Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone
Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone
复制标题
地塞米松增强人 ACAT1 基因表达促进巨噬细胞源性泡沫细胞形成
DOI：
10.1038/sj.cr.7290231
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发表时间：
2004-08-01
期刊：
影响因子：
44.1
通讯作者：
Li, BL
中科院分区：
文献类型：
--
作者：
Yang, L;Yang, JB;Li, BL
在巨噬细胞中，由激活的酰基辅酶A：胆固醇酰基转移酶-1(ACAT1)合成的胆固醇酯的积累导致泡沫细胞的形成，这是早期动脉粥样硬化病变的标志。在本研究中，在糖皮质激素地塞米松(Dex)的处理下，脂质染色结果清楚地显示，暴露于较低浓度的氧化型低密度脂蛋白(OX-LDL)的THP-1来源的巨噬细胞中，含有胆固醇酯的脂滴大量聚集。更值得注意的是，当与特定的抗ACAT抑制剂一起处理时，THP-1来源的巨噬细胞中丰富的胆固醇酯积累显著减少，证实ACAT是负责细胞内胆固醇酯合成的关键酶。RT-PCR和Western印迹结果表明，地塞米松可在THP-1和THP-1来源的巨噬细胞中上调人ACAT1的表达。荧光素酶活性检测表明，Dex能够以细胞特异性的方式增强人ACAT1基因P1启动子的活性，这是导致ACAT1激活的主要因素。进一步的实验证据表明，位于人ACAT1基因P1启动子内的糖皮质激素反应元件(GRE)可以与糖皮质激素受体(GR)蛋白在功能上结合。这些数据支持这样一种假设，即地塞米松的临床治疗增加了动脉粥样硬化的发生率，部分原因可能是由于增强了ACAT1的表达，促进了巨噬细胞来源的泡沫细胞形成过程中胆固醇酯的积累，巨噬细胞泡沫细胞形成是动脉粥样硬化的早期阶段。
In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.