Zinc inhibition of acute ethanol-induced liver injury.

摘要

Metallothionein (MT) is a ubiquitous small metal binding protein that contains up to seven gram atoms of zinc per mole. The protective mechanisms of MT are still to this date highly debated. However, what is known is that upon changes in the reduction/oxidation (redox) state of the intracellular environment, MT releases the bound zinc atoms. Therefore, the overall goal of this research was to identify and characterize possible protective effects of zinc independent of MT in alcohol-induced liver and intestinal injury.; The experimental approach in answering the specific aims of this research project involved the use of a metallothionein knockout (MT-KO) mouse model. Parallel studies of MT-KO mice and their wild type (WT) counterparts provided a means of delineating the protective effects of zinc from MT.; A binge drinking model of alcohol intoxication was employed to induce liver injury in WT and MT-KO mice. Acute ethanol exposure induced oxidative stress in the liver and zinc pretreatment was found to protect both WT and MT-KO mice indicating metallothionein-independent zinc protection from alcoholic liver injury.; Further in vivo studies identified acute ethanol-induced activation of a receptor mediated apoptotic cell death pathway in hepatocytes involving Fas ligand (FasL) and subsequent caspase activation in our model. Treatment of WT and MT-KO mice with zinc prior to acute ethanol revealed that zinc provides significant protection from Fas-mediated cell death in liver parenchyma.; Inflammation of the liver was found to occur following acute ethanol exposure in both WT and MT-KO mice as evidenced by increases in liver tumor necrosis factor (TNF-α) levels. This acute ethanol-induced increase in hepatic pro-inflammatory cytokine production was associated with an elevation in circulating plasma endotoxin. Importantly, the endotoxemia observed was correlated with an increase in damage to the small intestine following ethanol exposure. Zinc pretreatment inhibited increased liver TNF-α, endotoxemia and damage to the small intestine in WT and MT-KO mice.; These results illustrate the involvement of zinc at many levels in the inhibition of acute ethanol-induced liver injury, and provide data supporting the utilization of zinc in nutritional intervention of alcohol related liver disease in clinical settings.