Analysis of PPARalpha-dependent and PPARalpha-independent transcript regulation following fenofibrate treatment of human endothelial cells.
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.
Araki
Hiromitsu
H
Systems Pharmacology Research Institute, GNI Ltd, Fukuoka, Japan. hiromitsu_araki@cell-innovator.com
Tamada
Yoshinori
Y
Imoto
Seiya
S
Dunmore
Ben
B
Sanders
Deborah
D
Humphrey
Sally
S
Nagasaki
Masao
M
Doi
Atsushi
A
Nakanishi
Yukiko
Y
Yasuda
Kaori
K
Tomiyasu
Yuki
Y
Tashiro
Kousuke
K
Print
Cristin
C
Charnock-Jones
D Stephen
DS
Kuhara
Satoru
S
Miyano
Satoru
S
D000465:Algorithms; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects
C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011345:Fenofibrate