基于核受体FXR研究中药组分HJJB方调控NAFLD肝脏脂肪代谢的效应机制

Our previous reaserch has proved that HJJB formula composed of specific proportion of salidroside（H）, gypenosides（J）, curcumin（J）and atractylodes macrocephala polysaccharides（B）had an ideal effect on treating nonalcoholic fatty liver disease(NAFLD). Meanwhile we also found that HJJB formula had a great advantage compared with every single component, and significantly improved lipid metabolism of NAFLD in rat, and also significantly increased the hepatic nuclear receptor FXR content of NAFLD in rat. According to the theory that FXR is closely associated with lipid metabolism, we propose the hypothesis that the HJJB formula may regulate hepatic lipid metabolism through promoting hepatic FXR activation with compatibility synergy effects, which can treat NAFLD. We plan to use two kinds of NAFLD mice models (FXR gene knockout mice, high-fat diet induced ones) and two kinds of cellular models (FFA induced hepatic steatosis, FXR silenced HepG2 hepatocellular). Focusing on hepatic FXR and key links of lipid metabolism, we will test whether HJJB formula regulate hepatic lipid metabolism through activating hepatic FXR, and analyze the mechanism of HJJB formula in regulating lipid metabolism through activating hepatic FXR, and reveal the mechanism of HJJB formula on the treatment of NAFLD. The intervention effects of HJJB formula and each component on different targets and links were analyzed to reveal the combination advantage and compatibility significance of HJJB formula. This study will provide scientific bases for the new drug research and development of NAFLD in the future.

本项目在前期证实由红景天苷（H）、绞股蓝总苷（J）、姜黄素（J）、白术多糖（B）特定配比组成的HJJB方对非酒精性脂肪肝（NAFLD）有理想疗效，显著优于单一组分，可改善NAFLD大鼠肝脏脂肪代谢，并显著上调肝脏核受体FXR含量的基础上，结合“FXR与脂肪代谢密切关联”的理论认识，提出“HJJB方可能通过配伍增效激活肝脏FXR调控肝脏脂肪代谢治疗NAFLD”的假说。拟采用两种动物模型（高脂饮食诱导、FXR基因敲除小鼠）以及两种细胞模型（FFA诱导的肝细胞脂肪变性、FXR基因沉默HepG2细胞株），围绕肝脏FXR及脂肪代谢的关键环节，验证HJJB方是否通过激活FXR而调节肝脏脂肪代谢，并剖析HJJB方激活FXR调控肝脏脂肪代谢的效应机制，以揭示该方治疗NAFLD的作用机制。通过分析HJJB方与各单一组分对不同靶点和环节的干预效应，揭示HJJB方综合作用优势和配伍意义。为今后新药研发奠定基础。

目前，非酒精性脂肪性肝病(NAFLD)已成为世界上最常见的慢性肝病，NAFLD相关的肝硬化和肝细胞癌快速增加，带来了严重的经济和医疗负担，积极防治NAFLD，具有重要意义，但目前尚缺乏有效的治疗药物。本课题在前期反复证实由红景天苷（H）、绞股蓝总苷（J）、姜黄素（J）、白术多糖（B）特定配比组成的中药组分复方“HJJB方”具有良好的治疗NAFLD的疗效的基础上，分别采用两种动物模型（高脂饮食诱导、FXR基因敲除小鼠）以及两种细胞模型（FFA诱导的肝细胞脂肪变性、FXR基因沉默HepG2细胞株），围绕FXR（法尼醇X受体，Farnesoid X receptor，FXR）及其关联机制的关键环节，揭示HJJB方的作用机制。并围绕肠道菌群及其胆汁酸代谢的关键环节，探讨HJJB方激活FXR的效应是否与肠道菌群介导的胆汁酸代谢有关。研究发现：HJJB方能明显抑制NAFLD小鼠的肝脏脂质沉积，降低NAFLD小鼠的血清ALT、AST活性和血脂含量，激活FXR介导的肝脏脂代谢通路，改善肝脏脂肪代谢的关键环节，FXR敲除使HJJB方的上述药理效应明显减弱或消失；HJJB方能明显抑制FFA诱导的大鼠肝细胞脂肪变性模型的脂质沉积，降低细胞内TG和FFA含量，且显著优于其单一成分，但FXR抑制剂孕二烯二酮可以使HJJB方的上述药理效应明显减弱；HJJB方能明显抑制FFA诱导的HepG2细胞脂肪变性模型的脂质沉积，降低细胞内TG和FFA含量，且显著优于其单一成分，但FXR基因沉默可以部分逆转HJJB方的上述药理效应；HJJB方还能调节NAFLD小鼠的肠道菌群，调节胆汁酸代谢的关键环节，进而降低NAFLD小鼠的肝脏总胆汁酸含量。本课题在证实FXR是HJJB方治疗NAFLD的重要药理环节的同时，围绕脂肪代谢和胆汁酸代谢的关键环节，揭示了HJJB方激活FXR治疗NAFLD的作用机制。该研究将为研制有中药复方“整体配伍”优势、作用机理清晰、效应物质明确并具有自主知识产权的中药组分复方制剂奠定良好的基础。