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J Biol Chem. 2019 Sep 8. pii: jbc.RA119.010564. doi: 10.1074/jbc.RA119.010564. [Epub ahead of print]

Myeloid Acat1/Soat1 KO attenuates pro-inflammatory responses in macrophages and protects against atherosclerosis in a model of advanced lesions.

Author information

1
Geisel School of Medicine at Dartmouth, United States.
2
Department of Biochemistry, Geisel School of Medicine at Dartmouth, United States.

Abstract

Cholesterol esters (CE) are a key ingredient of foamy cells in atherosclerotic lesions; their formation is catalyzed by two enzymes, acyl-coenzyme A: cholesterol acyltransferases [ACAT] (sterol O-acyltransferase [SOATs]), ACAT1 and ACAT2. ACAT1 is present in all body cells and is the major isoenzyme in macrophages. Whether blocking ACAT1 benefits atherosclerosis has been under debate for more than a decade. Previously, our laboratory developed a myeloid-specific Acat1 KO mouse (Acat1-M/-M), devoid of ACAT1 only in macrophages, microglia, and neutrophils. In previous work using the ApoE KO (ApoE-/-) mouse model for early lesions, Acat1-M/-M significantly reduced lesion macrophage content and suppressed atherosclerosis progression. In advanced lesions, cholesterol crystals become a prominent feature. Here we evaluated the effects of Acat1-M/-M in the ApoE KO mouse model for more advanced lesions and found that lacking myeloid Acat1 had significantly reduced lesion cholesterol crystal contents. Acat1-M/-M also significantly reduced lesion size and macrophage content without increasing apoptotic cell death. Cell culture studies showed that inhibiting ACAT1 in macrophages cause cells to produce less proinflammatory responses upon cholesterol loading by acetyl LDL. In advanced lesions, Acat1-M/-M reduced but did not eliminate foamy cells. In advanced plaques isolated from ApoE-/- mice, immunostainings showed that both ACAT1 and ACAT2 are present. In cell culture, both enzymes are present in macrophages and smooth muscle cells and contribute to cholesterol ester biosynthesis. Overall, our results support the notion that targeting ACAT1 or targeting both ACAT1 and ACAT2 in macrophages is a novel strategy to treat advanced lesions.

KEYWORDS:

ACAT1/SOAT1; Inflammation; atherosclerosis; cholesterol; lipid metabolism; macrophage; vascular smooth muscle cells

PMID:
31495784
DOI:
10.1074/jbc.RA119.010564
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