Contribution of glutaredoxin-1 to Fas s-glutathionylation and inflammation in ethanol-induced liver injury

Abstract

AimsThe reversible protein S-glutathionylation (PSSG) modification of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas S-glutathionylation (Fas-SSG) in regulating ethanol-induced injury. Materials and methodsWe evaluated the Grx1 activity and oxidative damage, hepatic injury related indicators, Fas-SSG, we also assess the nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, Furthermore, the number of Kupffer cells and related proinflammatory cytokines between WT and Grx1- groups after alcohol exposure. Key findingsEthanol-fed mice had increased Grx1 activity and oxidative damage in the liver. Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced NF-κB signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1−/− mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1−/− livers than those of the controls. SignificanceGrx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.