Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria; Institute of Clinical Chemistry, University Hospital Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland.
Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
Biochem Pharmacol. 2020 Jul;177:114022. doi: 10.1016/j.bcp.2020.114022. Epub 2020 May 8.
Increased cholesterol efflux from macrophage foam cells in the subendothelial space confers protection against atherosclerosis. Soraphen A, a myxobacterial macrolactone, is an inhibitor of acetyl coenzyme A carboxylases (ACC), which control fatty acid synthesis and oxidation. To assess a potential direct link between macrophage cholesterol efflux and ACC inhibition, we examined [H]-cholesterol efflux from human THP-1-derived foam cells in the presence of soraphen A. We dissected underlying molecular events by western blot analyses, RT-qPCR, reporter gene and coactivator recruitment assays as well as relative quantification of free and total cholesterol. Soraphen A increased cholesterol efflux from macrophage foam cells via upregulation of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1). Soraphen A enhanced transcription of ABCA1 in an LXR-dependent manner, however, without direct binding to the ligand-binding domain of this nuclear receptor. Soraphen A elevated the cellular level of free cholesterol, and failed to activate LXR upon exogenous supplementation with fatty acids or inhibition of cholesterol synthesis. Thus, impeded conversion from acetyl- to malonyl-CoA by soraphen A may lead to more unesterified cholesterol and thus potential LXR agonists. The present study reveals ACC inhibition as a previously unrecognized mechanism to regulate macrophage cholesterol efflux via indirect LXR activation and ABCA1 upregulation.
在动脉粥样硬化中，血管内皮下的泡沫细胞中胆固醇流出的增加赋予了其保护作用。索拉芬 A 是一种粘细菌大环内酯，可抑制乙酰辅酶 A 羧化酶（ACC），ACC 控制脂肪酸的合成和氧化。为了评估巨噬细胞胆固醇流出与 ACC 抑制之间的潜在直接联系，我们研究了索拉芬 A 存在时人源性 THP-1 衍生泡沫细胞中[H]-胆固醇的流出。我们通过 Western blot 分析、RT-qPCR、报告基因和辅激活因子募集测定以及游离胆固醇和总胆固醇的相对定量，对潜在的分子事件进行了剖析。索拉芬 A 通过上调胆固醇转运体 ATP 结合盒转运体 A1（ABCA1）增加了巨噬细胞泡沫细胞中的胆固醇流出。索拉芬 A 以 LXR 依赖性的方式增强了 ABCA1 的转录，但没有与该核受体的配体结合域直接结合。索拉芬 A 增加了细胞内游离胆固醇的水平，并且在外源补充脂肪酸或抑制胆固醇合成时未能激活 LXR。因此，索拉芬 A 对从乙酰-CoA 到丙二酰-CoA 的转化的抑制可能导致更多未酯化的胆固醇，从而成为潜在的 LXR 激动剂。本研究揭示了 ACC 抑制作为一种以前未被认识的机制，通过间接激活 LXR 和上调 ABCA1 来调节巨噬细胞胆固醇流出。
