dl-NBP在肝脏离体常温灌注中对脂肪肝的修复作用及机制研究

The proportion of fatty liver in Chinese donors’ liver has reached 15% -30%. However, fatty liver cells undergo severe mitochondrial dysfunction after ischemia-reperfusion, resulting in a 35% to 40% increase in liver failure after transplantation. Normothermic liver perfusion has been shown to protect mitochondrial function and maintain liver physiological function. Our group has established a stable normothermic perfusion system, which provides the basis for the further study of repairing fatty liver by medicine’s intervention in vitro. dl-NBP can activate Cytochrome C Oxidase to reduce the oxidative stress response, which can also reduce cell necrosis by inhibiting PGAM5. PGAM5 is an important molecule in cell necroptosis, which can dephosphorylate DRP-1 and initiate cell necroptosis. Therefore, we form the hypothesis that dl-NBP can inhibit necroptosis through ROS/PGAM5/DRP-1 pathway, but its specific mechanisms need to be confirmed by further studies. Aiming to repair fatty liver injury, we intend to use dl-NBP to repair the mitochondrial dysfunction of fatty liver in normothermic perfusion and to explore its mechanism of inhibiting cell necroptosis of fatty liver cells through ROS/PGAM5/DRP-1 pathway, which providing new method in repairing of fatty liver in liver transplantation.

我国肝移植中供肝脂肪肝比例已达到15-30%。然而，脂肪肝细胞经过缺血再灌注后会发生严重的线粒体功能缺陷，导致移植术后发生肝功能衰竭的比例增加35-40%。肝脏常温灌注已被证明可以保护线粒体功能，维持肝脏生理功能。本课题组前期已建立稳定的常温灌注系统，为进一步离体使用药物修复脂肪肝提供了基础。dl-NBP可激活细胞色素c氧化酶，降低氧化应激反应，并且可通过抑制PGAM5，减轻细胞坏死。PGAM5是细胞程序性坏死机制中重要的分子，可使Drp-1去磷酸化，启动细胞程序性坏死。因此，我们推测dl-NBP可通过ROS/PGAM5/Drp-1通路抑制细胞程序性坏死，但其具体机制有待进一步研究证实。为进一步修复脂肪肝损伤，我们拟使用dl-NBP在常温灌注中对脂肪肝线粒体功能缺陷进行修复，并探讨其通过ROS/PGAM5/Drp-1通路抑制脂肪肝细胞程序性坏死的作用机制，为肝脏移植中修复脂肪肝提供新思路。

我国肝移植中供肝脂肪肝比例已达到15-30%。然而，脂肪肝细胞经过缺血再灌注后会发生严重的线粒体功能缺陷，导致移植术后发生肝功能衰竭的比例增加35-40%。肝脏离体灌注已被证明可以保护线粒体功能，维持肝脏生理功能。本项目组按照计划，通过建立大鼠脂肪肝模型，使用离体灌注处理大鼠脂肪肝，发现离体灌注可明显改善脂肪肝缺陷再灌注损伤。通过反向调节自嗜水平，检测自嗜相关分子标志物，揭示离体灌注可通过激活自嗜发挥保护肝脏作用。通过大鼠脂肪肝离体灌注，常温携氧灌注复灌，及体外细胞实验，发现离体灌注对脂肪肝的保护作用与Brg1/ Nrf2介导的HO-1基因转录有关，揭示了离体灌注对大鼠脂肪肝缺血再灌注损伤的保护机制，为探讨离体脂肪肝损伤的修复，寻找新的治疗靶点和治疗方式提供新思路。