title: Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression.
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.
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
authors.forename: Li-Hao
authors.initials: LH
authors.lastname: Huang
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Melton
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
authors.forename: Paul
authors.initials: P
authors.lastname: Sohn
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and.
authors.forename: Maximillian A
authors.initials: MA
authors.lastname: Rogers
authors.affiliation: the Departments of Surgery, Vascular Section.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
authors.affiliation: Immunology and Microbiology, and.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Pathology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756.
authors.forename: William F
authors.initials: WF
authors.lastname: Hickey
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and Catherine.Chang@Dartmouth.Edu.
authors.forename: Catherine C Y
authors.initials: CC
authors.lastname: Chang
authors.affiliation: From the Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755 and Ta.Yuan.Chang@Dartmouth.Edu.
authors.forename: Ta-Yuan
authors.initials: TY
authors.lastname: Chang
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007964:Leukocytosis / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology
chemical_list: C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase
keywords: acyltransferase; atherosclerosis; cholesterol; cholesterol metabolism; macrophage