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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:128.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

ACAT1 Deficiency Disrupts Cholesterol Efflux and Alters Cellular Morphology in Macrophages

Dwayne E. Dove; Yan Ru Su; Wenwu Zhang; W. Gray Jerome; Larry L. Swift; MacRae F. Linton; Sergio Fazio

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.

Correspondence to Sergio Fazio or MacRae F. Linton, Vanderbilt University Medical Center, Division of Cardiovascular Medicine, 383 Preston Research Building, Nashville, TN 37232-6300. E-mail sergio.fazio{at}vanderbilt.edu or macrae.linton{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 was 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.

To elucidate the mechanism of the increased atherosclerosis caused by the deletion of macrophage acyl-coenzyme A: cholesterol acyltransferase (ACAT1), studies of cholesterol storage and efflux were performed using ACAT1^(–/–) macrophages. These studies show that ACAT1 influences the efflux of cellular and lipoprotein-derived cholesterol and causes a pro-atherogenic transformation of macrophages.

Key Words: ACAT1 • ATP-binding cassette A1 • atherosclerosis • macrophages • cholesterol efflux

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