Overexpression of thioredoxin prevents thioacetamide-induced hepatic fibrosis in mice

Background/Aims

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-α-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.

Keywords: Thioredoxin, Hepatic fibrosis, Stellate cell

Abbreviations: ADF, adult T cell leukemia-derived factor, ALT, alanine aminotransferase, AP-1, activator protein-1, AST, aspartate aminotransferase, CHX, cycloheximide, DMEM, Dulbecco's modified eagle medium, EB, Epstein–Barr, ERK, extracellular signal-regulated kinase, FBS, fetal bovine serum, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, HIV, human immunodeficiency virus, H₂O₂, hydrogen peroxide, hTrx, human thioredoxin, HSC, hepatic stellate cell, IL, interleukin, LPS, lipopolysaccharide, MDA, malondialdehyde, mTrx, mouse thioredoxin, MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt, NAC, N-acetylcysteine, NF-κB, nuclear factor-κB, PAGE, polyacrylamide gel electrophoresis, PBS, phosphate-buffered saline, PDGF, platelet-derived growth factor, PDTC, pyrrolidine dithiocarbamate, Ref-1, redox factor-1, ROS, reactive oxygen species, SDS, sodium dodecylsulfate, SMA, smooth muscle α-actin, TAA, thioacetamide, Tg, transgenic, TNF, tumor necrosis factor, Trx, thioredoxin, WT, wild type