Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages.
Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages.
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槲皮素通过巨噬细胞中的p38依赖性途径增强了ABCA1表达和胆固醇外排。
DOI：
10.1194/jlr.m024471
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发表时间：
2012-09
影响因子：
6.5
通讯作者：
Chiang AN
中科院分区：
文献类型：
--
作者：
Chang YC;Lee TS;Chiang AN
ATP结合盒转运体A1（ABCA 1）在巨噬细胞输出胆固醇中起着至关重要的作用，这一功能与其参与预防动脉粥样硬化有关。槲皮素是黄酮类化合物之一，已被描述为减少动脉粥样硬化病变的形成。本研究旨在探讨槲皮素对巨噬细胞ABCA 1表达的调控作用及其机制。结果表明，槲皮素以浓度依赖性方式显著增强巨噬细胞胆固醇流出，这与ABCA 1 mRNA和蛋白表达的增加有关。值得注意的是，槲皮素能够通过活化转化生长因子β激活的激酶1（TAK 1）和促分裂原激活的激酶激酶3/6（MKK 3/6）在6 h时刺激p38磷酸化高达234倍。用药理学抑制剂或小发夹RNA（shRNA）抑制p38抑制槲皮素对ABCA 1表达和胆固醇流出的刺激作用。此外，使用染色质免疫沉淀分析，敲低p38降低了槲皮素增强的ABCA 1启动子活性以及特异性蛋白1（Sp1）和肝X受体α（LXRα）与ABCA 1启动子的结合。这些发现提供了证据表明，p38信号是必不可少的调节槲皮素诱导的ABCA 1表达和胆固醇流出的巨噬细胞。
ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in exporting cholesterol from macrophages, a function relevant to its involvement in the prevention of atherosclerosis. Quercetin, one of flavonoids, has been described to reduce atherosclerotic lesion formation. This study is aimed to investigate the effect of quercetin on regulation of ABCA1 expression and to explore its underlying mechanisms in macrophages. The results show that quercetin markedly enhanced cholesterol efflux from macrophages in a concentration-dependent manner, which was associated with an increase in ABCA1 mRNA and protein expression. Remarkably, quercetin is able to stimulate the phosphorylation of p38 by up to 234-fold at 6 h via an activation of the transforming growth factor β-activated kinase 1 (TAK1) and mitogen-activated kinase kinase 3/6 (MKK3/6). Inhibition of p38 with a pharmacological inhibitor or small hairpin RNA (shRNA) suppressed the stimulatory effects of quercetin on ABCA1 expression and cholesterol efflux. Moreover, knockdown of p38 reduced quercetin-enhanced ABCA1 promoter activity and the binding of specificity protein 1 (Sp1) and liver X receptor α (LXRα) to the ABCA1 promoter using chromatin immunoprecipitation assays. These findings provide evidence that p38 signaling is essential for the regulation of quercetin-induced ABCA1 expression and cholesterol efflux in macrophages.