Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor α, retinoid X receptor, and liver X receptor in mouse liver

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor alpha (PPARalpha) 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 PPARalpha, 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 PPARalpha-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 LXRalpha/LXRbeta-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 PPARalpha. Remarkably, similar to80% of genes regulated by AGN194,204 required PPARalpha including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPARalpha-dependent and -independent components. Overlaps of similar to31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPARalpha and LXRalpha/LXRbeta for statistical significance. 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 PPARalpha and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPARalpha in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPARalpha-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.