Abstract
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), α-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.
Highlights
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
The most efficient acceptor when normalized on the basis of protein was Reconstituted HDL (rHDL), and HDL2 and HDL3 were effective (Fig. 1A), while HDL3 proved to be the best acceptor when normalized on phospholipid concentration (Fig. 1B)
At a given protein or phospholipid concentration, the smaller acceptor particlesm such as rHDL disc, HDL3, and HDL2, were present in higher numbers and gave higher ABCG1mediated efflux compared with large particles such as LDL and small unilamellar vesicles (SUV)
Summary
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. In contrast to the situation with ABCA1, lipid-free apolipoprotein A-I (apoA-I) does not serve as an acceptor of cell cholesterol provided by ABCG1 [16, 21] Based on this broad array of potential acceptors and the 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. Journal of Lipid Research Volume 50, 2009 275 distribution of ABCG1 throughout the cell [22], it has been proposed that the protein may not serve as a direct transporter of membrane cholesterol to acceptors, but rather play a role by enriching the cell membrane with cholesterol that can be incorporated into a variety of acceptor particles [8, 14, 22]
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