Eicosapentaenoic acid reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through cyclic AMP/protein kinase A signaling pathway in THP-1 macrophage-derived foam cells.
Eicosapentaenoic acid reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through cyclic AMP/protein kinase A signaling pathway in THP-1 macrophage-derived foam cells.
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DOI：
10.1016/j.atherosclerosis.2008.11.003
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发表时间：
2009-06-01
期刊：
影响因子：
5.3
通讯作者：
Tang, Chao-Ke
中科院分区：
文献类型：
--
作者：
Hu, Yan-Wei;Ma, Xin;Tang, Chao-Ke
ABCA1是胆固醇负荷的巨噬细胞中胆固醇外流到apoA-I的关键介质，这是体内RCT的第一步。不饱和脂肪酸可以通过增加ABCA1的降解来抑制巨噬细胞的胆固醇外流。然而，不饱和脂肪酸调节ABCA1的详细机制还不完全清楚。在本研究中，我们研究了EPA对THP-1巨噬细胞源性泡沫细胞ABCA1表达和ABCA1依赖的胆固醇外流的影响，以及cAMP/PKA通路在EPA调控ABCA1中的作用。结果表明，EPA显著破坏ABCA1蛋白的稳定性，减少ABCA1依赖的胆固醇外流，但对ABCA1mRNA的表达没有影响。我们还发现，EPA显著降低cAMP水平、PKA活性和ABCA1丝氨酸磷酸化。PKA激动剂对PKA的特异性激活显著补偿了EPA对ABCA1丝氨酸磷酸化和ABCA1介导的胆固醇外流的下调，而PKA的siRNA导致ABCA1丝氨酸磷酸化和ABCA1介导的胆固醇外流的减少比EPA更显著。然而，PKA激动剂或PKA-siRNA对EPA诱导的ABCA1蛋白降解速率的增强没有影响。这些结果表明，EPA可能通过降低ABCA1蛋白水平和减少PKA介导的ABCA1丝氨酸磷酸化对THP-1巨噬细胞源性泡沫细胞ABCA1活性产生双重负面影响。
ABCA1 is a key mediator of cholesterol efflux to apoA-I in cholesterol loaded macrophages, a first step of RCT in vivo. Unsaturated fatty acids can inhibit cholesterol efflux from macrophages by increasing degradation of ABCA1. However, the detailed mechanisms of ABCA1 regulation by unsaturated fatty acids are not fully understood. In the present study, we investigated the effects of EPA on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of cAMP/PKA pathway on the regulation of ABCA1 by EPA in THP-1 macrophage-derived foam cells. Results showed that EPA significantly destabilized ABCA1 protein and reduced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 mRNA expression. We also revealed that EPA markedly reduced cAMP level and PKA activity and ABCA1 serine phosphorylation. PKA-specific activation by PKA agonist markedly compensated the down-regulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by EPA, while, siRNA of PKA leaded to reduce of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux more significantly than EPA. However, EPA-Induced enhancement of degradation rate of ABCA1 protein did not change by treatment with PKA agonist or PKA-siRNA. These results provide evidence that EPA may have dual negative effects on ABCA1 activity by decreasing ABCA1 protein level and by reducing PKA-mediated ABCA1 serine phosphorylation in THP-1 macrophage-derived foam cells.