Received for publication July 28, 2004.
Revised September 9, 2004.
Accepted for publication September 14, 2004.

Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor , Retinoid X Receptor and Liver X Receptor in Mouse Liver

Abstract

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor (PPAR) and liver X receptor (LXR) through regulation of genes involved in fatty acid and cholesterol metabolism. Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPAR and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these NR, transcript profiles were generated from the livers of wild-type and PPARnull mice exposed to the RXR pan-agonist AGN194,204 or the PPAR pan-agonist, WY-14,643 (WY) and compared to the profiles from the livers of wild-type and LXR[alpha]/LXR-null mice after exposure to the LXR agonist T0901317. All 218 WY-regulated genes altered in wild-type mice required PPAR. Remarkably, ~80% of genes regulated by AGN194,204 required PPAR including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPAR[alpha]-dependent and -independent components. Overlaps of ~31-62% in the transcript profiles of WY, AGN194,204 and T0901317 required PPAR[alpha] and LXR[alpha]/LXR for statistical significance. Out of the 50 overlapping genes regulated by T0901317 and WY, all but one were regulated in a similar direction. These results 1) identify new transcriptional targets of PPAR and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPAR in regulation of gene expression by a prototypical PP and by an RXR agonist and 3) provide support for an axis of PPARRXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.

Key words: PPARs, Pharmacogenomic analyses, Regulation of gene expression, Regulation - transcriptional, Toxicant-induced gene express, Cholesterol metabolism/lipoproteins