Synergistic Effect Of Alcohol And Viral Hepatitis On Liv

饮酒和肝炎病毒感染加速肝损伤，但其潜在机制尚未完全了解。我们检测了乙醇对B型肝炎X蛋白（HBX）或丙型肝炎核心蛋白（HCV核心蛋白）介导的NF-κ B（肝损伤和肿瘤转化中的关键信号）活化的影响。急性乙醇或乙醛暴露增强原代小鼠肝细胞中HBX或HCV核心蛋白对NF-κ B的活化乙醇代谢抑制剂4-甲基吡唑消除这种增强作用。显性阴性NIK、IKK或IkB的过表达减弱了HBX、HCV核心蛋白或NF-κ B的乙醛活化。在TNF受体1（TNFR 1）-/-肝细胞中，HBX和HCV核心蛋白而不是乙醇诱导的NF-κ B被完全消除，而百日咳毒素减弱了NF-κ B的乙醛激活。最后，慢性乙醇消耗诱导肝脏CYP 2 E1蛋白表达并增强肝脏中NF-κ B的HBX或HCV核心蛋白活化。这些发现表明，乙醇通过其代谢激活肝NF-kB，HBX或HCV核心蛋白通过TNFR 1激活肝NF-kB。鉴于TNFR 1在酒精性肝损伤中的重要作用，肝炎病毒蛋白靶向TNFR 1可能有助于饮酒和病毒性肝炎对肝脏疾病的协同作用。我们还证明了饮酒过程中白细胞介素-6水平的升高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对肝损伤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.