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

Angiogenesis. 2009;12(3):221-9. doi: 10.1007/s10456-009-9142-8. Epub 2009 Apr 9.


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

MeSH terms

  • Algorithms
  • Cells, Cultured
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Fenofibrate / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Gene Knockdown Techniques
  • Growth Differentiation Factor 15 / genetics
  • Growth Differentiation Factor 15 / metabolism
  • Growth Differentiation Factor 15 / physiology
  • Humans
  • Hypolipidemic Agents / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • PPAR alpha / antagonists & inhibitors
  • PPAR alpha / genetics
  • PPAR alpha / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Time Factors
  • Transcriptional Activation / drug effects


  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Hypolipidemic Agents
  • PPAR alpha
  • RNA, Messenger
  • RNA, Small Interfering
  • Fenofibrate