Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1

Abstract

The mechanisms that promote an inflammatory environment and accelerated atherosclerosis in diabetes are poorly understood. We show that macrophages isolated from two different mouse models of type 1 diabetes exhibit an inflammatory phenotype. This inflammatory phenotype associates with increased expression of long-chain acyl-CoA synthetase 1 (ACSL1), an enzyme that catalyzes the thioesterification of fatty acids. Monocytes from humans and mice with type 1 diabetes also exhibit increased ACSL1. Furthermore, myeloid-selective deletion of ACSL1 protects monocytes and macrophages from the inflammatory effects of diabetes. Strikingly, myeloid-selective deletion of ACSL1 also prevents accelerated atherosclerosis in diabetic mice without affecting lesions in nondiabetic mice. Our observations indicate that ACSL1 plays a critical role by promoting the inflammatory phenotype of macrophages associated with type 1 diabetes; they also raise the possibilities that diabetic atherosclerosis has an etiology that is, at least in part, distinct from the etiology of nondiabetic vascular disease and that this difference is because of increased monocyte and macrophage ACSL1 expression.

Genetic association of long-chain acyl-CoA synthetase 1 variants with fasting glucose, diabetes, and subclinical atherosclerosis

“…It is possible that the association occurs only with early atherosclerosis or with calcifi cation, rather than with more advanced lesions and clinical events. In this context, it is interesting that ACSL1 in mice is required for early lesions of atherosclerosis, with a less obvious effect on advanced lesions ( 6 ).…”

“…Both in mouse and human macrophages, plasma membrane-associated ACSL1 levels increase after TLR4 and IFN-␥ stimulation ( 6,9 ) and also increase in human macrophages exposed to increased metabolic activation by insulin, elevated glucose, and palmitate ( 10 ). When these cells are exposed to metabolic or infl ammatory activation, ACSL1 is required for effective phospholipid For each of the three SNPs identifi ed in consortium studies ( Table 1 ), primary analyses in MESA focused on the phenotype analyzed in discovery of each SNP, including glucose (log-transformed) and diabetes status.…”

“…Mice defi cient in ACSL1 selectively in myeloid cells or endothelial cells do not exhibit reduced blood glucose levels ( 6,12 ).…”

“…replenishment, neutral lipid accumulation, and early atherosclerosis in the context of diabetes ( 6,7,11 ). Mice defi cient in ACSL1 selectively in myeloid cells or endothelial cells do not exhibit reduced blood glucose levels ( 6,12 ).…”

Lysosomes Integrate Metabolic-Inflammatory Cross-talk in Primary Macrophage Inflammasome Activation

“…Complications of these metabolic diseases account for significant morbidity, mortality, and health care costs. Evidence is accumulating that macrophage dysfunction in diabetes may contribute to several clinically important sequelae including impaired wound healing, excessive atherosclerosis, adverse cardiac remodeling after myocardial infarction, and increased susceptibility to infection (1)(2)(3)(4)(5). However, the mechanisms underlying these inflammatory defects in macrophages are not well understood.…”