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: Li-Hao Huang, Elaina M Melton, Haibo Li, Paul Sohn, Maximillian A Rogers, Mary Jo Mulligan-Kehoe, Steven N Fiering, William F Hickey, Catherine C Y Chang, Ta-Yuan Chang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 12 Pg. 6232-44 (Mar 18 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 26801614 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Acat1 protein, mouse
• Acetyl-CoA C-Acetyltransferase

Topics

• Acetyl-CoA C-Acetyltransferase (genetics, metabolism)
• Animals
• Apoptosis
• Atherosclerosis (genetics, immunology, pathology)
• B-Lymphocytes (metabolism)
• Bone Marrow (pathology)
• Cell Movement
• Cell Proliferation
• Diet, High-Fat (adverse effects)
• Disease Progression
• Endothelium, Vascular (immunology, pathology)
• Female
• Hematopoietic Stem Cells (physiology)
• Leukocytosis (genetics, immunology)
• Macrophages (immunology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells (enzymology)