Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells
Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells
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DOI：
10.1007/s10456-009-9142-8
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发表时间：
2009-09-01
期刊：
影响因子：
9.8
通讯作者：
Miyano, Satoru
中科院分区：
文献类型：
--
作者：
Araki, Hiromitsu;Tamada, Yoshinori;Miyano, Satoru
非诺贝特是核受体过氧化物酶体增殖物激活受体（PPAR）α的合成配体，由于其降脂作用，已广泛用于治疗代谢紊乱，尤其是高血压。降脂的分子机制相对明确：激活的PPAR α形成PPAR-RXR异二聚体，通过与启动子区的PPAR反应元件结合，调节参与能量代谢的基因的转录，即所谓的“反式激活”。此外，非诺贝特对血管内皮细胞和平滑肌细胞也有抗炎和抗动脉粥样硬化作用。我们对非诺贝特的抗炎机制了解有限;然而，抑制炎性细胞因子和粘附分子产生的“反式阻遏”可能有助于该机制。此外，有报道称非诺贝特以不依赖于PPAR α的方式影响内皮细胞。为了鉴定PPAR α依赖性和PPAR α独立性调节的转录本，我们从用非诺贝特处理的人内皮细胞中产生了微阵列数据，以及有和没有siRNA介导的PPAR α敲低。我们还构建了动态贝叶斯转录组网络，以揭示PPAR α依赖性和非依赖性途径。我们的转录组网络分析确定了生长分化因子15（GDF 15）作为一个枢纽基因，具有PPAR α独立调节的转录本作为其直接下游的孩子。这一结果表明，GDF 15可能是非诺贝特在人内皮细胞中作用的非依赖于PPAR α的主调节因子。
Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPAR alpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. We have limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPAR alpha-independent manner. In order to identify PPAR alpha-dependently and PPAR alpha-independently regulated transcripts, we generated microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPAR alpha. We also constructed dynamic Bayesian transcriptome networks to reveal PPAR alpha-dependent and -independent pathways. Our transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPAR alpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPAR alpha-independent master-regulator of fenofibrate action in human endothelial cells.