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Publication
Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion
Macrophage Content and Suppresses Atherosclerosis Progression.
Authors Huang LH, Melton EM, Li H, Sohn P, Rogers MA, Mulligan-Kehoe MJ, Fiering SN,
Hickey WF, Chang CC, Chang TY
Submitted By Submitted Externally on 9/22/2017
Status Published
Journal The Journal of biological chemistry
Year 2016
Date Published 3/18/2016
Volume : Pages 291 : 6232 - 44
PubMed Reference 26801614
Abstract Acyl-CoA:cholesterol acyltransferase 1 (Acat1) converts cellular cholesterol to
cholesteryl esters and is considered a drug target for treating atherosclerosis.
However, in mouse models for atherosclerosis, global Acat1 knockout (Acat1(-/-))
did not prevent lesion development. Acat1(-/-) increased apoptosis within
lesions and led to several additional undesirable phenotypes, including hair
loss, dry eye, leukocytosis, xanthomatosis, and a reduced life span. To
determine the roles of Acat1 in monocytes/macrophages in atherosclerosis, we
produced a myeloid-specific Acat1 knockout (Acat1(-M/-M)) mouse and showed that,
in the Apoe knockout (Apoe(-/-)) mouse model for atherosclerosis, Acat1(-M/-M)
decreased the plaque area and reduced lesion size without causing leukocytosis,
dry eye, hair loss, or a reduced life span. Acat1(-M/-M) enhanced xanthomatosis
in apoe(-/-) mice, a skin disease that is not associated with diet-induced
atherosclerosis in humans. Analyses of atherosclerotic lesions showed that
Acat1(-M/-M) reduced macrophage numbers and diminished the cholesterol and
cholesteryl ester load without causing detectable apoptotic cell death.
Leukocyte migration analysis in vivo showed that Acat1(-M/-M) caused much fewer
leukocytes to appear at the activated endothelium. Studies in inflammatory
(Ly6C(hi)-positive) monocytes and in cultured macrophages showed that inhibiting
ACAT1 by gene knockout or by pharmacological inhibition caused a significant
decrease in integrin ß 1 (CD29) expression in activated monocytes/macrophages.
The sparse presence of lesion macrophages without Acat1 can therefore, in part,
be attributed to decreased interaction between inflammatory
monocytes/macrophages lacking Acat1 and the activated endothelium. We conclude
that targeting ACAT1 in a myeloid cell lineage suppresses atherosclerosis
progression while avoiding many of the undesirable side effects caused by global
Acat1 inhibition.




Strains
StrainDevelopment StatusCreation MethodOptions
B6.Cg-Apoetm1Unc Soat1tm1Far Lyz2tm1(cre)IfoPhenotyping ongoingknockout
View
B6.129S4-Soat1tm1FarPhenotyping ongoingknockout
View
B6.Cg-Soat1tm1Far Lyz2tm1(cre)IfoPhenotyping ongoingtransgenic
View




Genes
SymbolDescription
Apoeapolipoprotein E
Soat1sterol O-acyltransferase 1
Lyz2lysozyme 2

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