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

Hiromitsu Araki, Yoshinori Tamada, Seiya Imoto, Ben Dunmore, Deborah Sanders, Sally Humphrey, Masao Nagasaki, Atsushi Doi, Yukiko Nakanishi, Kaori Yasuda, Yuki Tomiyasu, Kousuke Tashiro, Cristin Print, D. Stephen Charnock-Jones, Satoru Kuhara, Satoru Miyano

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)221-229
Number of pages9
JournalAngiogenesis
Volume12
Issue number3
DOIs
Publication statusPublished - Sep 2009

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

Fingerprint Dive into the research topics of 'Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells'. Together they form a unique fingerprint.

  • Cite this

    Araki, H., Tamada, Y., Imoto, S., Dunmore, B., Sanders, D., Humphrey, S., Nagasaki, M., Doi, A., Nakanishi, Y., Yasuda, K., Tomiyasu, Y., Tashiro, K., Print, C., Charnock-Jones, D. S., Kuhara, S., & Miyano, S. (2009). Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells. Angiogenesis, 12(3), 221-229. https://doi.org/10.1007/s10456-009-9142-8