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Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells

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Abstract

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 PPARα 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 PPARα-independent manner. In order to identify PPARα-dependently and PPARα-independently regulated transcripts, we generated microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARα. We also constructed dynamic Bayesian transcriptome networks to reveal PPARα-dependent and -independent pathways. Our transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARα-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARα-independent master-regulator of fenofibrate action in human endothelial cells.

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Acknowledgments

The authors would like to thank two reviewers for their constructive comments and suggestions. Computation time was provided by the Super Computer System, Human Genome Center, Institute of Medical Science, University of Tokyo.

Author information

Author notes

  1. Atsushi Doi, Yukiko Nakanishi, Kaori Yasuda & Yuki Tomiyasu

    Present address: Cell Innovator Inc., 6-10-1 Hakozaki Higashi-ku, Fukuoka, 812-8581, Japan

Authors and Affiliations

  1. Systems Pharmacology Research Institute, GNI Ltd, Fukuoka, Japan

    Hiromitsu Araki, Atsushi Doi, Yukiko Nakanishi, Kaori Yasuda & Yuki Tomiyasu

  2. Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yoshinori Tamada, Seiya Imoto, Masao Nagasaki & Satoru Miyano

  3. Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK

    Ben Dunmore, Deborah Sanders, Sally Humphrey & D. Stephen Charnock-Jones

  4. Cambridge National Institute for Health Research Biomedical Research Centre, Cambridge, UK

    D. Stephen Charnock-Jones

  5. Graduate School of Genetic Resources Technology, Kyushu University, Fukuoka, Japan

    Kousuke Tashiro & Satoru Kuhara

  6. Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand

    Cristin Print

  7. Cell Innovator Inc., 6-10-1 Hakozaki Higashi-ku, Fukuoka, 812-8581, Japan

    Hiromitsu Araki

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  1. Hiromitsu Araki
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Corresponding author

Correspondence to Hiromitsu Araki.

Additional information

Hiromitsu Araki, Yoshinori Tamada and Seiya Imoto equally contributed to this work.

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Araki, H., Tamada, Y., Imoto, S. et al. Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells. Angiogenesis 12, 221–229 (2009). https://doi.org/10.1007/s10456-009-9142-8

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