Kim Won Ho, Hong Feng, Jaruga Barbara, Zhang Zheng Sheng, Fan Sai Jun, Liang T Jake, Gao Bin
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Mol Immunol. 2005 Feb;2(1):40-8.
It is well-documented that alcohol drinking together with hepatitis viral infection accelerates liver injury; however the underlying mechanisms remain unknown. In this paper, we demonstrated that primary hepatocytes from transgenic mice overexpressing hepatitis B virus X protein (HBX) were more susceptible to ethanol- and TNF-alpha-induced apoptotic killing. Compared to normal control mouse hepatocytes, ethanol and/or TNF-alpha treatment led to a significant increase in reactive oxygen species, mitochondrial permeability transition, cytochrome C release, caspase-3 activity, and poly (ADP-ribose) polymerase degradation in hepatocytes from HBX transgenic mice. Blocking caspase-3 activity antagonized ethanol- and TNF-alpha-induced apoptosis in primary hepatocytes from HBX transgenic mice. Taken together, our findings suggest that HBX sensitizes primary mouse hepatocytes to ethanol- and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism, which may partly explain the synergistic effects of alcohol consumption and hepatitis B virus infection on liver injury.
有充分文献记载，饮酒与肝炎病毒感染共同作用会加速肝脏损伤；然而，其潜在机制仍不清楚。在本文中，我们证明，来自过表达乙型肝炎病毒X蛋白（HBX）的转基因小鼠的原代肝细胞对乙醇和TNF-α诱导的凋亡杀伤更敏感。与正常对照小鼠肝细胞相比，乙醇和/或TNF-α处理导致HBX转基因小鼠肝细胞中的活性氧显著增加、线粒体通透性转换、细胞色素C释放、caspase-3活性以及聚（ADP-核糖）聚合酶降解。阻断caspase-3活性可拮抗乙醇和TNF-α诱导的HBX转基因小鼠原代肝细胞凋亡。综上所述，我们的研究结果表明，HBX通过caspase-3依赖性机制使原代小鼠肝细胞对乙醇和TNF-α诱导的凋亡敏感，这可能部分解释了饮酒和乙型肝炎病毒感染对肝脏损伤的协同作用。
