Apolipoprotein A-1 interaction with plasma membrane lipid rafts controls cholesterol export from macrophages.
Cholesterol efflux to apolipoprotein A-1 (apoA-1) from cholesterol-loaded macrophages is an important anti-atherosclerotic mechanism in reverse cholesterol transport. We recently provided kinetic evidence for two distinct pathways for cholesterol efflux to apoA-1 [Gaus et al. (2001) Biochemistry 40, 9363]. Cholesterol efflux from two membrane pools occurs sequentially with different kinetics; a small pool rapidly effluxed over the first hour, followed by progressive release from a major, slow efflux pool over several hours. In the present study, we propose that the rapid and slow cholesterol efflux pools represent cholesterol derived from lipid raft and nonraft domains of the plasma membrane, respectively. We provide direct evidence that apoA-1 binds to both lipid raft and nonraft domains of the macrophage plasma membrane. Conditions that selectively deplete plasma membrane lipid raft cholesterol, such as incorporation of 7-ketocholesterol or rapid exposure to cyclodextrins, block apoA-1 binding to these domains but also inhibit cholesterol efflux from the major, slow pool. We propose that cholesterol exported to apoA-1 from this major slow efflux pool derives from nonraft regions of the plasma membrane but that the interaction of apoA-1 with lipid rafts is necessary to stimulate this efflux.
Gaus
Katharina
K
Macrophage Biology Group, Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Kritharides
Leonard
L
Schmitz
Gerd
G
Boettcher
Alfred
A
Drobnik
Wolfgang
W
Langmann
Thomas
T
Quinn
Carmel M
CM
Death
Alison
A
Dean
Roger T
RT
Jessup
Wendy
W
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I / Q000502:physiology*; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007653:Ketocholesterols / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D047392:beta-Cyclodextrins
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008078:Cholesterol, LDL; D003505:Cyclodextrins; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; C032629:acetyl-LDL; D047392:beta-Cyclodextrins; C485987:heptakis(2,3,4-tri-O-methyl)beta-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol; C003001:7-ketocholesterol