Evolution of substrate specificity for the bile salt transporter ASBT (SLC10A2).
Evolution of substrate specificity for the bile salt transporter ASBT (SLC10A2).
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DOI：
10.1194/jlr.m025726
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发表时间：
2012-08
影响因子：
6.5
通讯作者：
Cai SY
中科院分区：
文献类型：
--
作者：
Lionarons DA;Boyer JL;Cai SY
顶端Na+依赖性胆盐转运蛋白（ASBT/SLC 10A 2）对维持胆盐的肝肠循环至关重要。目前尚不清楚Slc 10a 2是何时进化为胆盐转运蛋白的，也不知道它是如何适应胆盐结构在进化过程中的重大变化的。我们表征了来自两种原始脊椎动物的ASBT直系同源物，即利用早期5α-胆汁醇的七鳃鳗和利用结构不同的5β-胆汁醇的旱冰鱼，并将底物特异性与来自利用现代5β-胆汁酸的人类的ASBT进行了比较。外翻肠囊的溜冰鞋，而不是更原始的七鳃鳗运输3 H-牛磺胆酸（TCA），现代5β-胆汁酸。然而，分子克隆鉴定了来自两个物种的ASBT直系同源物。利用重组ASBT/Asbt's进行的基于细胞的测定表明，七鳃鳗Asbt对5α-胆汁醇具有高亲和力，对5β-胆汁醇具有低亲和力，对TCA缺乏亲和力，而旱冰鱼Asbt对5α-和5β-胆汁醇具有高亲和力，但对TCA具有低亲和力。相反，人ASBT对所有三种胆汁盐类型表现出高亲和力。这些发现表明，ASBT从最早的脊椎动物进化而来，通过获得对现代胆汁盐的亲和力，同时保留对旧胆汁盐的亲和力。此外，我们的研究结果表明，胆盐肠肝循环是保守的整个脊椎动物的进化。
The apical Na+-dependent bile salt transporter (ASBT/SLC10A2) is essential for maintaining the enterohepatic circulation of bile salts. It is not known when Slc10a2 evolved as a bile salt transporter or how it adapted to substantial changes in bile salt structure during evolution. We characterized ASBT orthologs from two primitive vertebrates, the lamprey that utilizes early 5α-bile alcohols and the skate that utilizes structurally different 5β-bile alcohols, and compared substrate specificity with ASBT from humans who utilize modern 5β-bile acids. Everted gut sacs of skate but not the more primitive lamprey transported 3H-taurocholic acid (TCA), a modern 5β-bile acid. However, molecular cloning identified ASBT orthologs from both species. Cell-based assays using recombinant ASBT/Asbt's indicate that lamprey Asbt has high affinity for 5α-bile alcohols, low affinity for 5β-bile alcohols, and lacks affinity for TCA, whereas skate Asbt showed high affinity for 5α- and 5β-bile alcohols but low affinity for TCA. In contrast, human ASBT demonstrated high affinity for all three bile salt types. These findings suggest that ASBT evolved from the earliest vertebrates by gaining affinity for modern bile salts while retaining affinity for older bile salts. Also, our results indicate that the bile salt enterohepatic circulation is conserved throughout vertebrate evolution.