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Journal of Lipid Research, Vol. 45, 592-601, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Methods

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

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

^* Department of Molecular Genetics, Novo Nordisk A/S, DK-2880 Bagsværd, Denmark
Departments of Pharmacological Research 2, Novo Nordisk Park, DK-2760 Måløv, Denmark
Medicinal Chemistry Research III, Novo Nordisk Park, DK-2760 Måløv, Denmark

To whom correspondence should be addressed. e-mail: ksf{at}novonordisk.com

Peroxisome proliferator-activated receptor (PPAR)- 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 toward PPAR-. To help elucidate the link between the gene regulation elicited by PPAR- 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 PPAR- efficacy of the drugs. Furthermore, using multivariate analysis, a strong relationship between the drug-induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.

Abbreviations: ACBP, acyl-CoA binding protein (diazepam binding inhibitor); apoC-III, apolipoprotein C-III; bifunctional enzyme, peroxisomal enoyl-CoA:hydrotase-3-hydroxyacyl-CoA bifunctional enzyme; Cyp4A10, cytochrome P450 4A10; HCD, high-cholesterol diet; PLS, partial least-squares projection to latent structures; PPAR, peroxisome proliferator-activated receptor

Supplementary key words dyslipidemia • pharmacodynamics • peroxisome proliferator-activated receptor- in vivo activation • transcriptional profiling

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