ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages

Dwayne E. Dove, Yan Ru Su, Larry L. Swift, MacRae F. Linton, Sergio Fazio

    Research output: Contribution to journalArticle

    16 Scopus citations

    Abstract

    Acyl-coenzyme A: cholesterol acyltransferase (ACAT) esterifies free cholesterol and stores cholesteryl esters in lipid droplets. Macrophage ACAT1 deficiency results in increased atherosclerotic lesion area in hyperlipidemic mice via disrupted cholesterol efflux, increased lipoprotein uptake, accumulation of intracellular vesicles, and accelerated apoptosis. The objective of this study was to determine whether lipid synthesis is affected by ACAT1. The synthesis, esterification, and efflux of new cholesterol were measured in peritoneal macrophages from ACAT1(-/-) mice. Cholesterol synthesis was increased by 134% (p = 0.001) in ACAT1(-/-) macrophages compared to wildtype macrophages. Increased synthesis resulted in a proportional increase in the efflux of newly synthesized cholesterol. Although the esterification of new cholesterol was reduced by 93% (p < 0.001) in ACAT1(-/-) macrophages, trace amounts of newly synthesized cholesteryl esters were detectable. Furthermore, the expression of SREBP1a mRNA was increased 6-fold in ACAT1(-/-) macrophages compared to wildtype macrophages, suggesting an up-regulation of cholesterol and fatty acid synthesis in ACAT1(-/-) macrophages. Increased cholesterol synthesis and up-regulation of SREBP in ACAT1(-/-) macrophages suggests that ACAT1 affects the regulation of lipid metabolism in macrophages. This change in cholesterol homeostasis may contribute to the atherogenic potential of ACAT1(-/-) macrophages.

    Original languageEnglish (US)
    Pages (from-to)267-274
    Number of pages8
    JournalAtherosclerosis
    Volume186
    Issue number2
    DOIs
    StatePublished - Jun 1 2006

    Keywords

    • Acetyl-low density lipoprotein (acLDL)
    • Acyl-coenzyme A: cholesterol acyltransferase (ACAT)
    • Atherosclerosis
    • Cholesterol synthesis
    • Macrophages
    • Mouse models
    • Oxidized-low density lipoprotein (oxLDL)

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

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