冬凌草甲素调控PXR-CYP3A4通路介导的胆汁淤积性肝损伤保护作用的研究

Hepatotoxicity hydrophobic bile acids are the main factors of cholestatic liver injury. Induce metabolism of hydrophobic bile acid is one of the strategies in the treatment of cholestatic liver injury. CYP3A4 is a key enzyme in hydrophobic bile acid detoxification metabolism, increased CYP3A4 can accelerate hydrophobic bile acid metabolism to reduce hepatotoxicity. Based on our preliminary studies and literature, we found that oridonin has a protective effect to cholestatic liver injury in rat, and induce CYP3A4 expression and activation via PXR dependent pathways. We will identify whether oridonin could increase metabolism of bile acids by unregulated CYP3A4 gene via activating PXR, then play a protective role in cholestatic liver injury. The obtained results will provide the scientific foundation for the development of innovative treatment and new drug targets in this disease.

疏水性胆汁酸的肝细胞毒性是导致胆汁淤积性肝损伤的主要因素，促进疏水性胆汁酸代谢是治疗胆汁淤积性肝损伤的策略之一。CYP3A4是疏水性胆汁酸解毒代谢的关键酶，上调CYP3A4可加速疏水性胆汁酸代谢，降低肝细胞毒性。本课题前期研究表明，冬凌草甲素可通过激活PXR上调CYP3A4的表达及活性。进一步研究确证，冬凌草甲素对大鼠胆汁淤积型肝损伤模型具有保护作用。基于此，本研究将进一步确证冬凌草甲素对胆汁淤积性肝损伤的保护作用，明确CYP3A4是否为该保护作用中的关键因子，并考察PXR-CYP3A4通路在冬凌草甲素促疏水性胆汁酸解毒代谢中的调控作用。本课研究成果不仅为冬凌草甲素治疗胆汁酸淤积型肝损伤提供理论支持，也将从胆汁酸解毒这一新的视角探讨胆汁淤积性肝损伤防治的新策略。

疏水性胆汁酸的肝细胞毒性是导致胆汁淤积性肝损伤的主要因素，促进疏水性胆汁酸代谢是治疗胆汁淤积性肝损伤的策略之一。CYP3A4是疏水性胆汁酸解毒代谢的关键酶，核受体PXR是其关键调控基因，激活该通路可加速疏水性胆汁酸代谢，降低肝细胞毒性。基于上述背景，本课题对冬凌草甲素对胆汁淤积型肝损伤的保护作用进行研究。首次发现了冬凌草甲素可通过激活PXR上调CYP3A4的表达及活性，进而对大鼠胆汁淤积型肝损伤模型具有保护作用。进一步，项目组采用AAV腺病毒肝脏定点干扰模型考察PXR-CYP3A4信号通路在冬凌草甲素对胆汁淤积性肝损伤保护作用中的意义。结果表明CYP3A4并非冬凌草甲素肝损伤保护作用的关键靶基因，但PXR是冬凌草保护作用中的重要因子。干扰PXR可逆转冬凌草甲素对胆汁淤积型肝损的保护作用。同时，冬凌草甲素存在上调核受体CAR和LXR进而诱导胆汁酸的二相代谢，改变胆汁酸谱组成，实现解毒作用。本课研究成果不仅为冬凌草甲素治疗胆汁酸淤积型肝损伤提供理论支持，也将从胆汁酸解毒这一新的视角探讨胆汁淤积性肝损伤防治的新策略。