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, Retinoid X Receptor, and Liver X Receptor in Mouse Liver
Investigative Toxicology and Pathology Group, Safety Assessment, GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina (S.A.P, L.Y.); Division of Biological Science, CIIT Centers for Health Research, Research Triangle Park, North Carolina (C.D., A.L., C.S., J.C.C.); Department of Internal Medicine III, University of Vienna, and Center of Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria (T.M.S.); Departments of BioSciences and Medical Nutrition, Novum, Karolinska Institute, Huddinge, Sweden (K.R.S., J.-Å.G.); Departments of Chemistry and Biology, Retinoid Research, Allergan Inc., Irvine, California (R.A.S.C.); and ToxicoGenomics, Chapel Hill, North Carolina (J.C.C.)
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 nuclear receptors, transcript profiles were generated from the livers of wild-type and PPAR-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 LXR/LXR
-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 PPAR. Remarkably, 
80% of genes regulated by AGN194,204 required PPAR including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPAR-dependent and -independent components. Overlaps of 31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPAR and LXR/LXR 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 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 PPAR-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.
Address correspondence to: Dr. J. Christopher Corton, ToxicoGenomics, 209 Silver Creek Trail, Chapel Hill, NC 27514. E-mail: ccorton{at}msn.com
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