Abstract
Acyl-CoA thioesterase 7 (ACOT7) is an intracellular enzyme that converts acyl-CoAs to FFAs. ACOT7 is induced by lipopolysaccharide (LPS); thus, we investigated downstream effects of LPS-induced induction of ACOT7 and its role in inflammatory settings in myeloid cells. Enzymatic thioesterase activity assays in WT and ACOT7-deficient macrophage lysates indicated that endogenous ACOT7 contributes a significant fraction of total acyl-CoA thioesterase activity toward C20:4-, C20:5-, and C22:6-CoA, but contributes little activity toward shorter acyl-CoA species. Lipidomic analyses revealed that LPS causes a dramatic increase, primarily in bis(monoacylglycero)phosphate species containing long (≥C20) polyunsaturated acyl-chains in macrophages, and that the limited effect observed by ACOT7 deficiency is restricted to glycerophospholipids containing 20-carbon unsaturated acyl-chains. Furthermore, ACOT7 deficiency did not detectably alter the ability of LPS to induce cytokines or prostaglandin E2 production in macrophages. Consistently, although ACOT7 was induced in macrophages from diabetic mice, hematopoietic ACOT7 deficiency did not alter the stimulatory effect of diabetes on systemic inflammation or atherosclerosis in LDL receptor-deficient mice. Thus, inflammatory stimuli induce ACOT7 and remodeling of phospholipids containing unsaturated long (≥C20)-acyl chains in macrophages, and, although ACOT7 has preferential thioesterase activity toward these lipid species, loss of ACOT7 has no major detrimental effect on macrophage inflammatory phenotypes.≥
Highlights
Acyl-CoA thioesterase 7 (ACOT7) is an intracellular enzyme that converts acyl-CoAs to FFAs
Nondiabetic mice had no lesions or very small lesions at this time point (Fig. 5M). These results suggest that subtle increases in ACOT7 expression, such as those seen in macrophages from diabetic mice, do not mediate macrophage accumulation in the artery wall or inflammation associated with diabetes
Our study is the first to investigate the effect of ACOT7 deficiency in macrophages
Summary
Acyl-CoA thioesterase 7 (ACOT7) is an intracellular enzyme that converts acyl-CoAs to FFAs. Previous studies have revealed that macrophages deficient in the FA binding protein FABP4 (aP2) exhibit reduced inflammatory activation, reduced activation of NF- B, and Abbreviations: ACOT, acyl-CoA thioesterase; ACSL, acyl-CoA synthetase; BMDM, bone marrow-derived macrophage; BMP, bis(monoacylglycero)phosphate; LPS, lipopolysaccharide; PG, prostaglandin; STZ, streptozotocin; TLR4, Toll-like receptor 4. Long-chain acyl-CoA synthetase 1 (ACSL1), an enzyme that converts FFAs into their acyl-CoA derivatives, is induced by Toll-like receptor 4 (TLR4) activation in macrophages, and its deletion in myeloid cells results in protection against early atherosclerosis in diabetic mice [5]. Elegant studies have demonstrated that unsaturated FAs (including omega-6 and -3 FAs) are increased in the late phase (12–24 h) of TLR4 activation in macrophages, concomitant with induction of enzymes involved in MUFA and PUFA metabolism, and that SREBP1 regulates this late resolution phase of the inflammatory response [6]
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