Lipid Metabolism Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA.
Atherosclerosis. 2010 Aug;211(2):361-70. doi: 10.1016/j.atherosclerosis.2010.01.011. Epub 2010 Jan 21.
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.
动脉粥样硬化是由炎症性脂质负荷病变驱动的，可导致冠状动脉阻塞并导致心肌梗死。这种慢性疾病是一个主要且昂贵的健康负担。然而，身体能够动员和排泄胆固醇和其他脂质，从而通过称为胆固醇逆转运（RCT）的过程来预防动脉粥样硬化。通过研究两种由 ABC 转运体基因座突变引起的罕见综合征，人们对 RCT 的机制有了深入的了解。在 Tangier 病中，ABCA1 的缺失阻止细胞输出胆固醇和磷脂，从而导致外周组织中胆固醇的积累和循环 HDL 的丧失。与 HDL 是一种抗动脉粥样硬化颗粒一致，Tangier 患者更容易发生动脉粥样硬化。同样，甾醇血症是另一种与早发性动脉粥样硬化相关的遗传性综合征。在这里，ABCG5 或 G8 基因座的突变阻止肝细胞和肠细胞将胆固醇和植物甾醇（包括甾醇）排泄到胆汁和肠腔中。因此，ABCG5 和 G8 形成异二聚体，构成将胆固醇和膳食固醇排泄回肠道的转运体，而 ABCA1 则在 HDL 生物合成过程中发挥作用，将多余的细胞胆固醇和磷脂输出。有趣的是，第三种蛋白 ABCG1 已被证明在小鼠中具有抗动脉粥样硬化活性，也可能作用于将胆固醇转移至成熟的 HDL 颗粒。在这里，我们回顾了这些蛋白的脂质转运活性及其抗动脉粥样硬化作用之间的关系，特别是它们如何减少炎症信号通路。特别有趣的是，最近的报道表明 ABCA1 和 ABCG1 均可调节细胞表面胆固醇水平并抑制其分配到脂筏中。鉴于脂筏可能为先天免疫受体提供响应炎症信号的平台，因此 ABCA1 和 ABCG1 的缺失通过增加筏的含量将增加通过这些受体的信号传递，正如实验所证明的那样。此外，其他报道表明 ABCA1，可能还有另一种 HDL 受体 SR-BI，可能独立于其脂质转运活性作为抗炎受体发挥作用。最后，我们更新了寻求刺激脂质通过 RCT 途径流动的治疗方法的进展和陷阱。
