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

Abstract

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 lipidlowering is relatively well defined: an activated PPARa 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, fenofi- brate 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 PPARa-independent manner. In order to identify PPARa-dependently and PPARaindependently regulated transcripts, we generated microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knockdown of PPARa. We also constructed dynamic Bayesian transcriptome networks to reveal PPARa-dependent and - independent pathways. Our transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARa-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARa-independent masterregulator of fenofibrate action in human endothelial cells.