Abstract
Cholesterol esters are a key ingredient of foamy cells in atherosclerotic lesions; their formation is catalyzed by two enzymes: acyl-CoA:cholesterol acyltransferases (ACATs; also called sterol O-acyltransferases, or 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 knockout (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 mice 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 caused cells to produce less proinflammatory responses upon cholesterol loading by acetyl low-density lipoprotein. 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.
Highlights
Cholesterol esters are a key ingredient of foamy cells in atherosclerotic lesions; their formation is catalyzed by two enzymes: acyl-CoA:cholesterol acyltransferases (ACATs; called sterol O-acyltransferases, or SOATs) ACAT1 and ACAT2
The results presented in the current work show that in a mouse model for advanced atherosclerotic lesions, lack of myeloid ACAT1 caused less macrophage presence, significantly reduced lesion size and the cholesterol crystals, without a detectable increase in apoptotic index within the lesion
These results confirm and extend our previous results reporting the effects of myeloid ACAT1 deficiency in the same mouse model for early atherosclerotic lesions [28] and show that in advanced lesions, myeloid selective silencing of ACAT1 is atheroprotective
Summary
Macrophages and smooth muscle cells and contribute to cholesterol ester biosynthesis. Myeloid ACAT1 deficiency prevents advanced atherosclerosis cells to look foamy in appearance These lipid droplets exist in a dynamic state: re-esterification by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT; called sterol O-acyltransferase (SOAT)) and hydrolysis by neutral cholesterol ester hydrolases constitute the cholesterol/CE cycle, causing CEs to undergo continuous turnover, as reviewed in Ref. 6. At the in vivo level, whether ACAT blockage affects cholesterol crystal formation in atherosclerotic lesions had not been closely examined, because of one important technical limitation: in mouse models, cholesterol crystals become a prominent feature within the necrotic core in advanced atherosclerotic lesions, and it takes continuous feedings of a atherosclerosis diet for 15–20 weeks to develop advanced lesions in mouse Both the total Acat KO mouse and the myeloid-specific Acat KO (Acat1ϪM/ϪM) mouse exhibit normal life spans. We took advantage of this opportunity and investigated the effects of myeloid-specific Acat KO in the ApoE KO mouse model for advanced and reported our findings
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