Fatty Acid-binding Protein 4, a Point of Convergence for Angiogenic and Metabolic Signaling Pathways in Endothelial Cells
Fatty Acid-binding Protein 4, a Point of Convergence for Angiogenic and Metabolic Signaling Pathways in Endothelial Cells
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DOI：
10.1074/jbc.m114.576512
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发表时间：
2014-08-15
影响因子：
4.8
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
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作者：
Harjes, Ulrike;Bridges, Esther;Harris, Adrian L.
脂肪酸结合蛋白4（FABP 4）是一种脂肪形成蛋白，与动脉粥样硬化、胰岛素抵抗和癌症有关。在内皮细胞中，FABP 4由VEGFA诱导，并且FABP 4的抑制阻断了大多数VEGFA作用。我们研究了DLL 4-NOTCH依赖性调节FABP 4在人脐静脉内皮细胞的基因/蛋白表达和相互作用分析抑制剂治疗和RNA干扰。我们发现FABP 4直接由NOTCH诱导。用人重组DLL 4刺激NOTCH信号传导导致FABP 4诱导，独立于VEGFA。通过阻断DLL 4与NOTCH的结合或抑制NOTCH信号转导来降低VEGFA对FABP 4的诱导。染色质免疫沉淀的NOTCH细胞内结构域显示增加的结合到两个特定区域的FABP 4启动子。FABP 4基因表达的诱导依赖于转录因子FOXO 1，其对于FABP 4的基础表达是必需的，并且FABP 4在VEGFA和/或NOTCH途径刺激后上调。因此，我们表明DLL 4-NOTCH通路介导内皮FABP 4表达。这表明血管生成限制性DLL 4-NOTCH的诱导可以通过该途径具有促血管生成作用。它还提供了DLL 4-NOTCH和FOXO 1介导的内皮基因转录调节之间的联系，并且它表明DLL 4-NOTCH是内皮细胞中促血管生成和代谢信号传导整合的节点。这可能对于肿瘤环境中的血管生成至关重要。
Fatty acid-binding protein 4 (FABP4) is an adipogenic protein and is implicated in atherosclerosis, insulin resistance, and cancer. In endothelial cells, FABP4 is induced by VEGFA, and inhibition of FABP4 blocks most of the VEGFA effects. We investigated the DLL4-NOTCH-dependent regulation of FABP4 in human umbilical vein endothelial cells by gene/protein expression and interaction analyses following inhibitor treatment and RNA interference. We found that FABP4 is directly induced by NOTCH. Stimulation of NOTCH signaling with human recombinant DLL4 led to FABP4 induction, independently of VEGFA. FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH or inhibition of NOTCH signal transduction. Chromatin immunoprecipitation of the NOTCH intracellular domain showed increased binding to two specific regions in the FABP4 promoter. The induction of FABP4 gene expression was dependent on the transcription factor FOXO1, which was essential for basal expression of FABP4, and FABP4 up-regulation following stimulation of the VEGFA and/or the NOTCH pathway. Thus, we show that the DLL4-NOTCH pathway mediates endothelial FABP4 expression. This indicates that induction of the angiogenesis-restricting DLL4-NOTCH can have pro-angiogenic effects via this pathway. It also provides a link between DLL4-NOTCH and FOXO1-mediated regulation of endothelial gene transcription, and it shows that DLL4-NOTCH is a nodal point in the integration of pro-angiogenic and metabolic signaling in endothelial cells. This may be crucial for angiogenesis in the tumor environment.