title: Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha.
abstract: Peroxisome-proliferator-activated receptor (PPAR) gamma co-activator 1 alpha (PGC-1 alpha/PPARGC1) plays an important role in energy metabolism by co-ordinating transcriptional programmes of mitochondrial biogenesis, adaptive thermogenesis and fatty acid beta-oxidation. PGC-1 alpha has also been identified to play a role in the intermediary metabolism by co-activating key transcription factors of hepatic gluconeogenesis and glucose uptake in muscles. In the present study, we show that PGC-1 alpha serves as a co-activator for the liver X receptor (LXR) alpha, known to contribute to the regulation of cellular cholesterol homoeostasis. In transient transfection studies, PGC-1 alpha amplified the LXR-mediated autoregulation of the LXR alpha promoter in a human brown adipocyte line and in 3T3-L1 cells via an LXR response element described previously. LXR-mediated transactivation via a natural LXR response element from the cholesteryl ester transfer-protein gene promoter was also enhanced by PGC-1 alpha in a ligand-dependent manner. Mutational analysis showed that the LXXLL signature motif (L2) of PGC-1 alpha was essential for co-activation of LXR-mediated transcriptional responses. This motif is located in the vicinity of the binding region for a putative repressor described previously. The repressor sequesters PGC-1 alpha from PPAR alpha and the glucocorticoid receptor, and this repressor did not interfere with PGC-1 alpha-mediated co-activation of LXR-dependent gene transcription. Moreover, inhibition of p38 mitogen-activated protein kinase signalling, shown to abolish the co-activation of PPAR alpha by PGC-1 alpha, had only a moderate inhibitory effect on the co-activation of LXR. These results identify PGC-1 alpha as a bona fide LXR co-activator and implicate distinct interfaces of PGC-1 alpha and/or additional cofactors in the modulation of LXR and PPAR alpha transcriptional activities.
authors.affiliation: Department of Laboratory Medicine, Landeskliniken Salzburg, A-5020 Salzburg, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Oberkofler
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schraml
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole