Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Division of Health Chemistry, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1606-1618. doi: 10.1016/j.bbalip.2019.07.013. Epub 2019 Jul 31.
Long-chain acyl-coenzyme A synthetases (ACSLs) are a family of enzymes that convert free long-chain fatty acids into their acyl-coenzyme A (CoA) forms. ACSL4, belonging to the ACSL family, shows a preferential use of arachidonic acid (AA) as its substrate and plays a role in the remodeling of AA-containing phospholipids by incorporating free AA. However, little is known about the roles of ACSL4 in inflammatory responses. Here, we assessed the roles of ACSL4 on the effector functions of bone marrow-derived macrophages (BMDMs) obtained from mice lacking ACSL4. Liquid chromatography-tandem mass spectrometry analysis revealed that various highly unsaturated fatty acid (HUFA)-derived fatty acyl-CoA species were markedly decreased in the BMDMs obtained from ACSL4-deficient mice compared with those in the BMDMs obtained from wild-type mice. BMDMs from ACSL4-deficient mice also showed a reduced incorporation of HUFA into phosphatidylcholines. The stimulation of BMDMs with lipopolysaccharide (LPS) elicited the release of prostaglandins (PGs), such as PGE, PGD and PGF, and the production of these mediators was significantly enhanced by ACSL4 deficiency. In contrast, neither the LPS-induced release of cytokines, such as IL-6 and IL-10, nor the endocytosis of zymosan or dextran was affected by ACSL4 deficiency. These results suggest that ACSL4 has a crucial role in the maintenance of HUFA composition of certain phospholipid species and in the incorporation of free AA into the phospholipids in LPS-stimulated macrophages. ACSL4 dysfunction may facilitate inflammatory responses by an enhanced eicosanoid storm.
长链酰基辅酶 A 合成酶 (ACSLs) 是一类将游离长链脂肪酸转化为酰基辅酶 A (CoA) 形式的酶。ACSL4 属于 ACSL 家族，对花生四烯酸 (AA) 具有优先的利用作用，通过将游离 AA 掺入到含有 AA 的磷脂中，在 AA 含量磷脂的重塑中发挥作用。然而，ACSL4 在炎症反应中的作用知之甚少。在这里，我们评估了 ACSL4 在缺乏 ACSL4 的小鼠骨髓来源的巨噬细胞 (BMDM) 的效应功能中的作用。液相色谱-串联质谱分析显示，与野生型小鼠的 BMDM 相比，ACSL4 缺失小鼠的 BMDM 中各种高度不饱和脂肪酸 (HUFA) 衍生的脂肪酸酰基辅酶 A 种类明显减少。ACSL4 缺失的 BMDM 也显示 HUFA 掺入到磷脂酰胆碱中的减少。用脂多糖 (LPS) 刺激 BMDM 会引发前列腺素 (PG) 的释放，如 PGE、PGD 和 PGF，而 ACSL4 的缺失显著增强了这些介质的产生。相比之下，LPS 诱导的细胞因子（如 IL-6 和 IL-10）的释放或酵母聚糖或葡聚糖的内吞作用不受 ACSL4 缺失的影响。这些结果表明，ACSL4 在维持某些磷脂物种的 HUFA 组成和将游离 AA 掺入 LPS 刺激的巨噬细胞中的磷脂中具有关键作用。ACSL4 功能障碍可能通过增强的类花生酸风暴促进炎症反应。
