact of fetuin-A on TGF-beta effects could be confirmed with a cell reporter bioassay. Here fetuin-A interfered with the activation of the PAI-1-promoter activity by TGF-beta. Against the background of these data we determined the fetuin-A concentration in the serum at different degrees of the cirrhosis of the liver as well as the acute viral human hepatitis. The measured fetuin-A serum values with different human liver illnesses supported our previous data. As with the wild type mice in the postoperative acute phase reaction, within acute hepatitis it came to an increase of the fetuin-A serum concentration. Consequently during the early hepatitis or liver regeneration phase fetuin-A is able to antagonise TGF-beta. Nevertheless, with progressive liver fibrosis the fetuin-A concentration is reduced and a TGF-beta neutralisation is not possible anymore. To sum up, it can be said that fetuin-A operates as a selective antagonist of the TGF-beta effect in vitro and also paracrin in vivo in presence of high fetuin-A concentrations temporally correlated to the TGF-beta induction, so that fetuin-A presumably works as an intermittent proliferation modulator. It was not possible to prove a systemic antagonism. By our study we could win a more differentiated understanding of the fetuin-A/TGF-beta interaction which can be the basis for further investigations.
KW  - Proliferation (SWD)
KW  - Fibrose (SWD)
LB  - PUB:(DE-HGF)11
UR  - https://publications.rwth-aachen.de/record/51145
ER  -