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Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles
Klaus Stensgaard Frederiksen1, Erik Max Wulff, Per Sauerberg
1Department of Molecular Genetics, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark. ksf@novonordisk.com
Journal of Lipid Research
|March 5, 2004
Summary
Peroxisome proliferator-activated receptor (PPAR)-alpha ligands, like fibrates, impact lipid metabolism. This study links PPAR-alpha gene regulation to triglyceride-lowering effects in dyslipidemia models.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Peroxisome proliferator-activated receptor (PPAR)-alpha regulates lipid metabolism genes.
- PPAR-alpha is the target for hypolipidemic fibrate drugs.
Purpose of the Study:
- To investigate the molecular and physiological effects of seven PPAR-activating drugs.
- To link gene regulation by PPAR-alpha ligands to physiological changes.
Main Methods:
- Utilized a rodent model of dyslipidemia.
- Employed cDNA microarray analysis to identify predictive gene sets.
- Performed multivariate analysis to correlate transcriptional profiles with drug effects.
Main Results:
- Identified genes strongly correlated with PPAR-alpha efficacy.
- Found a significant relationship between drug-induced triglyceride lowering and transcriptional profiles.
Conclusions:
- PPAR-alpha ligands modulate lipid metabolism through specific gene expression patterns.
- Transcriptional profiles can predict the triglyceride-lowering efficacy of PPAR-alpha activators.