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目的探讨雌激素受体α(estrogen receptorα,ERα)对参与调节胆汁酸转运相关的基因,如法尼醇X受体(farnesoid X receptor,FXR)、钠离子-牛磺胆酸共转运蛋白(sodium taurocholate co-transprorting polypeptide,NTCP)、胆盐输出泵(bile salt export pump,BSEP)的调控作用及其对孕鼠肝内胆汁淤积发生的影响。方法将40只SPF级SD孕鼠随机均分为4组。自孕第15 d起,对照组颈部皮下注射精制植物油2.0 m L/kg·d;低、中、高剂量组分别皮下注射17α-乙炔雌二醇1.0 mg/kg·d、1.25 mg/kg·d、1.5 mg/kg·d。于妊娠第21 d采血2 m L,后采用颈部脱臼法处死,提取母鼠肝脏行活体组织学检查。检测各组孕鼠血清中的生化指标及肝脏组织中各目的蛋白和mRNA表达量。结果生化指标:低、中、高剂量组孕鼠各蛋白表达水平明显高于对照组,差异有统计学意义(P<0.05),低、中、高剂量组组间比较,差异有统计学意义(P<0.05);蛋白表达及mRNA的表达水平:ER在对照组、低剂量组、中剂量组、高剂量组的表达量依次升高,而FXR、NTCP、BSEP在对照组、低剂量组、中剂量组、高剂量组的表达量依次降低,各组目的基因表达量与对照组比较,差异均有统计学意义(P<0.05)。结论随着雌激素剂量的增加,ERα表达水平升高,而FXR、NTCP、BSEP表达水平均降低,提示胆汁酸代谢转运功能降低,可能为雌激素诱导孕鼠肝内胆汁淤积的发生机制之一。
Objective To investigate the effects of estrogen receptor α (ERα) on the genes involved in the regulation of bile acid transport, such as farnesoid X receptor (FXR), sodium-taurocholic co-transporter (NTCP), bile salt export pump (BSEP) and its effect on intrahepatic cholestasis in pregnant rats. Methods Forty SPF SD pregnant rats were randomly divided into 4 groups. From the 15th day of pregnancy, the control group was subcutaneously injected with 2.0 m L / kg · d of plant oil on the neck, and 17α-ethinyl estradiol 1.0 mg / kg · d and 1.25 mg / kg · D, 1.5 mg / kg · d. On the 21st day of pregnancy, blood was collected for 2 m L and then sacrificed by neck dislocation. Histological examination of the liver of the female rats was performed. The biochemical indexes in serum of pregnant rats in each group and the expression of each protein and mRNA in liver tissues were detected. Results Biochemical indexes: The protein expression levels of pregnant rats in low, medium and high dose groups were significantly higher than those in control group (P <0.05), and there was significant difference between low, medium and high dose groups (P <0.05). The protein expression and the mRNA expression level of ER in the control group, low dose group, medium dose group and high dose group increased in turn, while the expression of FXR, NTCP, BSEP in the control group, low dose group , The middle dose group and the high dose group decreased in turn, and the gene expression levels of each group were significantly different from the control group (P <0.05). Conclusions With the increase of estrogen dose, the expression of ERα increased, while the expression of FXR, NTCP and BSEP decreased, suggesting that bile acid metabolism and transport function decreased, which may be one of the mechanisms of estrogen-induced intrahepatic cholestasis in pregnant rats .