Center for Bioenergetics, Department of Medicine, Houston Methodist Research Institute, Houston, TX, USA.
Weill Cornell Medicine, New York, NY, USA.
Nat Rev Cardiol. 2021 Oct;18(10):712-723. doi: 10.1038/s41569-021-00538-z. Epub 2021 Apr 8.
Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process - that is, the transfer of FCh from HDL to macrophages - in the aetiology of increased ASCVD under conditions of very high plasma HDL-FCh concentrations.
血浆高密度脂蛋白胆固醇浓度与动脉粥样硬化性心血管疾病（ASCVD）的风险呈负相关。根据一个广为引用的模型，高密度脂蛋白通过其在胆固醇逆转运中的作用发挥抗动脉粥样硬化作用，胆固醇逆转运包括胆固醇从巨噬细胞流出到早期高密度脂蛋白，然后将高密度脂蛋白中所含的游离胆固醇（FCh）转化为胆固醇酯，高密度脂蛋白受体从血浆中提取胆固醇酯并将其转移到胆汁中进行肠道排泄。由于通过遗传方法增加血浆高密度脂蛋白胆固醇水平不能降低 ASCVD 的风险，因此研究的重点已转移到高密度脂蛋白的功能上，特别是在巨噬细胞胆固醇流出的背景下。多项大型研究支持胆固醇逆转运模型，表明巨噬细胞胆固醇流出到血浆高密度脂蛋白与 ASCVD 呈负相关。然而，其他研究对潜在的胆固醇逆转运机制提出了质疑：在小鼠和人类中，高密度脂蛋白中的 FCh 迅速从血浆中清除（在几分钟内），与酯化和肝脏对 HDL 完整颗粒的摄取无关。此外，巨噬细胞和 HDL 之间 FCh 转移的可逆性表明，在非常高的血浆 HDL-FCh 浓度条件下，FCh 从 HDL 向巨噬细胞的反向转移过程与 ASCVD 增加的发病机制有关。
