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

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.

Short-Term Acyl-CoA:Cholesterol Acyltransferase Inhibition, Combined with Apoprotein A1 Overexpression, Promotes Atherosclerosis Inflammation Resolution in Mice

“…On one hand, the aforementioned mouse knock out studies imply that complete deficiency of ACAT1, at least when combined with APOE and LDLR deficiencies either in all tissues (Accad et al, 2000) or in transplanted bone marrow myeloid cells in Ldlr -/recipient mice (Fazio et al, 2001) is too extreme. On the other hand, in another study, Apoe -/mice with advanced atherosclerosis and macrophage/neutrophil deficiency of ACAT1 (compared to Apoe -/controls) exhibit reduced plaque macrophage content and inflammation (Melton et al, 2019), just as we found. However, myeloid ACAT1 deficiency reduced overall survival by approximately 25% in comparison to Apoe -/controls (Melton et al, 2019), suggesting that there may be negative effects when ACAT1 is absent, even in myeloid cells, and that such effects are avoided by only inhibiting ACAT activity partially.…”

“…On the other hand, in another study, Apoe -/mice with advanced atherosclerosis and macrophage/neutrophil deficiency of ACAT1 (compared to Apoe -/controls) exhibit reduced plaque macrophage content and inflammation (Melton et al, 2019), just as we found. However, myeloid ACAT1 deficiency reduced overall survival by approximately 25% in comparison to Apoe -/controls (Melton et al, 2019), suggesting that there may be negative effects when ACAT1 is absent, even in myeloid cells, and that such effects are avoided by only inhibiting ACAT activity partially.…”

Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy

“…Cell models show that unlike statins (which inhibit cholesterol efflux), ACAT1 blockade promotes cholesterol efflux via ABCA1 mediated lipid efflux (Yamauchi et al, 2004 ). Mouse studies portray that reduction in myeloid ACAT1 alleviates diet-induced atherosclerosis (Huang et al, 2016 ; Melton et al, 2019 ). In AD studies, ACAT inhibitors significantly reduced amyloid accumulation in cell culture (Puglielli et al, 2001 ) and mouse models (Hutter-Paier et al, 2004 ).…”

Acat1gene KO restores TGN cholesterol deficiency in mutant NPC1 cells and expands mutantNpc1mouse lifespan

“…Interestingly, recent studies have shown that, in mouse models, total A1 -/reduces pathologies associated with Alzheimer's disease (91). Myeloid A1 -/-suppresses atherosclerosis development and progression (93), (94), and suppresses diet induced obesity (95). Additional studies show that inhibiting A1 suppresses the development and progression of pancreatic cancer (96), suppresses the development of hepatocellular carcinoma (97), and potentiates the antitumor activities of cytotoxic T cells (98).…”