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

    Research output: Contribution to journalArticle

    44 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)128-134
    Number of pages7
    JournalArteriosclerosis, thrombosis, and vascular biology
    Volume25
    Issue number1
    DOIs
    StatePublished - Jan 1 2005

    Keywords

    • ACAT1
    • ATP-binding cassette A1
    • Atherosclerosis
    • Cholesterol efflux
    • Macrophages

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

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