Synergistic Effect Of Alcohol And Viral Hepatitis On Liv

饮酒和感染肝炎病毒会加速肝脏损伤，但其潜在机制尚不完全清楚。我们研究了乙醇对乙肝病毒蛋白X(HBX)或丙型肝炎病毒核心蛋白(丙型肝炎病毒核心蛋白)介导的核因子-kB的激活的影响，核因子-kB是肝脏损伤和肿瘤转化的关键信号。急性乙醇或乙醛暴露可增强原代小鼠肝细胞中HBx或丙型肝炎病毒核心蛋白对核因子-kB的激活。乙醇代谢抑制剂4-甲基拉唑可消除这种增强作用。过表达显性阴性的Nik、IKK或IkB可减弱HBx、丙型肝炎病毒核心蛋白或乙醛对核因子-kB的激活。在肿瘤坏死因子受体1(TNFR1)-/-肝细胞中，HBx和丙型肝炎病毒核心蛋白诱导的核因子-kB完全消失，而乙醇不能，而百日咳毒素可减弱乙醛对核因子-kB的激活。最后，慢性酒精摄入可诱导肝脏细胞色素P450 2E1蛋白表达，增强肝脏中HBx或丙型肝炎病毒核心蛋白对核因子-kB的激活作用。这些结果表明，乙醇通过其代谢激活了肝组织中的核因子-kB，HBx或丙型肝炎病毒核心蛋白通过TNFR1激活了肝组织中的核因子-kB。鉴于TNFR1在酒精性肝损伤中的重要作用，通过肝炎病毒蛋白靶向TNFR1可能有助于酒精性肝炎和病毒性肝炎对肝病的协同作用。我们还证明，在饮酒期间升高的白介素6水平可以保护酒精诱导的肝脏细胞凋亡。目前，我们正在继续研究饮酒和病毒性肝炎感染在肝损伤中协同作用的分子机制。

Alcohol drinking and infection with hepatitis virus accelerate liver injury, but the underlying mechanism is not fully understood. We have examined the effects of ethanol on hepatitis B protein X (HBX)- or hepatitis C core protein (HCV core protein)-mediated activation of NF-kB, a critical signal in hepatic injury and tumor transformation. Acute ethanol or acetaldehyde exposure potentiates HBX or HCV core protein activation of NF-kB in primary mouse hepatocytes. The ethanol metabolism inhibitor 4-methylprazole abolishes such potentiation. Overexpression of dominant negative NIK, IKK, or IkB attenuates HBX, HCV core protein, or acetaldehyde activation of NF-kB. Induction of NF-kB by HBX and HCV core protein but not ethanol is completely abolished in TNF receptor 1 (TNFR1) -/- hepatocytes, whereas pertussis toxin attenuates acetaldehyde activation of NF-kB. Finally, chronic ethanol consumption induces hepatic CYP2E1 protein expression and potentiates HBX or HCV core protein activation of NF-kB in the liver. These findings suggest that ethanol activates hepatic NF-kB via its metabolism and HBX or HCV core protein activates hepatic NF-kB via TNFR1. In view of the essential role of TNFR1 in alcoholic liver injury, targeting TNFR1 by hepatitis viral proteins could contribute to cooperative effects of alcohol drinking and viral hepatitis on liver disease. We have also demonstrated that elevated interleukin-6 levels during alcohol consumption protect alcohol-induced apoptosis in the liver. Currently, we are continuing to investigate the molecular mechanism underlying the synergistic effect of alcohol drinking and viral hepatitis infection on liver injury.