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J Biol Chem. 2016 Mar 18;291(12):6232-44. doi: 10.1074/jbc.M116.713818. Epub 2016 Jan 21.

Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression.

Author information

1
From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
2
the Departments of Surgery, Vascular Section.
3
Immunology and Microbiology, and.
4
Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756.
5
From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and Catherine.Chang@Dartmouth.Edu.
6
From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and Ta.Yuan.Chang@Dartmouth.Edu.

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 β 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.

KEYWORDS:

acyltransferase; atherosclerosis; cholesterol; cholesterol metabolism; macrophage

PMID:
26801614
PMCID:
PMC4813549
DOI:
10.1074/jbc.M116.713818
[Indexed for MEDLINE]
Free PMC Article

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