Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux*
Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux*
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DOI：
10.1074/jbc.m109.073601
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Xiaoye Zhou;Z. Yin;Xian-zhi Guo;D. Hajjar;Jihong Han
中科院分区：
文献类型：
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作者：
Xiaoye Zhou;Z. Yin;Xian-zhi Guo;D. Hajjar;Jihong Han
atp结合盒转运蛋白A1 （ABCA1）是一种介导游离胆固醇从外周组织向apoAI和高密度脂蛋白（HDL）外流的分子，可抑制脂质巨噬细胞/泡沫细胞的形成和动脉粥样硬化的发展。ERK1/2是调节细胞生长和分化的重要信号分子。ERK1/2信号通路与心脏发育和肥厚有关。然而，ERK1/2在动脉粥样硬化发展中的作用，特别是在巨噬细胞胆固醇稳态中的作用尚不清楚。在这项研究中，我们研究了ERK1/2活性对巨噬细胞ABCA1表达和胆固醇外排的影响。与抑制其他激酶的轻微影响相比，抑制ERK1/2显著增加巨噬细胞胆固醇向apoAI和HDL的外排。相反，ERK1/2的激活降低了巨噬细胞胆固醇外排和ABCA1的表达。ERK1/2抑制剂增加的胆固醇外排与ABCA1水平升高和apoAI与细胞结合有关。ERK1/2抑制剂增加ABCA1是由于ABCA1 mRNA和蛋白稳定性增加。ERK1/2抑制剂对ABCA1表达和胆固醇外排的诱导呈浓度依赖性。机制研究表明，肝脏X受体（LXR）的激活对ERK1/2的表达和激活影响不大。ERK1/2抑制剂对巨噬细胞LXRα/β表达没有影响，而它们不影响LXR或甾醇调节元件结合蛋白（SREBP）对ABCA1启动子的激活或抑制。然而，抑制ERK1/2和激活LXR协同诱导巨噬细胞胆固醇外排和ABCA1表达。我们的数据表明ERK1/2活性在巨噬细胞胆固醇运输中发挥重要作用。
ATP-binding cassette transporter A1 (ABCA1), a molecule mediating free cholesterol efflux from peripheral tissues to apoAI and high density lipoprotein (HDL), inhibits the formation of lipid-laden macrophage/foam cells and the development of atherosclerosis. ERK1/2 are important signaling molecules regulating cellular growth and differentiation. The ERK1/2 signaling pathway is implicated in cardiac development and hypertrophy. However, the role of ERK1/2 in the development of atherosclerosis, particularly in macrophage cholesterol homeostasis, is unknown. In this study, we investigated the effects of ERK1/2 activity on macrophage ABCA1 expression and cholesterol efflux. Compared with a minor effect by inhibition of other kinases, inhibition of ERK1/2 significantly increased macrophage cholesterol efflux to apoAI and HDL. In contrast, activation of ERK1/2 reduced macrophage cholesterol efflux and ABCA1 expression. The increased cholesterol efflux by ERK1/2 inhibitors was associated with the increased ABCA1 levels and the binding of apoAI to cells. The increased ABCA1 by ERK1/2 inhibitors was due to increased ABCA1 mRNA and protein stability. The induction of ABCA1 expression and cholesterol efflux by ERK1/2 inhibitors was concentration-dependent. The mechanism study indicated that activation of liver X receptor (LXR) had little effect on ERK1/2 expression and activation. ERK1/2 inhibitors had no effect on macrophage LXRα/β expression, whereas they did not influence the activation or the inhibition of the ABCA1 promoter by LXR or sterol regulatory element-binding protein (SREBP). However, inhibition of ERK1/2 and activation of LXR synergistically induced macrophage cholesterol efflux and ABCA1 expression. Our data suggest that ERK1/2 activity can play an important role in macrophage cholesterol trafficking.