Caveolin-1 facilitates internalization and degradation of ABCA1 and probucol oxidative products interfere with this reaction to increase HDL biogenesis
Caveolin-1 facilitates internalization and degradation of ABCA1 and probucol oxidative products interfere with this reaction to increase HDL biogenesis
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DOI：
10.1016/j.atherosclerosis.2016.08.025
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发表时间：
2016-10-01
期刊：
影响因子：
5.3
通讯作者：
Yokoyama, Shinji
中科院分区：
文献类型：
--
作者：
Lu, Rui;Tsuboi, Tomoe;Yokoyama, Shinji
背景和目标：ATP结合盒转运体（ABC）A1是高密度脂蛋白（HDL）生物合成的关键膜蛋白，其表达不仅受基因转录调控，还受细胞内降解调控，从而调节血浆HDL浓度。我们以前表明，抑制ABCA 1降解普罗布考氧化产物，螺醌（SQ）和联苯醌（DQ），增加HDL的生物合成和胆固醇的逆向转运，并实现减少动脉粥样硬化的动物模型。方法：Caveolin-1是一种在细胞生物学中具有多种功能的蛋白质，特别是在胆固醇运输中，它在ABCA 1降解中的作用以及SQ和DQ对该反应的影响已经被研究。在小窝蛋白-1缺陷小鼠胚胎成纤维细胞中ABCA 1蛋白增加，不是通过增加转录，而是通过减少其内化和降解。小窝蛋白-1的转染和表达使ABCA 1的蛋白水平和降解速率正常化。免疫沉淀实验表明ABCA 1和小窝蛋白-1和SQ和DQ之间的关联破坏了这种相互作用。SQ和DQ增加ABCA 1和载脂蛋白A-I诱导的细胞胆固醇释放的作用依赖于caveolin-1的表达。荧光成像的ABCA 1和小窝蛋白-1在培养的细胞中表现出他们的共同定位，以及其中断SQ和DQ，是一致的生化findings.Conclusions：小窝蛋白-1增强内化和降解的ABCA 1通过其协会与ABCA 1。普罗布考氧化产物干扰这种相互作用抑制ABCA 1降解和增加HDL生物合成。(C)2016爱思唯尔爱尔兰有限公司版权所有。
Background and aims: Expression of ATP binding cassette transporter (ABC) A1, a key membrane protein for biogenesis of high-density lipoprotein (HDL), is regulated not only by its gene transcription but also by its intracellular degradation to modulate plasma HDL concentration. We previously showed that inhibition of ABCA1 degradation by probucol oxidative products, spiroquinone (SQ) and diphenoquinone (DQ), increased HDL biogenesis and reverse cholesterol transport, and achieved reduction of atherosclerosis in animal models. The background mechanism has thus been investigated.Methods: Involvement of caveolin-1, a protein of multiple functions in cell biology, particularly in cholesterol trafficking, has been examined for its roles in ABCA1 degradation as well as the effects of SQ and DQ on the reaction.Results: ABCA1 protein was increased in caveolin-1-deficient mouse embryonic fibroblasts, not by increase of transcription but by decrease in its internalization and degradation. Transfection and expression of caveolin-1 normalized the protein level and the rate of degradation of ABCA1. Immunoprecipitation experiments demonstrated association between ABCA1 and caveolin-1 and SQ and DQ disrupted this interaction. The effects of SQ and DQ to increase ABCA1 and cell cholesterol release induced by apolipoprotein A-I were dependent on expression of caveolin-1. Fluorescence imaging of ABCA1 and caveolin-1 in cultured cells demonstrated their co-localization as well as its disruption by SQ and DQ, being consistent with the biochemical findings.Conclusions: Caveolin-1 enhances internalization and degradation of ABCA1 by its association with ABCA1. Interference of this interaction by probucol oxidative products suppresses ABCA1 degradation and increase HDL biogenesis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.