Atger V M, de la Llera Moya M, Stoudt G W, Rodrigueza W V, Phillips M C, Rothblat G H
Hôpital Broussais, Paris, France.
J Clin Invest. 1997 Feb 15;99(4):773-80. doi: 10.1172/JCI119223.
Low concentrations of cyclodextrins (< 1.0 mM) added to serum act catalytically, accelerating the exchange of cholesterol between cells and lipoproteins. J774 macrophages incubated with serum and 2-hydroxypropyl-beta-cyclodextrin (< or = 1 mM) released fivefold more labeled cholesterol than with serum alone. Increased efflux was not accompanied by a change in cell cholesterol mass; thus, cyclodextrin functioned as a cholesterol shuttle, enhancing cholesterol bidirectional flux without changing the equilibrium cholesterol distribution between cells and medium. The addition of phospholipid vesicles to serum and cyclodextrin shifted the equilibrium distribution to favor the medium, producing rapid and extensive depletion of cell cholesterol mass. The combination of serum, phospholipid vesicles, and cyclodextrin also stimulated the rapid clearance of both free and esterified cholesterol from mouse peritoneal macrophages loaded with free and esterified cholesterol. This study: (a) demonstrates that a compound can function as a catalyst to enhance the movement of cholesterol between cells and serum, (b) illustrates the difference between cholesterol exchange and net transport in a cell/serum system, (c) demonstrates how net movement of cholesterol is linked to concentration gradients established by phospholipids, (d) provides a basis for the development of the shuttle/sink model for the first steps in reverse cholesterol transport, (e) validates the model using artificial shuttles (cyclodextrins) and sinks (large unilamellar vesicles), and (f) suggests that cyclodextrin-like cholesterol shuttles might be of pharmacological significance in treating unstable atherosclerotic plaques.
向血清中添加低浓度的环糊精（<1.0 mM）具有催化作用，可加速胆固醇在细胞与脂蛋白之间的交换。用血清和2-羟丙基-β-环糊精（≤1 mM）孵育的J774巨噬细胞释放的标记胆固醇比仅用血清孵育时多五倍。胆固醇流出增加但细胞胆固醇总量未发生变化；因此，环糊精起到胆固醇穿梭体的作用，增强了胆固醇的双向通量，而不改变细胞与培养基之间胆固醇的平衡分布。向血清和环糊精中添加磷脂囊泡会使平衡分布向有利于培养基的方向移动，导致细胞胆固醇总量迅速且大量减少。血清、磷脂囊泡和环糊精的组合还能刺激载有游离胆固醇和酯化胆固醇的小鼠腹腔巨噬细胞快速清除游离胆固醇和酯化胆固醇。本研究：（a）证明一种化合物可作为催化剂增强胆固醇在细胞与血清之间的移动；（b）阐明细胞/血清系统中胆固醇交换与净转运的差异；（c）证明胆固醇的净移动如何与磷脂建立的浓度梯度相关联；（d）为逆向胆固醇转运第一步的穿梭体/汇聚体模型的开发提供依据；（e）使用人工穿梭体（环糊精）和汇聚体（大单层囊泡）验证该模型；（f）表明类似环糊精的胆固醇穿梭体在治疗不稳定动脉粥样硬化斑块方面可能具有药理学意义。
