Overexpression of thioredoxin prevents thioacetamide-induced hepatic fibrosis in mice.
OBJECTIVE
Thioredoxin is a small redox-active protein with anti-oxidant and anti-apoptotic effects. We have previously reported that thioacetamide-induced acute hepatitis was attenuated in thioredoxin transgenic mice. The aim of the present study was to investigate the protective effect of thioredoxin for hepatic fibrosis.


METHODS
We subjected thioredoxin transgenic mice to thioacetamide-induced hepatic fibrosis. We also studied the effect of thioredoxin on the activation process of primary-cultured hepatic stellate cell.


RESULTS
The expression of endogenous thioredoxin was induced in hepatocytes of thioacetamide-induced murine and rat fibrotic livers. Overexpression of thioredoxin inhibited tumor necrosis factor-alpha-induced apoptosis of HepG2 cells. Thioacetamide-induced fibrosis and accumulation of malondialdehyde were suppressed in transgenic mice as compared with wild type mice. Hepatic stellate cells isolated from transgenic mice were less proliferative than those isolated from wild type mice. Recombinant thioredoxin significantly inhibited DNA synthesis of primary-cultured stellate cells under serum or platelet-derived growth factor stimulation.


CONCLUSIONS
Thioredoxin has a potential to attenuate hepatic fibrosis via suppressing oxidative stress and inhibiting proliferation of stellate cells.
Okuyama
Hiroaki
H
Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nakamura
Hajime
H
Shimahara
Yasuyuki
Y
Uyama
Naoki
N
Kwon
Yong-Won
YW
Kawada
Norifumi
N
Yamaoka
Yoshio
Y
Yodoi
Junji
J
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity*; D013879:Thioredoxins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D013879:Thioredoxins; D003513:Cycloheximide