A pathway-dependent on apoE, ApoAI, and ABCA1 determines formation of buoyant high-density lipoprotein by macrophage foam cells.

Yancey PG, Yu H, Linton MF, Fazio S
Arterioscler Thromb Vasc Biol. 2007 27 (5): 1123-31

PMID: 17303773 · DOI:10.1161/ATVBAHA.107.139592

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 > 1.21 g/mL, whereas apoE from wild-type cells floated at density of 1.09 to 1.17 g/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 > or = 1.17 g/mL. In apoE-/- cells, apoAI and cholesterol floated at similar density, but the peak fraction only contained 4 microg 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.

MeSH Terms (14)

Animals Apolipoprotein A-I Apolipoproteins E Atherosclerosis ATP-Binding Cassette Transporters ATP Binding Cassette Transporter 1 Cell Count Cholesterol Disease Progression Female Foam Cells Mice Mice, Inbred C57BL Ultracentrifugation

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