Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice
Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice
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DOI：
10.1021/bi050943e
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发表时间：
2005-09-20
期刊：
影响因子：
2.9
通讯作者：
Ling, V
中科院分区：
文献类型：
--
作者：
Lam, P;Wang, RX;Ling, V
在脊椎动物中，胆汁流动对于水和溶质穿过肝小管膜的运动至关重要。近年来，小管胆汁酸分泌的分子马达已被确定为ATP结合盒转运蛋白（ABC）超家族的成员，被称为P-糖蛋白（Spgp）或胆汁盐输出泵（Bsep，ABCB11）的姐妹。在人类中，BSEP 基因的突变与极低水平的胆汁酸分泌和严重的胆汁淤积有关。然而，正如之前报道的，由于spgp(-/-)敲除小鼠不表现出严重的胆汁淤积并且具有大量胆汁酸分泌，因此我们研究了使这些小鼠生理相对正常的“替代运输系统”。我们检测了spgp(-/-)小鼠中几种ABC转运蛋白的表达水平，发现多药耐药性Mdr1（P-糖蛋白）的水平显着增加，而Mdr2、Mrp2和Mrp3的水平仅中等程度增加。我们假设 spgp(-/-) 敲除小鼠中 Mdr1 水平升高，作为运输胆汁酸的替代途径，并保护肝细胞免受胆汁酸诱导的胆汁淤积。为了支持这一假设，我们证明从表达高水平 P-糖蛋白的耐药细胞系中分离的质膜囊泡能够转运胆汁酸，尽管亲和力比 Spgp 低 5 倍。这一发现是 P-糖蛋白 (Mdr1) 能够转运胆汁酸的第一个直接证据。
In vertebrates, bile flow is essential for movement of water and solutes across liver canalicular membranes. In recent years, the molecular motor of canalicular bile acid secretion has been identified as a member of the ATP binding cassette transporter (ABC) superfamily, known as sister of P-glycoprotein (Spgp) or bile salt export pump (Bsep, ABCB11). In humans, mutations in the BSEP gene are associated with a very low level of bile acid secretion and severe cholestasis. However, as reported previously, because the spgp(-/-) knockout mice do not express severe cholestasis and have substantial bile acid secretion, we investigated the "alternative transport system" that allows these mice to be physiologically relatively normal. We examined the expression levels of several ABC transporters in spgp(-/-) mice and found that the level of multidrug resistance Mdr1 (P-glycoprotein) was strikingly increased while those of Mdr2, Mrp2, and Mrp3 were increased to only a moderate extent. We hypothesize that an elevated level of Mdr1 in the spgp(-/-) knockout mice functions as an alternative pathway to transport bile acids and protects hepatocytes from bile acid-induced cholestasis. In support of this hypothesis, we showed that plasma membrane vesicles isolated from a drug resistant cell line expressing high levels of P-glycoprotein were capable of transporting bile acids' albeit with a 5-fold lower affinity compared to Spgp. This finding is the first direct evidence that P-glycoprotein (Mdr1) is capable of transporting bile acids.