HDL Particle Size Is a Critical Determinant of ABCA1-Mediated Macrophage Cellular Cholesterol Export

Abstract

However, not all studies show a clear association between HDL-cholesterol and cardiovascular disease. 4,5 The observation that the capacity of serum to promote macrophage Molecular Medicine© 2015 American Heart Association, Inc. Objective: Our aims were to determine which HDL particle subfractions are most efficient in mediating cellular cholesterol efflux from foam cell macrophages and to identify the cellular cholesterol transporters involved in this process. Methods and Results:We used reconstituted HDL particles of defined size and composition, isolated subfractions of human plasma HDL, cell lines stably expressing ABCA1 or ABCG1, and both mouse and human macrophages in which ABCA1 or ABCG1 expression was deleted. We show that ABCA1 is the major mediator of macrophage cholesterol efflux to HDL, demonstrating most marked efficiency with small, dense HDL subfractions (HDL3b and HDL3c). ABCG1 has a lesser role in cholesterol efflux and a negligible role in efflux to HDL3b and HDL3c subfractions. Conclusions:

HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity

“…In macrophages, cholesterol effl ux is thought to be facilitated by ABCA1, with contributions from ABCG1, scavenger receptor class B type I (SR-BI), and passive diffusion ( 33 ). In turn, the prevailing understanding is that ABCA1-mediated cholesterol effl ux is most effi ciently driven by small dense HDL and/or lipid-poor apoA-I ( 29,34 ). In this study, we investigated the relationship between HDL dynamics and cholesterol effl ux capacity in human subjects.…”

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

“…Specifically, CEC was measured from J774 mouse macrophages in which cholesterol efflux is dependent mostly on SR‐B1 and passive diffusion as well as mouse ABCA1 after its overexpression on overnight treatment with cAMP10; and baby hamster kidney (BHK) cells that overexpress human ABCA1 after overnight treatment with mifepristone 11. The ABCA1 transporter is especially important because it allows unidirectional flux of cholesterol to lipid‐free apolipoprotein A‐I and small HDL particles,12 and was tested with mifepristone‐stimulated BHK and cAMP‐stimulated J774 cells.…”

Eicosapentaenoic Acid-Enriched High-Density Lipoproteins Exhibit Anti-Atherogenic Properties

“…Du et al suggested that the capacity of small HDL species for ABCA1-dependent cell surface binding may be related to their ability to promote cholesterol efflux. 28 Conversely, in the study by Marmillot et al, the cholesterol efflux capacity of saturated lipid-based rHDL was higher than that of rHDL incorporating unsaturated lipids. 29 However, results from all studies are not easily comparable because the experimental conditions, such as cell type, rHDL concentration, and duration of incubation with rHDL and cells, varied.…”