Long-chain acyl -CoA synthesis at the crossroads between glucose and fatty acid-enhanced inflammation and atherosclerosis in diabetes

People with diabetes have an increased risk of cardiovascular disease due to underlying atherosclerosis. However the mechanisms whereby diabetes accelerates atherosclerosis are unknown. Evidence suggests that diabetes is associated with an increased pro-inflammatory phenotype of macrophages. This pro-inflammatory state can be mimicked in isolated cells by elevated glucose and fatty acids. Here we show that an enzyme involved in esterification of fatty acids (long-chain acyl-CoA synthetase 1; Acsl1) in macrophages is upregulated in diabetes and by inflammatory stimuli, especially under elevated glucose conditions. Macrophage-targeted deletion of Acsl1 results in protection against inflammation and diabetes-accelerated atherosclerosis, via a reduction in omega-6-derived pro-inflammatory lipid mediators generated via the COX-2 pathway. In addition, Acsl1 plays a key role in regulating fatty acid-mediated inhibition of cholesterol efflux from macrophages, suggesting that Acsl1 could influence not only inflammation but also cholesterol accumulation, under conditions of a high fatty acid load. Finally, we demonstrate that despite displaying reduced inflammatory potential, Acsl1-deficient macrophages do not protect against diet-induced insulin resistance. In fact, macrophage Acsl1-deficency worsens insulin resistance, potentially by resulting in a reduced uptake of saturated fatty acids by macrophages in the liver, thereby exposing hepatocytes to elevated levels of fatty acids that cause insulin resistance.;In summary, we have highlighted the importance of macrophage fatty acid metabolism in diabetes, and demonstrated that long-chain acyl-CoA synthesis sits at the crossroads between glucose and fatty acid-enhanced inflammation and atherosclerosis in diabetes.