炔雌醇通过NF-κB p65信号轴诱导肝脂变的分子机制研究

药物性肝损伤是严重的药物不良反应，女性较男性更容易发展为急性肝衰竭。炔雌醇是一种人工合成的雌激素，在激素替代治疗和妇科肿瘤等领域有重要作用。研究发现炔雌醇可以引起肝内胆汁淤积等肝毒性改变。我们前期在C57BL/6J小鼠模型上发现炔雌醇可以明显引起肝脂变和肝脏炎症反应，进一步研究发现，肝细胞特异性敲除NF-κB p65小鼠的炎症明显减轻。 细胞学实验显示，炔雌醇可以抑制原代肝细胞活性，诱导肝细胞凋亡，使NF-κB p65磷酸化水平明显增加。申请人据此推测：炔雌醇通过NF-κB p65信号轴诱导肝脂变。本项目拟从细胞、动物及临床三个层面探讨炔雌醇是否通过NF-κB p65信号轴调控肝脏的脂肪代谢，诱导肝脂变及其具体的分子机制，取得炔雌醇诱导肝脂变的可靠证据。研究结果有望指导临床上含炔雌醇药物的正确使用，为减少或避免该类药物对肝脏的损害提供临床价值和科学依据。

Drug-induced liver injury is a serious adverse drug reaction. Women are more likely to develop acute liver failure than men. Ethinylestradiol is a synthetic estrogen and plays an important role in hormone replacement therapy and gynecologic tumors. It was found that ethinylestradiol can cause hepatotoxic changes such as intrahepatic cholestasis. We previous experiment found hepatic lipidosis and liver inflammation in ethinylestradiol-induced C57BL/6J mice. However, liver inflammation could attenuate in mice with hepatocyte specific NF-κB p65 knockout. Cytological experiments showed that ethinylestriol could inhibit the activity of primary hepatocyte and induce apoptosis. Ethinylestriol also increase the phosphorylation level of NF-κB p65 in hepatocyte. The applicant speculated that ethinylestradiol induced hepatic lipidosis via the NF-κB p65 signal axis. The purpose of this project is to investigate whether ethinylestradiol regulates liver fat metabolism and induces hepatic lipidosis through the signal axis of NF-κB p65 in cell, animal and human aspects, so as to obtain reliable evidence of ethinylestradiol-induced liver lipidosis. The results of this study are expected to guide the use of ethinylestradiol drugs in clinical practice and provide scientific basis for reducing or avoiding the damage of ethinylestradiol drugs to the liver.