Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages

Sergio Fazio, Amy S. Major, Larry L. Swift, Linda A. Gleaves, Michel Accad, MacRae F. Linton, Robert V. Farese

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

During atherogenesis, circulating macrophages migrate into the subendothelial space, internalize cholesterol-rich lipoproteins, and become foam cells by progressively accumulating cholesterol esters. The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis. We show here, however, that hypercholesterolemic LDL receptor-deficient (LDLR-/-) mice reconstituted with ACAT1-deficient macrophages unexpectedly develop larger atherosclerotic lesions than control LDLR-/- mice. The ACAT1-deficient lesions have reduced macrophage immunostaining and more free cholesterol than control lesions. Our findings suggest that selective inhibition of ACAT1 in lesion macrophages in the setting of hyperlipidemia can lead to the accumulation of free cholesterol in the artery wall, and that this promotes, rather than inhibits, lesion development.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalJournal of Clinical Investigation
Volume107
Issue number2
StatePublished - 2001
Externally publishedYes

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LDL Receptors
Atherosclerosis
Macrophages
Foam Cells
Cholesterol Esters
Cholesterol
Sterol O-Acyltransferase
Acyl Coenzyme A
Hyperlipidemias
Arteries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fazio, S., Major, A. S., Swift, L. L., Gleaves, L. A., Accad, M., Linton, M. F., & Farese, R. V. (2001). Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. Journal of Clinical Investigation, 107(2), 163-171.

Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. / Fazio, Sergio; Major, Amy S.; Swift, Larry L.; Gleaves, Linda A.; Accad, Michel; Linton, MacRae F.; Farese, Robert V.

In: Journal of Clinical Investigation, Vol. 107, No. 2, 2001, p. 163-171.

Research output: Contribution to journalArticle

Fazio, S, Major, AS, Swift, LL, Gleaves, LA, Accad, M, Linton, MF & Farese, RV 2001, 'Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages', Journal of Clinical Investigation, vol. 107, no. 2, pp. 163-171.
Fazio S, Major AS, Swift LL, Gleaves LA, Accad M, Linton MF et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. Journal of Clinical Investigation. 2001;107(2):163-171.
Fazio, Sergio ; Major, Amy S. ; Swift, Larry L. ; Gleaves, Linda A. ; Accad, Michel ; Linton, MacRae F. ; Farese, Robert V. / Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. In: Journal of Clinical Investigation. 2001 ; Vol. 107, No. 2. pp. 163-171.
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AU - Farese, Robert V.

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