on October 21, 2004
Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148323.94021.e5
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Submitted on April 21, 2004
Accepted on October 11, 2004
ACAT1 Deficiency Disrupts Cholesterol Efflux and Alters Cellular Morphology in Macrophages
Dwayne E. Dove ;
From the Department of Pathology (D.E.D., W.G.J., L.L.S., S.F.), the Department of Medicine (Y.R.S., W.Z., M.F.L., S.F.), Division of Cardiovascular Medicine, the Department of Cancer Biology (W.G.J.), and the Department of Pharmacology (M.F.L.), Vanderbilt University Medical Center, Nashville, Tenn.
* To whom correspondence should be addressed. E-mail: sergio.fazio{at}vanderbilt.edu.
Objective--Acyl-coenzyme A: cholesterol acyltransferase (ACAT) converts intracellular free cholesterol (FC) into cholesteryl esters (CE) for storage in lipid droplets. Recent studies in our laboratory have shown that the deletion of the macrophage ACAT1 gene results in apoptosis and increased atherosclerotic lesion area in the aortas of hyperlipidemic mice. The objective of the current study is to elucidate the mechanism of the increased atherosclerosis.
Methods and Results--CE storage and FC efflux were studied in ACAT1(-/-) peritoneal macrophages that were treated with acetylated low-density lipoprotein (acLDL). Our results show that efflux of cellular cholesterol was reduced by 25% in ACAT1-deficient cells compared with wild-type controls. This decrease occurred despite the upregulated expression of ABCA1, an important mediator of cholesterol efflux. In contrast, ACAT1 deficiency increased efflux of the cholesterol derived from acLDL by 32%. ACAT1-deficient macrophages also showed a 26% increase in the accumulation of FC derived from acLDL, which was associated with a 75% increase in the number of intracellular vesicles.
Conclusions--Together, these data show that macrophage ACAT1 influences the efflux of both cellular and lipoprotein-derived cholesterol and propose a pathway for the pro-atherogenic transformation of ACAT1(-/-) macrophages.
Key words: Acyl-coenzyme A • cholesterol acyltransferase • ATP-binding cassette A1 • acetyl-low-density lipoprotein • macrophages • cholesterol efflux
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