ABC transporters, atherosclerosis and inflammation.
ABC transporters, atherosclerosis and inflammation.
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DOI：
10.1016/j.atherosclerosis.2010.01.011
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发表时间：
2010-08
期刊：
影响因子：
5.3
通讯作者：
Tamehiro N
中科院分区：
文献类型：
--
作者：
Fitzgerald ML;Mujawar Z;Tamehiro N
动脉粥样硬化是由炎性载脂病变引起的，可阻塞冠状动脉并导致心肌梗死。这种慢性病是一个重大且昂贵的健康负担。然而，人体能够动员和排泄胆固醇和其他脂质，从而通过一种称为反向胆固醇运输(RCT)的过程来预防动脉粥样硬化。通过对ABC转运蛋白基因突变引起的两种罕见综合征的研究，对RCT的发病机制有了更深入的认识。在丹吉尔病中，ABCA1的缺失阻止了细胞输出胆固醇和磷脂，从而导致周围组织中胆固醇的积聚和循环中高密度脂蛋白的损失。与高密度脂蛋白是一种动脉粥样硬化保护颗粒相一致，丹吉尔患者更容易发生动脉粥样硬化。同样，谷固醇血症是另一种与过早动脉粥样硬化相关的遗传综合征。在这里，ABCG5或G8基因座的突变阻止肝细胞和肠道细胞将胆固醇和包括谷甾醇在内的植物类固醇排泄到胆汁和肠腔中。因此，来自异源二聚体的ABCG5和G8构成了一种转运体，将胆固醇和饮食中的甾醇排泄回肠道，而ABCA1在高密度脂蛋白的生物发生过程中起到了输出多余的细胞胆固醇和磷脂的作用。有趣的是，第三种蛋白质Abcg1在小鼠身上被证明具有抗动脉粥样硬化的活性，它也可能将胆固醇转移到成熟的高密度脂蛋白颗粒中。在这里，我们综述了这些蛋白质的脂质转运活性与它们的抗动脉粥样硬化作用之间的关系，特别是它们如何可能减少炎症信号通路。特别令人感兴趣的是最近的报道，表明ABCA1和Abcg1都调节细胞表面胆固醇水平，并抑制其进入脂筏。鉴于脂筏可能为先天免疫受体提供平台来响应炎症信号，因此，正如实验所证明的那样，通过增加脂筏含量而失去ABCA1和Abcg1将增加通过这些受体的信号传递。此外，更多的报道表明，ABCA1，以及可能的SR-BI，另一种高密度脂蛋白受体，可能直接作为抗炎受体发挥作用，而不依赖于其脂质运输活性。最后，我们给出了寻求通过RCT途径刺激脂质流动的治疗方法的进展和陷阱的最新进展。
Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier Disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.
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