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A more recent version of this article appeared on March 1, 2004

Papers In Press, published online ahead of print December 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300239-JLR200
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Submitted on June 6, 2003
Revised on December 1, 2003
Accepted on December 8, 2003

Prediction of PPAR-alpha ligand-mediated physiological changes using gene expression profiles

Klaus Stensgaard Frederiksen, Erik Max Wulff, Per Sauerberg, John Patrick Mogensen, Lone Jeppesen, and Jan Fleckner

Molecular Genetics, Novo Nordisk A/S, Bagsvaerd DK-2880

Corresponding Author: ksf{at}novonordisk.com

Peroxisome proliferator-activated receptor (PPAR)-a controls the transcription of a variety of genes involved in lipid metabolism and is the target receptor for the hypolipidemic drug-class of fibrates. In the present study the molecular and physiological effects of seven different PPAR activating drugs have been examined in a rodent model of dyslipidemia. The drugs examined were selected to display varying potencies and efficacies towards PPARa. To help elucidate the link between the gene regulation elicited by PPARa ligands and the concomitant physiological changes, we have used cDNA microarray analysis to identify smaller gene sets that are predictive of the function of these ligands. A number of genes showed strong correlations to the relative PPARa efficacy of the drugs. Furthermore, using multi variate analysis a strong relationship between the drug induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.


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