基于肝细胞膜转运蛋白转录调控信号通路的清热化湿、凉血活血法治疗急性肝内胆汁淤积的机制研究

Acute intrahepatic cholestasis (AIC) is a difficult problem in the field of the treatment of liver diseases, ourlong-term clinical practice shows that the method of clearing away damp and heat,clooing and activating blood which is based on “Compound Yindan Decoction” has better clinical curative effect. Basic research was found that IC is closely related to the expression and localization arrhythmias of transporters(taurine symport polypeptide(NTCP), bile salt export pump side distribution and small bile canalicular membrane (BSEP), themultidrug resistance associated protein 2 (MRP2)) which are located on the hepatocyte sinusoidal surface basement membrane. The expression of these transporters are mainly affected by the farnesoid X receptor (FXR), pregnane X receptor (PXR), and the constitutive androstane receptor (CAR) transcriptional factor. Our clinical investigation has found that Compound Yindan Decoction can improve AIC in patients with liver function, promoting bilirubin.Therefore,this study put forward the hypothesis of "capillaris dcoction can regulate can regulate FXR, PXRand CAR transcription factors which further to upregulate the NTCP, BSEP and MRP2 mRNA and protein expression and improve the effect of IC". The purpose of this study was to further explore the molecular biological mechanism of Compound Yindan Decoction in the treatment of AIC.

急性肝内胆汁淤积（AIC）的治疗是肝病领域的难题，我们长期的临床实践表明以清热化湿、凉血活血为法的复方茵丹汤治疗AIC具有较好的临床疗效。基础研究发现AIC的发生与肝细胞血窦面基底膜上 (牛磺酸共转运多肽（NTCP）、及小胆管侧肝细胞毛细胆管膜上分布的胆盐输出泵（BSEP）、多药耐药相关蛋白2（MRP2）)等转运体的表达、定位失常密切相关，这些转运体的表达主要受到类法尼醇X受体（FXR）、孕烷X受体（PXR）、和组成性雄烷受体（CAR）转录因子的调控。我们在前期的临床研究发现复方茵丹汤能够改善AIC患者的肝脏功能、促进胆红素消退。因此本研究提出假说“复方茵丹汤可能通过调控FXR、PXR和CAR转录因子上调肝细胞膜上NTCP、BSEP和MRP2 mRNA及其蛋白表达而起到改善胆汁淤积的作用”。本研究旨在进一步探索复方茵丹汤治疗AIC的机制。

急性肝内胆汁淤积（AIC）的治疗是肝病领域的难题，我们长期的临床实践表明以清热化湿、凉血活血为法的复方茵丹汤治疗AIC具有较好的临床疗效。基础研究发现AIC的发生与肝细胞血窦面基底膜上 (牛磺酸共转运多肽（NTCP）、及小胆管侧肝细胞毛细胆管膜上分布的胆盐输出泵（BSEP）、多药耐药相关蛋白2（MRP2）)等转运体的表达、定位失常密切相关，这些转运体的表达主要受到类法尼醇X受体（FXR）、孕烷X受体（PXR）和组成性雄烷受体（CAR）转录因子的调控。我们在前期的临床研究发现复方茵丹汤能够改善AIC患者的肝脏功能、促进胆红素消退。因此本研究在前期研究的基础上进一步探讨了复方茵丹汤对AIC大鼠肝细胞膜转运蛋白MRP2, Bsep, Ntcp及其相关转录因子FXR, PXR, CAR mRNA和蛋白表达等方面的影响。结果提示：中医清热化湿、凉血活血法代表方剂复方茵丹汤治疗AIC主要是通过转录因子FXR, PXR, CAR 对MRP2, Bsep及Ntcp调控信号通路，上调转录因子 FXR, PXR, CAR mRNA及膜转运体MRP2, Bsep, Ntcp mRNA及蛋白表达，影响胆红素及胆汁酸的排泄而发挥作用，验证了我们课题组提出的研究假说。研究结果进一步深化了对AIC发病机制的认识，从整体上阐明了中药复方茵丹汤治疗AIC疗效机制，为中医药的有效治疗提供了理论基础。