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  • Title: Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha.
    Author: Oberkofler H, Schraml E, Krempler F, Patsch W.
    Journal: Biochem J; 2003 Apr 01; 371(Pt 1):89-96. PubMed ID: 12470296.
    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.
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