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 language | English |
|---|---|
| Pages (from-to) | 221-229 |
| Number of pages | 9 |
| Journal | Angiogenesis |
| Volume | 12 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Sep 1 2009 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Clinical Biochemistry
- Cancer Research
Cite this
Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cells. / Araki, Hiromitsu; Tamada, Yoshinori; Imoto, Seiya; Dunmore, Ben; Sanders, Deborah; Humphrey, Sally; Nagasaki, Masao; Doi, Atsushi; Nakanishi, Yukiko; Yasuda, Kaori; Tomiyasu, Yuki; Tashiro, Kousuke; Print, Cristin; Charnock-Jones, D. Stephen; Kuhara, Satoru; Miyano, Satoru.
In: Angiogenesis, Vol. 12, No. 3, 01.09.2009, p. 221-229.Research output: Contribution to journal › Article
}
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
PY - 2009/9/1
Y1 - 2009/9/1
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.
UR - http://www.scopus.com/inward/record.url?scp=70349510747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349510747&partnerID=8YFLogxK
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 -