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Role of renal and inteslinal ABC transporters during cholestatic liver disease

肾脏和肠道 ABC 转运蛋白在胆汁淤积性肝病中的作用

基本信息

批准号：
15590473
负责人：
KAMISAKO Toshinori
金额：
$ 1.22万
依托单位：
KINKI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Background and Aim : Multidrug resistance protein 2 (Mrp2), Mrp3, bile salt export pump (Bsep) and Mdrlb have been identified as bile acid or drug transporter The purpose of this study is to evaluate hepatic, renal and intestinal ABC transporter expressions during cholestasis. Methods : Experiment 1 : Rats were subjected to bile duct ligation or sham operation. Blood, liver and small intestine were obtained 24 and 72 hours after operation. Experiment 2 : Rats were subjected to four groups as follows : 1)Control group. 2)Diosgenin group (fed with diosgenin in diet [1%(wt/wt)] for seven days). 3)Ethinyl estradiol group (recieved ethinyl estradiol (5mg/kg daily) for five days). 4)Diosgenin-ethinyl estradiol group (received ethinyl estradiol and diosgenin). After treatment, blood, bile, liver and intestine were obtained. The mRNA related to lipid and bile acid metabolism was analyzed by RT-PCR. Results : Intestinal Mrp2 mRNA expression remarkably decreased 24 hours after bile duct and recovered 72 hours after bile duct ligation. Intestinal Mrp3 mRNA expression did not change after BDL. Intestinal Mrp2 mRNA expression was remarkably increased in Diosgenin and Diosgenin-ethinyl estradiol groups in comparison with the control group. There were no significant differences in intestinal Mrp3 mRNA expression among the four groups. Hepatic Mrp3 mRNA expression was remarkably increased in the D, EE and DE groups in comparison with the control group (531 %, 321% and 1160 % of control, respectively, p<0.01). Conclusion : 1)Bile duct ligation affects not only hepatic but also the intestinal Mrp2 expressions. 2)Intestinal Mrp2 mRNA level is regulated by factor in the lumen (e.g. diosgenin feeding). 3)Cholestasis by ethinyl estradiol treatment was enhanced by diosgenin and the increase in hepatic Mrp3 mRNA level may affect the enhancement.

背景与目的：多药耐药蛋白2 （Mrp2）、Mrp3、胆盐输出泵（Bsep）和Mdrlb已被鉴定为胆汁酸或药物转运体，本研究的目的是评估胆汁淤积时肝脏、肾脏和肠道ABC转运体的表达。方法：实验一：采用大鼠胆管结扎或假手术。术后24、72 h取血、取肝、取小肠。实验二：将大鼠分为四组：1)对照组。2)薯蓣皂苷元组（饲粮中添加薯蓣皂苷元[1%(wt/wt)]，饲喂7 d）。3)乙炔雌二醇组（给予乙炔雌二醇（5mg/kg / d），连续5 d）。4)薯蓣皂苷元-乙基雌二醇组（给予乙基雌二醇和薯蓣皂苷元）。治疗后取血、胆、肝、肠。RT-PCR分析脂质和胆汁酸代谢相关mRNA。结果：胆管结扎后24小时肠道Mrp2 mRNA表达显著降低，结扎后72小时肠道Mrp2 mRNA表达恢复。BDL后肠道Mrp3 mRNA表达无明显变化。与对照组相比，薯蓣皂苷元组和薯蓣皂苷元-乙炔雌二醇组肠道Mrp2 mRNA表达显著升高。四组间肠道Mrp3 mRNA表达量无显著差异。与对照组相比，D组、EE组和DE组肝脏Mrp3 mRNA表达量显著升高（分别为对照组的531%、321%和1160%，p<0.01）。结论：1)胆管结扎不仅影响肝脏，还影响肠道Mrp2的表达。2)肠道Mrp2 mRNA水平受管腔因子（如投喂薯蓣皂苷元）的调控。3)薯蓣皂苷元对乙炔雌二醇处理后的胆汁淤积有增强作用，肝脏Mrp3 mRNA水平升高可能影响这种增强作用。