ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes.
ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes.
复制标题
ATP11C靶向小鼠中央肝细胞中的基底外侧胆汁盐转运蛋白。
DOI：
10.1002/hep.28522
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Paulusma CC
中科院分区：
文献类型：
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作者：
de Waart DR;Naik J;Utsunomiya KS;Duijst S;Ho-Mok K;Bolier AR;Hiralall J;Bull LN;Bosma PJ;Oude Elferink RP;Paulusma CC
ATP 11 C是ATP 8B 1的同源物，两者都催化磷脂在生物膜中的转运。ATP 8B 1突变导致人类进行性家族性肝内胆汁淤积1型，其特征为小管胆汁淤积。缺乏ATP 11 C的小鼠的特征在于结合型高胆固醇血症和非结合型高胆固醇血症。在这里，我们研究了ATP 11 C缺乏会干扰非结合胆盐的基底外侧摄取的假设，这是一个由有机阴离子转运多肽（OATP）1B 2介导的过程。ATP 11 C定位于对照小鼠肝小叶中央肝细胞的基底外侧膜。在ATP 11 C缺陷小鼠中，血浆总胆红素水平是对照组的6倍，其中约65%为结合型，约35%为非结合型。血浆总胆汁盐增加10倍，主要以非结合物质存在。在ATP 11 C缺陷小鼠中的功能研究表明，未结合胆汁盐的肝脏摄取严重受损，而结合胆汁盐的摄取不受影响。Western印迹和免疫荧光分析表明，仅在ATP 11 C缺陷肝的中央肝细胞中，几乎不存在基底外侧胆盐摄取转运蛋白OATP 1B 2、OATP 1A 1、OATP 1A 4和Na+-牛磺胆酸盐共转运多肽。在体内应用的蛋白酶体抑制剂，硼替佐米，部分恢复这些蛋白质的表达，但不是他们的本地化。此外，我们观察到胆汁淤积小鼠肝脏中ATP 11 C蛋白的翻译后下调，这与OATP 1B 2水平降低一致。ATP 11 C对于中央肝细胞中多种胆盐转运蛋白的基底外侧膜定位是必需的，并且可能充当防止肝胆盐过载的看门人。ATP 11 C缺陷肝脏中结合性高胆红素血症和非结合性高胆固醇血症以及OATP表达缺失与Rotor综合征的特征非常相似，表明ATP 11 C突变可易感Rotor综合征。
ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Here, we have studied the hypothesis that ATP11C deficiency interferes with basolateral uptake of unconjugated bile salts, a process mediated by organic anion-transporting polypeptide (OATP) 1B2. ATP11C localized to the basolateral membrane of central hepatocytes in the liver lobule of control mice. In ATP11C-deficient mice, plasma total bilirubin levels were 6-fold increased, compared to control, of which ~65% was conjugated and ~35% unconjugated. Plasma total bile salts were 10-fold increased and were mostly present as unconjugated species. Functional studies in ATP11C-deficient mice indicated that hepatic uptake of unconjugated bile salts was strongly impaired whereas uptake of conjugated bile salts was unaffected. Western blotting and immunofluorescence analysis demonstrated near absence of basolateral bile salt uptake transporters OATP1B2, OATP1A1, OATP1A4, and Na+-taurocholate-cotransporting polypeptide only in central hepatocytes of ATP11C-deficient liver. In vivo application of the proteasome inhibitor, bortezomib, partially restored expression of these proteins, but not their localization. Furthermore, we observed post-translational down-regulation of ATP11C protein in livers from cholestatic mice, which coincided with reduced OATP1B2 levels. ATP11C is essential for basolateral membrane localization of multiple bile salt transport proteins in central hepatocytes and may act as a gatekeeper to prevent hepatic bile salt overload. Conjugated hyperbilirubinemia and unconjugated hypercholanemia and loss of OATP expression in ATP11C-deficient liver strongly resemble the characteristics of Rotor syndrome, suggesting that mutations in ATP11C can predispose to Rotor syndrome.