Research Unit on Lipids and Atherosclerosis, Internal Medicine Department, Sant Joan University Hospital, IISPV, Universitat Rovira i Virgili, CIBERDEM, Reus, Spain.
Atherosclerosis. 2013 Oct;230(2):216-22. doi: 10.1016/j.atherosclerosis.2013.07.043. Epub 2013 Aug 1.
In macrophages, adipocyte fatty acid-binding protein (FABP4) coordinates key events in oxidized LDL-induced foam cell formation, such as cholesterol trafficking and inflammatory responses. Nrf2 is a redox-sensitive transcription factor with antioxidant and anti-inflammatory properties. We investigated the involvement of the Nrf2 signaling pathway in FABP4-upregulation in response to aldehydes that are derived from polyunsaturated fatty acid (PUFA) oxidation.
Using RT-PCR and western blotting, we found that the aldehyde 2,4-decadienal (2,4-DDE) produced a marked increase in FABP4 mRNA and protein levels. 2,4-DDE acts at the transcriptional level of FABP4 by promoting mRNA synthesis and prolonging the half-life of the de novo synthesized mRNA. 2,4-DDE consistently enhanced nuclear translocation of phosphorylated Nrf2, which was mediated by the activation of the Akt and ERK signaling pathways. A chromatin immunoprecipitation assay showed the in vivo binding of activated Nrf2 to a newly identified ARE site in the human FABP4 promoter.
We propose an Akt and ERK/Nrf2-dependent FABP4 upregulation pathway in response to PUFA oxidation end-products in human macrophages. These results open a new avenue for putative therapeutic targets addressed to control atherogenesis.
在巨噬细胞中，脂肪细胞脂肪酸结合蛋白（FABP4）协调氧化型 LDL 诱导泡沫细胞形成中的关键事件，如胆固醇转运和炎症反应。Nrf2 是一种具有抗氧化和抗炎特性的氧化还原敏感转录因子。我们研究了 Nrf2 信号通路在醛类物质（源自多不饱和脂肪酸（PUFA）氧化）诱导 FABP4 上调中的作用。
通过 RT-PCR 和 Western blot，我们发现醛 2,4-癸二烯醛（2,4-DDE）显著增加了 FABP4 mRNA 和蛋白水平。2,4-DDE 通过促进 mRNA 合成和延长新合成的 mRNA 的半衰期，在 FABP4 的转录水平上发挥作用。2,4-DDE 一致增强了磷酸化 Nrf2 的核易位，这是由 Akt 和 ERK 信号通路的激活介导的。染色质免疫沉淀试验显示，激活的 Nrf2 在体内与人类 FABP4 启动子中的新鉴定的 ARE 位点结合。
我们提出了一种在人巨噬细胞中针对 PUFA 氧化终产物的 Akt 和 ERK/Nrf2 依赖性 FABP4 上调途径。这些结果为控制动脉粥样硬化的潜在治疗靶点开辟了新的途径。
