FXR介导的胆汁酸代谢在非酒精性脂肪肝中的作用及降脂颗粒干预的分子机制研究

Based on our clinical investigations and data mining methods,we proposed a new Traditional Chinese Medicine (TCM) pathomechanism of Nonalcoholic Fatty Liver (NAFL): "Spleen-Deficiency as primary, Damp-Heat and Blood Stasis as secondary cause". Devised according to this theory, the herb formula Jiangzhi Granula showed benifits in treating NAFL and related metabolic disorders, but the mechanisms were not so clear. Farnesoid X receptor (FXR) blongs to ligand nuclear receptor class and involves in regulating bile acid metabolism, the bile acid activated FXR signaling plays critical roles of in improving cholesterol transport, lipid and glucose metabolism, inflammation, and other NAFL realting metabolic pathways, suggesting FXR could be a potential target for NAFL regression. This project aims to explore the potential mechanism of Jiangzhi Granula in regulating bile acid activated FXR signaling, through developing both animal and cell models, ustilizing tools such as histology, molecular biology, metabonomics et al, we will observe the dynamic changes of FXR signaling along with NAFL progress, and further investigate the influence of Jiangzhi Granula on these pathways. This project are expected to set fundamental modes for studying herb medicine in preventing and treating NAFL, metabolic syndrome and insulin resistance related diseases.

课题组基于临床流行病学和数据挖掘技术研究非酒精性脂肪性肝（NAFL），提出"脾虚为本，湿热瘀血为标"的病机新模式，研制的降脂颗粒经临床及实验研究证实对改善NAFL具有良好效果，但具体机制尚未完全明确。法尼酯衍生物X受体(FXR)是调节胆汁酸代谢的关键代谢性核受体，新近研究证实胆汁酸-FXR信号在改善胆固醇转运、糖脂代谢、炎症调节中的发挥关键作用，参与调控NAFL相关的多条代谢通路，被认为是NAFL治疗的新靶点。本课题将从胆汁酸-FXR信号调节途径深入研究降脂颗粒对NAFL治疗机制，通过复制体内外NAFL模型，采用组织学、分子生物学、代谢组学等技术，从整体-组织-细胞三个层次探讨胆汁酸-FXR信号通路相关分子在NAFL进展中的动态变化，及降脂颗粒对这一通路相关分子的调节作用，预期研究结果对促进中医药防治NAFL、代谢综合征等胰岛素抵抗相关疾病有重要的基础及应用价值。

作为代谢综合征的肝脏表现，非酒精性脂肪性肝病（nonalcoholic fatty liver disease）对肝病进展和代谢损伤的风险日渐凸显。针对NAFLD早期单纯性脂肪肝阶段（NAFL）目前尚缺乏有效的治疗药物，中医药成为重要选择。近年来，胆汁酸代谢在NAFLD中的作用逐渐被发现，称为重要的药物靶点。前期研究证实中药复方降脂颗粒能有效改善NAFLD，但具体的机制还有待于进一步的研究。本项目分别评价了高脂诱导NAFL大鼠模型的糖脂代谢动态变化，降脂颗粒对高脂诱导NAFL大鼠模型胆汁酸法尼醇X受体（FXR）信号通路的影响以及降脂颗粒对肝细胞脂肪变性模型FXR信号通路的影响。结果表明随着高脂饮食时间的延长，大鼠出现NAFL的同时也呈现糖脂代谢紊乱；降脂颗粒可有效调节胆汁酸代谢谱及FXR相关代谢通路分子的表达，稳定胆汁酸平衡；体外实验证实，降脂颗粒的醇提物（JE）可上调HepG2细胞FXR-SHP通路分子的表达，在FXR抑制剂预处理的条件下，JE可上调FXR和SHP表达，而在FXR激动剂预处理条件下，JE并未进一步升高FXR和SHP的表达。以上结果表明降脂颗粒对胆汁酸平衡和FXR通路有很好的调节作用，可能是其效应的关键机制。我们的研究FXR介导的胆汁酸代谢是降脂颗粒改善脂肪肝脂质代谢异常，防治脂肪肝的新靶点。围绕降脂颗粒的机制研究我们发现了胆汁酸代谢的改变，对深入探索降脂颗粒的药效机制奠定了一定的基础。