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


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.
Yancey
Patricia G
PG
Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232-6300, USA. patricia.g.yancey@vanderbilt.edu
Yu
Hong
H
Linton
MacRae F
MF
Fazio
Sergio
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001057:Apolipoproteins E / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D014461:Ultracentrifugation
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002784:Cholesterol