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

Abstract

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor α (PPARα) 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 PPARα, and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these nuclear receptors, transcript profiles were generated from the livers of wild-type and PPARα-null mice exposed to the RXR pan-agonist 3,7-dimethyl-6S,7S-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]-2E,4E-heptadienoic acid (AGN194,204) or the PPAR pan-agonist WY-14,643 (WY; pirinixic acid) and compared with the profiles from the livers of wild-type and LXRα/LXRβ-null mice after exposure to the LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)phenyl] sulfonamide (T0901317). All 218 WY-regulated genes altered in wild-type mice required PPARα. Remarkably, ∼80% of genes regulated by AGN194,204 required PPARα including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPARα-dependent and -independent components. Overlaps of ∼31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPARα and LXRα/LXRβ for statistical significance. Ofthe 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 PPARα and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPARα in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPARα-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.