期刊
LIFE SCIENCES
卷 264, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2020.118678
关键词
Ethanol; Oxidant; Glutaredoxin-1; Protein s-glutathionylation; Fas
资金
- National Natural Science Foundation of China [30973440, 30770950]
- Key Project of the Chonqing Natural Science Foundation [cstc2016jcyjA0471, cstc2012jjA0155]
- Chongqing Health Planning Commission of Research Fund [2016MSXM044]
The study demonstrates that Grx1 plays a crucial role in regulating ethanol-induced liver injury, with Grx1-deficient mice showing more severe liver damage when exposed to ethanol. Grx1 ablation suppresses NF-kappa B and Akt signaling cascades, leading to increased Fas-induced apoptosis.
Aims: The 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 methods: We evaluated the Grx1 activity and oxidative damage, hepatic injury related indicators, Fas-SSG, we also assess the nuclear factor-kappa B (NF-kappa B) 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 findings: Ethanol-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-kappa B signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-kappa B 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. Significance: Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.
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