基于内质网应激对肝星状细胞NF-κB凋亡通路的调控探讨太白楤木总皂苷抗肝纤维化作用机制

Liver fibrosis is a pathological changesresult from a variety of causes lead to chronic liver injury.It is the typical pathological that hepatocyte excessive proliferation of extracellular matrix and anomalous deposition lead to the liver structure change and/or dysfunction.It is not effective means of prevention and treatment in clinical now.There are High morbidity and mortality.Traditional Chinese medicine treatment of liver fibrosis has a unique advantage. Our team preliminary experimental results show that total saponin of Aralia Taibaiensis(SAT) has remarkable curative effect,the SAT is isolated and extract from theroot bark of Aralia Taibaiensis. But its mechanism has not clear.As HSC plays a crucial role in liver fibrosis, the elimination of activated HSC through cell death is proposed as a mechanism to attenuate or reverse fibrogenesis. Therefore, it is necessary to accelerate the apoptosis of activated HSC and it is a significant target in reversing liver fibrosis. When a variety of stimulation in the cell,there are many protein aggregation of misfolded or unfold in the endoplasmic reticulum,this phenomenon is known as the endoplasmic reticulum stress(ERS).It is in the initial stage of liver fibrosis,it is the key trigger to active HSC apoptosis.And the NF-kappa B pathway activated HSC apoptosis.On the basis of the above all, through the in vivo and in vitro experiments, This research want to explore the the role of SAT regulating the activation of hepatic stellate cell apoptosis based on the NF-kappa B apoptosis pathway,in the endoplasmic reticulum stress as the breakthrough point. The purpose is to reveal the SAT of the molecular mechanism of liver fibrosis,to provide theoretical basis for anti liver fibrosis.

肝纤维化是多种病因致慢性肝损伤的共有病理变化，肝组织中细胞外基质过度增生与异常沉积所导致的肝脏结构和/或功能异常是典型病理改变，临床防治效果不佳，发病率和死亡率居高不下，中医药治疗肝纤维化具有独特优势，本课题组前期研究结果显示，从太白楤木根皮中分离提取的太白楤木总皂苷抗肝纤维化效果显著，但其作用机制机尚未明了。肝星状细胞的激活是肝纤维化发生的关键环节，是细胞外基质大量产生的主要细胞来源。当细胞受到多种刺激，内质网中错误折叠或未折叠蛋白质大量聚集导致内质网应激发生，内质网应激发生于肝纤维化的初始阶段，是触发活化HSC凋亡的关键靶点，而NF-κB通路启动了HSC的凋亡，在上述基础上，本研究通过在体、离体实验，以内质网应激为切入点，基于NF-κB凋亡通路，探究太白楤木总皂苷在调节活化肝星状细胞凋亡中的作用，以期揭示太白楤木总皂苷抗肝纤维化的分子机制，为太白楤木抗肝纤维化研究提供理论依据。

肝纤维化是多种病因致慢性肝损伤的共有病理变化，肝组织中细胞外基质过度增生与异常.沉积所导致的肝脏结构和/或功能异常是典型病理改变，中医药治疗肝纤维化具有独特优势，本课题组前期研究结果显示，从太白楤木根皮中分离提取的太白楤木总皂苷抗肝纤维化效果显著，但其作用机制机尚未明了。肝星状细胞的激活是肝纤维化发生的关键环节，是细胞外基质大量产生的主要细胞来源。当细胞受到多种刺激，内质网中错误折叠或未折叠蛋白质大量聚集导致内质网应激发生，内质网应激发生于肝纤维化的初始阶段，是触发活化HSC凋亡的关键靶点，而NF-κB通路启动了HSC的凋亡。体内实验研究显示，在CCL4致肝纤维化大鼠模型中，太白楤木总皂苷从模型建立4W起即能够有效减低血清ALT、AST水平，减轻肝损伤，同时减少胶原在肝组织中的沉积，并在肝纤维化发生发展过程中持续发挥作用，发挥防治纤维化作用，同时通过抑制肝组织中肝星状细胞内质网应激，促进HSC凋亡。体外实验采用HSC-T6细胞，给予PDGF活化，模拟肝纤维化发生过程中HSC的活化，并采用TG作为内质网应激的激动剂，建立HSC活化后的内质网应激模型，结果显示，太白楤木总皂苷能够抑制HSC增殖，呈时间和剂量依赖性，同时能够通过诱发HSC细胞内质网应激反应的发生促进HSC凋亡，在此过程中可激活NF-κB通路，参与HSC凋亡过程。太白楤木具有防止肝纤维化作用，其作用机制与通过诱发活化肝星状细胞内质网应激，活化NF-κB通路，促进HSC凋亡有关。