TY - JOUR
T1 - Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells
AU - Araki, Hiromitsu
AU - Tamada, Yoshinori
AU - Imoto, Seiya
AU - Dunmore, Ben
AU - Sanders, Deborah
AU - Humphrey, Sally
AU - Nagasaki, Masao
AU - Doi, Atsushi
AU - Nakanishi, Yukiko
AU - Yasuda, Kaori
AU - Tomiyasu, Yuki
AU - Tashiro, Kousuke
AU - Print, Cristin
AU - Charnock-Jones, D. Stephen
AU - Kuhara, Satoru
AU - Miyano, Satoru
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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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U2 - 10.1007/s10456-009-9142-8
DO - 10.1007/s10456-009-9142-8
M3 - Article
C2 - 19357976
AN - SCOPUS:70349510747
VL - 12
SP - 221
EP - 229
JO - Angiogenesis
JF - Angiogenesis
SN - 0969-6970
IS - 3
ER -