Published online before print February 15, 2007, doi: 10.1161/ATVBAHA.107.139592
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© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
A Pathway-Dependent on ApoE, ApoAI, and ABCA1 Determines Formation of Buoyant High-Density Lipoprotein by Macrophage Foam Cells
From the Atherosclerosis Research Unit (P.G.Y., H.Y., M.F.L., S.F.), Division of Cardiovascular Medicine, Departments of Medicine, Pharmacology (S.F.), and Pathology (M.F.L.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Patricia G. Yancey, Sergio Fazio, or MacRae F. Linton, 383 PRB, 2220 Pierce Ave, Vanderbilt University Medical Center, Nashville, TN 37232-6300. E-mail patricia.g.yancey{at}vanderbilt.edu, macrae.linton@vanderbilt.edu, or sergio.fazio@vanderbilt.edu
Objective— ABCA1-dependent and ABCA1-independent pathways may operate in high-density lipoprotein formation by macrophages secreting apolipoprotein (apo) E. We examined the impact of ABCA1 on apoE-mediated efflux from cholesterol-enriched macrophages.
Methods and Results— Without acceptors, wild-type, ABCA1–/–, and apoE–/– macrophages released 5.7%±0.3%, 1.8%±0.1%, and 2.3%±0.2% of their cholesterol, and the LXR agonist, TO-901317, enhanced efflux by 137%, 10%, and 20%. Although similar amounts of apoE were secreted from ABCA1–/– and wild-type cells, apoE from ABCA1–/– cells was only partially phospholipidated and floated at density >1.21g/mL, whereas apoE from wild-type cells floated at density of 1.09 to 1.17g/mL and paralleled the density of cholesterol. With apoAI, LXR stimulation increased efflux by 139% and 86% from wild-type and apoE–/– cells, resulting in a large difference in efflux (29.5%±0.2% versus 17.0%±0.5%). The density of apoE and cholesterol from wild-type cells did not change with apoAI, and most apoAI floated at density 
1.17g/mL. In apoE–/– cells, apoAI and cholesterol floated at similar density, but the peak fraction only contained 4 µg cholesterol/mg protein versus 18 in WT cells.
Conclusions— Macrophage apoE requires ABCA1 for formation of high-density lipoprotein. ApoAI facilitates association of apoE with more buoyant high-density lipoprotein, suggesting that apoE, plasma apoAI, and ABCA1 operate together to optimize mobilization of macrophage cholesterol, a process critical to limiting plaque development.
ABCA1-independent and ABCA1-dependent pathways may operate in lipidation of macrophage apoE. We demonstrate that ABCA1 is required for lipidation of macrophage foam cell apoE, and that apoE promotes formation of buoyant HDL in the presence of apoAI. Thus, apoE, apoAI, and ABCA1 work in concert to maximize cholesterol mobilization.
Key Words: ABCA1 • apolipoprotein AI • cholesterol efflux • endogenous apolipoprotein E • LXR stimulation • macrophage foam cell • nascent high-density lipoprotein
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