Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements
Nrf2 regulates the alternative first exons of CD36 in macrophages through specific antioxidant response elements
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DOI：
10.1016/j.abb.2008.06.004
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发表时间：
2008-09-01
影响因子：
3.9
通讯作者：
Itoh, Ken
中科院分区：
文献类型：
--
作者：
Maruyama, Atsushi;Tsukamoto, Saho;Itoh, Ken
我们先前证明Nrf 2调节巨噬细胞中氧化LDL介导的CD 36表达。本研究旨在确定Nrf 2介导的巨噬细胞CD 36诱导的机制。用Nrf 2激活剂马来酸二乙酯而不是PPAR γ特异性配体处理，引起小鼠巨噬细胞RAW 264.7细胞中CD 36的显著上调。类似地，Nrf 2激活剂以Nrf 2依赖性方式诱导骨髓源性巨噬细胞中的CD 36表达。小鼠CD 36的三个替代性第一外显子（被认为是1A、1B和1C）的诱导表达发生在Nrf 2活化后，外显子1A主要促进CD 36表达。四个抗氧化反应元件（战神）位于这三个外显子的附近，染色质免疫沉淀试验表明，外显子1A上游的两个战神，远端1A-ARE 1和近端1A-ARE 2，是Nrf 2反应性的。荧光素酶报告基因分析最终证明1A-ARE 2是Nrf 2介导的基因表达的关键调控元件。因此，Nrf 2通过与1A-ARE 2结合直接调节CD 36基因表达。
We previously demonstrated that Nrf2 regulates oxidized LDL-mediated CD36 expression in macrophages. The current study aimed to determine the mechanism of Nrf2-mediated macrophage CD36 induction. Treatment with the Nrf2 activator diethylmaleate, but not PPAR gamma specific ligands, caused marked upregulation of CD36 in mouse macrophage RAW264.7 cells. Similarly, Nrf2 activators induced CD36 expression in bone marrow-derived macrophages in a Nrf2-dependent manner. Induced expression of the three alternative first exons of mouse CD36, deemed 1A, 1B, and 1C, occurred upon Nrf2 activation with exon 1A mainly contributing to the CD36 expression. Four antioxidant response elements (AREs) lie within close proximity to these three exons, and chromatin immunoprecipitation assays demonstrated that two AREs upstream of exon1A, the distal 1A-ARE1, and the proximal 1A-ARE2, were Nrf2-responsive. Luciferase reporter assays conclusively demonstrated that 1A-ARE2 is the critical regulatory element for the Nrf2-mediated gene expression. Thus Nrf2 directly regulates CD36 gene expression by binding to 1A-ARE2.