 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Nov 25, 2008 |
| Title |
Molecular characterization of novel peroxisome proliferator-activated receptor alpha agonists |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist.
Keywords: acute versus chronic treatment of piperidine PPARalpha agonists
|
| |
|
| Overall design |
Male C57Bl/6 mice (n=4 for all except 5 day treatment of 146-02 was n=2) were treated with the piperidine agonists for 24hr or 5 days at 1mg/kg/day, or water (vehicle) as control.
|
| |
|
| Contributor(s) |
Kane CD, Stevens KA, Fischer JE, Haghpassand M, Royer L, Aldinger C, Landschulz KT, Zagouras P, Bagley SW, Hada W, Dullea R, Hayward CM, Francone OL |
| Citation(s) |
18971326 |
| |
| Submission date |
Jul 17, 2008 |
| Last update date |
Feb 18, 2018 |
| Contact name |
James E Fischer |
| E-mail(s) |
[email protected]
|
| Phone |
(860) 715-0704
|
| Organization name |
Pfizer, Inc
|
| Department |
Exploratory Medicinal Sciences
|
| Lab |
Dullea Lab
|
| Street address |
M/S 8118D-3036
|
| City |
Groton |
| State/province |
CT |
| ZIP/Postal code |
06340 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL81 |
[MG_U74Av2] Affymetrix Murine Genome U74A Version 2 Array |
|
| Samples (30)
|
|
| Relations |
| BioProject |
PRJNA113757 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE12147_RAW.tar |
83.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...