Characterization of the Role of ABCG2 as a Bile Acid Transporter in Liver and Placenta
Characterization of the Role of ABCG2 as a Bile Acid Transporter in Liver and Placenta
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DOI：
10.1124/mol.111.075143
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发表时间：
2012-02-01
影响因子：
3.6
通讯作者：
Marin, Jose J. G.
中科院分区：
文献类型：
--
作者：
Blazquez, Alba G.;Briz, Oscar;Marin, Jose J. G.
ABCG2参与上皮运输/屏障功能。在这里，我们研究了它在肝脏和胎盘中运输胆汁酸的能力。不表达胆汁盐输出泵（BSEP）的wi - b9 /R细胞可输出胆酰甘酰基荧光素（CGamF）。对典型抑制剂的敏感性提示CGamF的输出主要由ABCG2介导。在中国仓鼠卵巢（CHO细胞）中，共表达大鼠Oatp1a1和人ABCG2分别增强了CGamF、胆酸（CA）、糖CA （GCA）、牛磺酰胆酸（tauroCA）和牛磺酰胆酸-3-硫酸盐（taurostone cholic acid-3-sulfate）的摄取和排出。通过将ABCG2与菊粉一起微注射到表达该泵的非洲爪蟾卵母细胞中，证实了ABCG2输出胆汁酸的能力。雌二醇- 17 β - d -葡糖苷和复美霉素c可抑制abcg2介导的胆汁酸运输。妊娠大鼠梗阻性胆汁淤积引起的母体胆汁酸屏障增加14倍。在大鼠胎盘中，Abcg2的表达远高于Bsep，不受短期胆汁淤积的影响。在妊娠大鼠中，呋霉素C不影响肝脏对GCA的摄取/分泌，但抑制其母婴转移。与野生型小鼠相比，Abcg2（-/-）基因敲除小鼠的梗阻性胆汁淤积在母体血清中引起的胆汁酸积累与野生型小鼠相似，但在胎盘、胎儿血清和肝脏中的积累更高。综上所述，ABCG2具有转运胆汁酸的能力。这种功能的重要性取决于在其他胆汁酸输出细胞的相同上皮中的相对表达。因此，ABCG2可能在胎盘胆汁酸转运中发挥关键作用，正如BSEP在肝脏中的作用一样。
ABCG2 is involved in epithelial transport/barrier functions. Here, we have investigated its ability to transport bile acids in liver and placenta. Cholylglycylamido fluorescein (CGamF) was exported by WIF-B9/R cells, which do not express the bile salt export pump (BSEP). Sensitivity to typical inhibitors suggested that CGamF export was mainly mediated by ABCG2. In Chinese hamster ovary (CHO cells), coexpression of rat Oatp1a1 and human ABCG2 enhanced the uptake and efflux, respectively, of CGamF, cholic acid (CA), glycoCA (GCA), tauroCA, and taurolithocholic acid-3-sulfate. The ability of ABCG2 to export these bile acids was confirmed by microinjecting them together with inulin in Xenopus laevis oocytes expressing this pump. ABCG2-mediated bile acid transport was inhibited by estradiol 17 beta-D-glucuronide and fumitremorgin C. Placental barrier for bile acids accounted for 14-fold increased maternal cholanemia induced by obstructive cholestasis in pregnant rats. In rat placenta, the expression of Abcg2, which was much higher than that of Bsep, was not affected by short-term cholestasis. In pregnant rats, fumitremorgin C did not affect uptake/secretion of GCA by the liver but inhibited its fetal-maternal transfer. Compared with wild-type mice, obstructive cholestasis in pregnant Abcg2(-/-) knockout mice induced similar bile acid accumulation in maternal serum but higher accumulation in placenta, fetal serum, and liver. In conclusion, ABCG2 is able to transport bile acids. The importance of this function depends on the relative expression in the same epithelium of other bile acid exporters. Thus, ABCG2 may play a key role in bile acid transport in placenta, as BSEP does in liver.