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J. Biol. Chem., Vol. 277, Issue 14, 11811-11820, April 5, 2002
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From the This study elucidates the factors
underlying the enhancement in efflux of human fibroblast unesterified
cholesterol and phospholipid (PL) by lipid-free apolipoprotein (apo)
A-I that is induced by cholesterol enrichment of the cells. Doubling
the unesterified cholesterol content of the plasma membrane by
incubation for 24 h with low density lipoprotein and
lipid/cholesterol dispersions increases the pools of PL and cholesterol
available for removal by apoA-I from about 0.8-5%; the initial rates
of mass release of cholesterol and PL are both increased about 6-fold.
Expression of the ATP binding cassette transporter A1 (ABCA1) is
critical for this increased efflux of lipids, and cholesterol loading
of the fibroblasts over 24 h increases ABCA1 mRNA about
12-fold. The presence of more ABCA1 and cholesterol in the plasma
membrane results in a 2-fold increase in the level of specific binding of apoA-I to the cells with no change in binding affinity.
Characterization of the species released from either control or
cholesterol-enriched cells indicates that the plasma membrane domains
from which lipids are removed are cholesterol-enriched with respect to
the average plasma membrane composition. Cholesterol enrichment of
fibroblasts also affects PL synthesis, and this leads to enhanced
release of phosphatidylcholine (PC) relative to sphingomyelin (SM); the ratios of PC to SM solubilized from control and cholesterol-enriched fibroblasts are ~2/1 and 5/1, respectively. Biosynthesis of PC is
critical for this preferential release of PC and the enhanced cholesterol efflux because inhibition of PC synthesis by choline depletion reduces cholesterol efflux from cholesterol-enriched cells.
Overall, it is clear that enrichment of fibroblasts with unesterified
cholesterol enhances efflux of cholesterol and PL to apoA-I because of
three effects, 1) increased PC biosynthesis, 2) increased PC transport
via ABCA1, and 3) increased cholesterol in the plasma membrane.
Effects of Enrichment of Fibroblasts with Unesterified
Cholesterol on the Efflux of Cellular Lipids to Apolipoprotein A-I*
§,
,, Department of Biochemistry,
MCP-Hahnemann University, Philadelphia, Pennsylvania 19129, ¶ The Children's Hospital of Philadelphia, University of
Pennsylvania School of Medicine, Abramson Research Center,
Philadelphia, Pennsylvania 19104-4318, ** Central Research
Division, Pfizer Inc., Groton, Connecticut 06340, and
Center for Experimental Surgery and
Anesthesiology, University of Leuven, B-3000 Leuven, Belgium
*
This work was supported by National Institutes of Health
Program Project HL22633 and Training Grant HL07443, a pre-doctoral fellowship from the American Heart Association, Southeastern
Pennsylvania Affiliate (to K. G.-T.), and Foonds voor
Wetenschappelijk Onderzoek-Vlaanderen Program G.0265.01.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Review Branch, NHLBI, NIH, 6701 Rockledge
Dr., Bethesda, MD 20892.
§§
To whom correspondence should be addressed. Tel.: 215-590-0587;
Fax: 215-590-0583; E-mail: phillipsmi@email.chop.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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