Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

• Published in: Journal of lipid research Vol. 56; no. 5; pp. 972 - 985
• Main Authors: Luthi, Andrea J., Lyssenko, Nicholas N., Quach, Duyen, McMahon, Kaylin M., Millar, John S., Vickers, Kasey C., Rader, Daniel J., Phillips, Michael C., Mirkin, Chad A., Thaxton, C.Shad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2015; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Apolipoprotein A-I - metabolism; Apolipoprotein A-I - pharmacology; atherosclerosis; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-binding cassette transporter A1; ATP-binding cassette transporter G1; ATP-Binding Cassette Transporters - metabolism; Biological Transport; Cardiotonic Agents - pharmacology; Cell Line; Cholesterol - metabolism; cholesterol efflux; Coronary Artery Disease - drug therapy; Cricetinae; Drug Evaluation, Preclinical; Drug Stability; Gold - metabolism; Lipoproteins - metabolism; macrophages; Macrophages - metabolism; Molecular Mimicry; Nanoparticles - metabolism; Phospholipids - pharmacology; scavenger receptor class B type I; Scavenger Receptors, Class B - metabolism; atherosclerosis; scavenger receptor class B type I; ATP-binding cassette transporter G1; macrophages; ATP-binding cassette transporter A1; cholesterol efflux
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M054635

The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1.