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Journal of Lipid Research, Vol. 50, 275-284, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux^*

Sandhya Sankaranarayanan^*, John F. Oram, Bela F. Asztalos, Ashley M. Vaughan, Sissel Lund-Katz^*, Maria Pia Adorni^*, Michael C. Phillips^* and George H. Rothblat^1,*

^* Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
Deapartment of Medicine, University of Washington, Seattle, WA
United States Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, MA

^* This work was supported by HL-22633 (G.H.R., M.C.P., S.L.K.), HL-63768 (G.H.R.), RO1HL055362 (J.O.) from National Institute of Health/National Heart, Lung, and Blood Institute, and Contract 53-3K06-5-10 (B.A.) from US Department of Agriculture.

Published, JLR Papers in Press, September 30, 2008.

¹ To whom correspondence should be addressed. e-mail: rothblat{at}email.chop.edu

Among the known mechanisms of reverse cholesterol transport (RCT), ATP binding cassette transporter G1 (ABCG1)-mediated free cholesterol (FC) transport is the most recent and least studied. Here, we have characterized the efficiencies of different acceptors using baby hamster kidney (BHK) cells transfected with human ABCG1 cDNA, which is inducible upon treatment with mifepristone. When normalized on particle number and particle surface area, the acceptor efficiency for FC efflux was as follows: small unilamellar vesicles (SUV)>LDL>reconstituted HDL>HDL₂ = HDL₃. Based on phospholipid content, the order was reversed. ABCG1 also mediated phospholipid efflux to human serum and HDL₃. ABCG1-mediated FC efflux correlated significantly with a number of HDL subfractions and components in serum collected from 25 normolipidemic individuals: apolipoprotein A-II (apoA-II) (r² = 0.7), apolipoprotein A-I (apoA-I) (r² = 0.5), HDL-C (r² = 0.4), HDL-PL (r² = 0.4), -2 HDL (r² = 0.4), and preβ HDL (r² = 0.2). ABCG1 did not enhance influx of FC or cholesteryl oleyl ether (COE) when cells were incubated with radiolabeled HDL₃. ABCG1 expression did not increase the association of HDL₃ with cells. Compared with control cells, ABCG1 expression significantly increased the FC pool available for efflux and the rate constant for efflux. In conclusion, composition and particle size determine the acceptor efficiency for ABCG1-mediated efflux. ABCG1 increases cell membrane FC pools and changes its rate of desorption into the aqueous phase without enhancing the association with the acceptor.

Supplementary key words apolipoproteins • ATP binding cassette transporter G1 • BHK cells • binding • high density lipoprotein • influx • phospholipid efflux • time course

Abbreviations: ABC, ATP binding cassette; apoA-I, apolipoprotein A-I; apoA-II, apolipoprotein A-II; BHK, baby hamster kidney; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; COE, cholesteryl oleyl ether; FC, free cholesterol; FPLC, fast-protein liquid chromatography; DMPC, 1, 2-dimyristoyl-sn-glycerophosphocholine; egg PC, egg glycerophosphocholine; MLV, multilamellar vesicle; PEG, polyethylene glycol; RCT, reverse cholesterol transport; rHDL, reconstituted HDL disc; SM, sphingomyelin; SR-BI, scavenger receptor class B type I; SUV, small unilamellar vesicles

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