Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages.
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.
Fazio
S
S
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 315 Medical Research Building, Nashville, Tennessee 37232-6300, USA. sergio.fazio@mcmail.vanderbilt.edu
Major
A S
AS
Swift
L L
LL
Gleaves
L A
LA
Accad
M
M
Linton
M F
MF
Farese
R V
RV
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D017690:Cell Transplantation; D002784:Cholesterol / Q000378:metabolism; D004396:Coloring Agents; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000196:embryology; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000172:deficiency*; D015854:Up-Regulation
D004396:Coloring Agents; D011973:Receptors, LDL; D002784:Cholesterol; D002785:Sterol O-Acyltransferase