Institute of Pharmaceutical Biology, Biocenter, Goethe University, Frankfurt, Germany.
Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany.
J Lipid Res. 2018 Feb;59(2):298-311. doi: 10.1194/jlr.M080101. Epub 2017 Dec 5.
The enzyme acetyl-CoA carboxylase (ACC) plays a crucial role in fatty acid metabolism. In recent years, ACC has been recognized as a promising drug target for treating different diseases. However, the role of ACC in vascular endothelial cells (ECs) has been neglected so far. To characterize the role of ACC, we used the ACC inhibitor, soraphen A, as a chemical tool, and also a gene silencing approach. We found that ACC1 was the predominant isoform in human umbilical vein ECs as well as in human microvascular ECs and that soraphen A reduced the levels of malonyl-CoA. We revealed that ACC inhibition shifted the lipid composition of EC membranes. Accordingly, membrane fluidity, filopodia formation, and migratory capacity were reduced. The antimigratory action of soraphen A depended on an increase in the cellular proportion of PUFAs and, most importantly, on a decreased level of phosphatidylglycerol. Our study provides a causal link between ACC, membrane lipid composition, and cell migration in ECs. Soraphen A represents a useful chemical tool to investigate the role of fatty acid metabolism in ECs and ACC inhibition offers a new and valuable therapeutic perspective for the treatment of EC migration-related diseases.
酶乙酰辅酶 A 羧化酶 (ACC) 在脂肪酸代谢中起着至关重要的作用。近年来，ACC 已被认为是治疗各种疾病的有前途的药物靶点。然而，到目前为止，ACC 在血管内皮细胞 (EC) 中的作用一直被忽视。为了研究 ACC 的作用，我们使用 ACC 抑制剂索拉芬 A 作为化学工具，并采用基因沉默的方法。我们发现 ACC1 是在人脐静脉内皮细胞和人微血管内皮细胞中占主导地位的同工酶，并且索拉芬 A 降低了丙二酰辅酶 A 的水平。我们揭示了 ACC 抑制会改变 EC 膜的脂质组成。因此，膜流动性、丝状伪足形成和迁移能力均降低。索拉芬 A 的抗迁移作用依赖于细胞内多不饱和脂肪酸比例的增加，最重要的是，依赖于磷脂酰甘油水平的降低。本研究在 ACC、膜脂质组成和 EC 迁移之间建立了因果关系。索拉芬 A 是研究脂肪酸代谢在 EC 中的作用的有用化学工具，而 ACC 抑制为治疗与 EC 迁移相关的疾病提供了新的有价值的治疗视角。
