基于肠道菌群稳态探讨皂术茵陈方调控线粒体自噬治疗非酒精性脂肪性肝炎的作用机制

Nonalcoholic steatohepatitis (NASH), with the characteristics of metabolic diseases, is the primary cause of chronic liver disease. How to cut off its development has become the focus of prevention and treatment of liver diseases. The steady regulation on the intestinal microflora is the mechanism of the oral administration of Chinese herbal compound exerts its multi-pathway and multi-link pharmacological effects, which highlights the characteristics of TCM's "concept of wholism ". It has been proved that Zaozhuyinchen Decoction (ZZYCD) is effective in the treatment of NASH. It has the characteristics of improving intestinal microflora, inhibiting oxidative stress injury, increasing Parkin protein expression, which help regulate mitochondrial autophagy and improve energy metabolism. Therefore, the scientific hypothesis has been proposed: “ZZYCD regulates mitochondrial autophagy through the PINK1/Parkin signaling pathway to cure NASH is based on regulating the homeostasis of the intestinal microflora”.In order to verify this hypothesis, the research group prepare to use Parkin-/-C57BL/6 mice model of NASH induced by the high-fat-diet, hepatic steatosis model induced by FFA and mitochondrial autophagy disorder model of siRNA-Parkin HepG2 cell induced by LPS to elucidate the mechanism of ZZYCD in the treatment of NASH from pathological aspects of intestinal microflora, endotoxemia, oxidative stress and the PINK1/Parkin signal pathway of mitochondrial autophagy.

具有代谢性疾病特征的非酒精性脂肪性肝炎（NASH）为慢性肝病首要病因，截断其发展已成为肝病防治的焦点。中药复方口服给药对肠道菌群的稳态调控是其发挥多途径、多环节药理效应的作用机制，彰显中医“整体观念”学科特色。研究证实皂术茵陈方治疗NASH疗效显著，具有改善肠道菌群、抑制氧化应激损伤、提高Parkin蛋白表达的作用特点，或通过调控线粒体自噬改善机体的能量代谢。故课题组提出科学假说：“皂术茵陈方通过PINK1/Parkin信号通路调控线粒体自噬治疗NASH是基于肠道菌群稳态”。为验证该假说，拟采用高脂饮食诱导的Parkin-/-C57BL/6小鼠NASH模型、FFA诱导肝细胞脂肪变性及LPS诱导siRNA-Parkin HepG2细胞线粒体自噬功能失调模型，围绕肠道菌群、内毒素血症、氧化应激损伤等病理环节以及线粒体自噬PINK1/Parkin信号通路，阐明皂术茵陈方治疗NASH的作用机制。

具有代谢性疾病特征的非酒精性脂肪性肝炎（NASH）为慢性肝病首要病因，截断其发展已成为肝病防治的焦点。中药复方口服给药对肠道菌群的稳态调控是其发挥多途径、多环节药理效应的作用机制，彰显中医“整体观念”学科特色。研究证实皂术茵陈方治疗NASH疗效显著，具有改善肠道菌群、抑制氧化应激损伤、提高Parkin蛋白表达的作用特点。课题组提出科学假说：“皂术茵陈方通过PINK1/Parkin信号通路调控线粒体自噬治疗NASH是基于肠道菌群稳态”。为验证该假说，研究项目采用高脂饮食诱导的Parkin-/-C57BL/6小鼠NASH模型、FFA诱导肝细胞脂肪变性及LPS诱导siRNA-Parkin HepG2细胞线粒体自噬功能失调模型，围绕肠道菌群、内毒素血症、氧化应激损伤等病理环节以及线粒体自噬PINK1/Parkin信号通路，阐明皂术茵陈方治疗NASH的作用机制。.动物整体实验结果表明，皂术茵陈方具有较好降低体重、肝重、脂肪重量、肝组织TG含量、血清ALT、AST活性、MDA含量，升高血清SOD水平，以及改善肝组织病理的药理效应，提示其通过抑制氧化应激损伤发挥治疗NASH的作用特点。同时，皂术茵陈方具有显著抑制血浆 LPS表达以及提升肠道菌群群落丰富度和多样性的作用效应，同时对肠壁通透性具有较好的改善效应，提示其通过调控肠道菌群稳态治疗NASH的作用机制。.FFA诱导的肝细胞脂肪变性研究表明，皂术茵陈方组具有显著抑制TG含量、ALT、AST活性、MDA含量以及升高SOD含量，提示其具有拮抗ROS、抑制氧化应激损伤治疗NASH的作用特点。而LPS诱导siRNA-Parkin HepG2细胞线粒体自噬功能失调研究表明，皂术茵陈方具有提升SOD含量，降低MDA含量、降低线粒体膜电位以及升高细胞上清PINK1、Parkin、p63、atg5、LC3II/I、MFN1、MFN2蛋白和基因表达的作用特点，提示其作用机制与氧化应激损伤，通过PINK1/Parkin信号通路调控线粒体自噬功能密切相关。.本研究项目取得成果较为丰硕，发表期刊论文5篇；荣获福建省科技进步三等奖1项、厦门市科技进步二等奖1项；申请专利1项。研究项目具有较高的学术价值和社会影响。