熊脱氧胆酸对抗乙炔雌二醇诱发孕大鼠肝内胆汁淤积的作用机制

Effect of ursodeoxycholic acid on the expression of the hepatocellular BSEP and FXR in pregnant rats with ethinylestradiol induced intrahepatic cholestasis.

目的:研究熊脱氧胆酸(ursodeoxycholicacid,UDCA)对雌激素诱发孕鼠肝内胆汁淤积肝脏胆盐输出泵(bilesaltexportpump,BSEP)及肝脏法尼醇受体(farnesoidXreceptor,FXR)表达的影响,探讨UDCA治疗妊娠期肝内胆汁淤积症(intrahepatischolesta-sisofpregnancy,ICP)的作用机制。方法:随机将孕15d的大鼠40只分成4组,1,2-丙二醇(propyleneGlycol,PG)组,17-α-乙炔雌二醇(ethinylestradiol,EE)组,UDCA组和UDCA+EE组。用药前,用药后5d测血浆中谷丙转氨酶(ALT),谷草转氨酶(AST),碱性磷酸酶(ALP),总胆酸(TBA)。同时观察肝脏形态学变化及胎鼠生长发育情况;应用免疫组化法分析肝脏BSEP及FXR的表达。结果:用药后EE组的孕鼠ALT、AST、ALP、TBA比用药前显著升高(P<0·05),PG组无明显变化(P>0·05),UDCA组,UDCA+EE组ALT,AST,ALP无明显变化(P>0·05),但TBA明显升高(P<0·05)。EE组孕鼠肝脏出现肝内胆汁淤积表现,其余3组肝脏形态结构正常。EE组胎仔身长,尾长,体重,死胎数,活胎数,孕天数与其余3组比较有显著差异(P<0·05)。EE组BSEP表达降低,FXR表达升高,与PG组,UDCA组,UDCA+EE组差异均有显著性(P<0·05)。结论:UDCA对雌激素诱发孕鼠肝内胆汁淤积肝脏具有保护作用,能改善胎仔预后,可能是通过恢复肝脏BSEP的表达促进胆汁分泌,而不是通过影响FXR表达调节胆汁酸的合成。

Objective: To investigate the effects of ursodeoxycholic acid(UDCA)on the expression of hepatocellular BSEP and FXR in pregnant rats with ethinylestradiol induced intrahepatic cholestasis.Methods: Fourty trimester pregnant rats were randomized into four groups: EE group,PG group,UDCA group and UDCA+EE group.2ml blood was taken before and 5 days after the treatment to measure the level of AST,ALT,ALP and TBA.After delivery,the liver of pregnant rats were taken to observe morphologic changes and the growth and development of the fetal rats was also observed.The expression of BSEP and FXR in liver were analyzed by immunohistochemical method(ABC).Results: The serum levels of ALT,AST,ALP,TBA in the EE group were increased significiantly(P<0.05).PG groups had no changes(P>0.05).In UDCA and UDCA+EE group the level of ALT,AST and ALP had on changes(P>0.05) but TBA increased significantly(P<0.05).The pathological changes showed intrahepatic cholestasis in pregnant rats in EE group.Body weight,body length and tail length of fetal rats in the EE group were lighter and shorter than those of other three groups (P<0.05).The expression of hepatocellular BSEP was lower (P<0.05) but the FXR was higher (P<0.05) in the rats treated with EE than in the other three groups.Conclusion:UDCA can protect the liver from the injury of intrahepatic cholestasis and improve the outcome of fetal rats.This improvement is related to a normalization of the expreesion of the bile acid canalicular transporter BSEP other than the expression of FXR.