ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages.
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.


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.
Dove
Dwayne E
DE
Department of Pathology, Vanderbilt University Medical Center, Nashville, Tenn 37232-6300, USA.
Su
Yan Ru
YR
Zhang
Wenwu
W
Jerome
W Gray
WG
Swift
Larry L
LL
Linton
MacRae F
MF
Fazio
Sergio
S
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism* / Q000633:toxicity; D002788:Cholesterol Esters / Q000378:metabolism; D008078:Cholesterol, LDL / Q000737:chemistry / Q000378:metabolism; D011992:Endosomes / Q000737:chemistry; D005487:Foam Cells / Q000378:metabolism; D008247:Lysosomes / Q000737:chemistry; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000172:deficiency* / Q000502:physiology; D014316:Tritium / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D014316:Tritium; C014409:cholesteryl oleate; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase