Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
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DOI：
10.1161/circulationaha.111.066589
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发表时间：
2012-04-17
期刊：
影响因子：
37.8
通讯作者：
Yvan-Charvet L
中科院分区：
文献类型：
--
作者：
Rosenson RS;Brewer HB Jr;Davidson WS;Fayad ZA;Fuster V;Goldstein J;Hellerstein M;Jiang XC;Phillips MC;Rader DJ;Remaley AT;Rothblat GH;Tall AR;Yvan-Charvet L
高密度脂蛋白（HDL）已被认为具有几种抗动脉粥样硬化特性，包括介导巨噬细胞胆固醇流出的能力、抗氧化能力、抗氧化特性、一氧化氮促进活性和转运具有自身内在生物活性的蛋白质的能力。1 HDL颗粒是来自载脂巨噬细胞的胆固醇的关键受体，从而参与维持动脉壁中的净胆固醇平衡和减少动脉胆固醇负载巨噬细胞的促炎反应。调节HDL介导的巨噬细胞胆固醇流出和胆固醇处置的途径涉及细胞膜结合转运蛋白、血浆脂质受体、血浆蛋白和酶以及肝细胞受体（图1）。从最早提出的HDL介导的胆固醇流出的概念开始，2，3 HDL颗粒中胆固醇含量的浓度被认为是“胆固醇逆向转运”（RCT）过程效率的替代测量;然而，巨噬细胞来源的胆固醇代表HDL颗粒转运的胆固醇的次要组分。4-7胆固醇介导的巨噬细胞泡沫细胞外排的一个重要途径涉及ATP结合盒转运蛋白A1（ABCA 1）与胆固醇缺乏和磷脂耗尽的载脂蛋白（apo）AI复合物（前胆固醇迁移HDL或极小HDL [HDL-VS];图2）之间的相互作用。1，8随后，ATP结合盒转运蛋白G1（ABCG 1）通过与球形含胆固醇的α-HDL颗粒（小HDL [HDL-S]、中HDL [HDL-M]、大HDL [HDL-L]和极大（HDLVL））相互作用（图3）介导巨噬细胞胆固醇流出。1相反，清道夫受体B类I型（SR-BI）是一种多功能受体，介导巨噬细胞中的双向脂质转运，这取决于载脂巨噬细胞中胆固醇的含量。SR-BI在胆固醇运输中更确定的作用涉及肝脏从成熟HDL中选择性摄取胆固醇酯。最近的研究表明，SR-BI的多态性有助于该胆固醇处置途径的功能能力，9从而为RCT中该受体的参与提供了重要的见解。在这篇综述中，我们讨论了参与巨噬细胞胆固醇流出和胆固醇处置的分子和细胞途径，以及最近的临床试验，旨在更好地了解HDL的功能。具体来说，我们解决了HDL生物学的新进展，挑战了长期以来对HDL和胆固醇从动脉壁和非动脉壁部位流出的误解，通过使用特定的术语来解决胆固醇流出和消除所涉及的各种组织位置（表1）。然而，nonmacrophage动脉壁流出和nonarterial壁胆固醇流出没有解决在这篇评论。对于理解促进动脉胆固醇流出的过程至关重要，最近的实验研究确定，粪便固醇排泄增加不一定是HDL介导的巨噬细胞胆固醇流出和动脉粥样硬化保护的先决条件。10，11因此，这一新信息需要修订RCT的初始模型，以促进对有效HDL介导的动脉粥样硬化保护所需的关键步骤的准确描述。
High-density lipoprotein (HDL) has been proposed to have several antiatherosclerotic properties, including the ability to mediate macrophage cholesterol efflux, antioxidant capacity, antiinflammatory properties, nitric oxide–promoting activity, and ability to transport proteins with their own intrinsic biological activities. 1 HDL particles are critical acceptors of cholesterol from lipid-laden macrophages and thereby participate in the maintenance of net cholesterol balance in the arterial wall and in the reduction of proinflammatory responses by arterial cholesterol-loaded macrophages. The pathways that regulate HDL-mediated macrophage cholesterol efflux and disposition of cholesterol involve cell membrane–bound transporters, plasma lipid acceptors, plasma proteins and enzymes, and hepatic cellular receptors (Figure 1). From the earliest proposed concept for HDL-mediated cholesterol efflux, 2, 3 the concentration of the cholesterol content in HDL particles has been considered a surrogate measurement for the efficiency of the “reverse cholesterol transport”(RCT) process; however, macrophagederived cholesterol represents a minor component of the cholesterol transported by HDL particles. 4–7 One important pathway for cholesterol-mediated efflux from macrophage foam cells involves interaction between the ATP-binding cassette transporter A1 (ABCA1) and cholesterol-deficient and phospholipid-depleted apolipoprotein (apo) AI complexes (pre-ß migrating HDL or very small HDL [HDL-VS]; Figure 2). 1, 8 Subsequently, the ATP-binding cassette transporter G1 (ABCG1) mediates macrophage cholesterol efflux through interactions (Figure 3) with spherical, cholesterolcontaining α-HDL particles (small HDL [HDL-S], medium HDL [HDL-M], large HDL [HDL-L], and very large (HDLVL). 1 In contrast, the scavenger receptor class B type I (SR-BI) is a multifunctional receptor that mediates bidirectional lipid transport in the macrophage, which is dependent on the content of cholesterol in lipid-laden macrophages. A more established role for SR-BI in cholesterol trafficking involves selective uptake of cholesteryl esters from mature HDL by the liver. Recent studies suggest that polymorphisms in SR-BI contribute to the functional capacity of this cholesterol disposition pathway, 9 thereby providing important insights into the involvement of this receptor in RCT. In this review, we discuss the molecular and cellular pathways involved in macrophage cholesterol efflux and cholesterol disposition, as well as recent clinical trials aimed at better understanding HDL function. Specifically, we address new advances in HDL biology that challenge longstanding misperceptions about HDL and cholesterol efflux from arterial wall and nonarterial wall sites through the use of specific terminology that addresses the various tissue locations involved in cholesterol efflux and elimination (Table 1). However, nonmacrophage arterial wall efflux and nonarterial wall cholesterol efflux are not addressed in this review. Critical to understanding the processes that facilitate arterial cholesterol efflux, recent experimental studies establish that increased fecal sterol excretion is not necessarily a prerequisite for HDL-mediated macrophage cholesterol efflux and atheroprotection. 10, 11 Thus, this new information necessitates revision of initial models of RCT to foster accurate description of the critical steps required for effective HDL-mediated atheroprotection.