on February 15, 2007
Published online before print February 15, 2007, doi: 10.1161/ATVBAHA.107.139592
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Submitted on August 28, 2006
Accepted on January 26, 2007
A Pathway-Dependent on ApoE, ApoAI, and ABCA1 Determines Formation of Buoyant High-Density Lipoprotein by Macrophage Foam Cells
Patricia G. Yancey *;
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.
* To whom correspondence should be addressed. E-mail: patricia.g.yancey{at}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.
Key words: ABCA1 • apolipoprotein AI • cholesterol efflux • endogenous apolipoprotein E • LXR stimulation • macrophage foam cell • nascent high-density lipoprotein
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