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Mentions: It is clear that expression of ABCG1 stimulates cell cholesterol efflux; however, no information is available on this transporter's ability to enhance influx of either FC or COE from HDL3 particles. As shown in Fig. 4, the influx of FC and COE were the same for untreated and mifepristone-treated cells, indicating that ABCG1 expression did not enhance either FC or COE influx at any HDL3 concentration. The enhanced cholesterol efflux mediated by ABCG1 without a parallel increase in FC and cholesteryl ester (CE) influx, as indicated by the isotopic data, should result in a greater net loss of cell cholesterol when exposed to HDL. To confirm the isotopic data, we compared the FC content of media supplemented with 25 μg/ml HDL3 that had been incubated with BHK control and ABCG1-upregulated cells for 8 h and 18 h. The results are presented in Table 1. Expression of ABCG1 produced an increase in cell cholesterol efflux and an increase in the labeled cholesterol recovered in the media. Importantly, the mass of FC in the incubation media from upregulated cells was greater than the media from control cells, and this difference was evident after 8 h and 18 h of exposure to HDL3. This greater cholesterol mass in the media is consistent with the data derived from isotopic assays.
Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux*
Bottom Line: ABCG1 did not enhance influx of FC or cholesteryl oleyl ether (COE) when cells were incubated with radiolabeled HDL(3).ABCG1 expression did not increase the association of HDL(3) with cells.In conclusion, composition and particle size determine the acceptor efficiency for ABCG1-mediated efflux.
Affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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>HDL(2) = HDL(3). Based on phospholipid content, the order was reversed. ABCG1 also mediated phospholipid efflux to human serum and HDL(3). 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) (r(2) = 0.7), apolipoprotein A-I (apoA-I) (r(2) = 0.5), HDL-C (r(2) = 0.4), HDL-PL (r(2) = 0.4), alpha-2 HDL (r(2) = 0.4), and prebeta HDL (r(2) = 0.2). ABCG1 did not enhance influx of FC or cholesteryl oleyl ether (COE) when cells were incubated with radiolabeled HDL(3). ABCG1 expression did not increase the association of HDL(3) 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.
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