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Diabetes-accelerated atherosclerosis: Myeloid ACSL1 is a key perpetrator

Lipidomics Gateway (25 April 2012) [doi:10.1038/lipidmaps.2012.11]

Myeloid-specific deficiency of ACSL1, which promotes the production of the lipid-derived inflammatory mediator PGE2 and inflammatory cytokines, prevents diabetes-accelerated atherosclerosis.


An investigation by Kanter et al. into the relationship between diabetes, inflammation and atherosclerosis has identified the long-chain acyl-CoA synthetase ACSL1 as a key perpetrator of the inflammatory phenotype in macrophages and associated atherosclerosis.

Diabetes has a proinflammatory effect on macrophages and monocytes, potentially directly influencing these cells within atherosclerotic lesions; moreover, fatty acids are also known to promote inflammatory effects in these cells. Kanter et al. began their studies by demonstrating increased levels of the inflammatory mediators interleukin-1β (IL-1β), tumor necrosis factor (TNF), cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) in macrophages derived from mouse models of type 1 diabetes. Concomitantly, levels of ACSL1, which catalyzes the thioesterification of fatty acids within cells, were also upregulated in monocytes and macrophages in these mouse models and in human subjects with type 1 diabetes; consequently, so too were levels of arachidonoyl-CoA (20:4-CoA). The authors then ascertained that the increase in ACSL1 levels in these cells was a result of inflammatory activation.

Next, the research team generated a myeloid-specific ACSL1-deficient mouse model to investigate the consequence of a marked deficiency in ACSL1 protein and enzyme activity levels in macrophages from these animals (designated ACSL1M−/− mice). ACSL1 has previously been implicated in the accumulation of neutral lipids and in β-oxidation, but ACSL1-deficient macrophages showed no changes in either of these. However, the deficiency did cause a reduction in 20:4-CoA levels, consistent with the increase in the levels of this acyl-CoA species seen with elevated ACSL1 levels in macrophages from diabetic mice; furthermore, lower levels of PGE2 and PGD2 were produced in response to high glucose concentrations. Accordingly, when diabetes was induced in these animals, the myeloid-specific ACSL1 deficiency completely prevented the increased release from macrophages of PGE2, IL-1β, IL-6, CC-chemokine ligand 2 (CCL2) and TNF that was seen in wild-type mice.

To test the hypothesis that, in a diabetic setting, ACSL1 deficiency prevents the release of a 20:4-derived inflammatory lipid mediator, Kanter et al. exposed macrophages from diabetic wild-type or diabetic ACSL1M−/− mice to an inhibitor of COX2, which promotes the production of PGE2 from 20:4-CoA. Consistent with PGE2 promoting an inflammatory phenotype, COX2 inhibition prevented the production of TNF, IL-1β and CCL2 in diabetic mice.

Given that ACSL1 deficiency attenuated the inflammatory capacity of macrophages in a diabetic setting, the authors then investigated a potential protective effect on diabetes-associated atherosclerosis by transplanting bone marrow from ACSL1M−/− mice into diabetic mice. Myeloid ACSL1 deficiency prevented the accumulation of macrophages in atherosclerotic lesions in the resultant chimeric mice. Notably, myeloid ACSL1 deficiency did not reduce the size of lesions in nondiabetic mice, which indicates that the etiology of diabetic atherosclerosis is potentially different to that of nondiabetic disease.

So, the increased expression of ACSL1 in inflammatory macrophages induced by diabetes is associated with an increase in the levels of 20:4-CoA, the release of the lipid-derived inflammatory mediator PGE2 and the subsequent release of inflammatory cytokines. In the absence of ACSL1, fewer macrophages are likely to be recruited to atherosclerotic lesions, thereby preventing diabetes-accelerated atherosclerosis.

Katrin Legg

- Copyright © 2012 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission



  1. Kanter, J.E. et al. Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.

    Proc. Natl Acad. Sci. USA 109, 715-724 (2012). doi:10.1073/pnas.1111600109

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