Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor γ co-activator 1α

Peroxisome-proliferator-activated receptor (PPAR) gamma co-activator 1alpha (PGC-1alpha/PPARGC1) plays an important role in energy metabolism by co-ordinating transcriptional programmes of mitochondrial biogenesis, adaptive thermogenesis and fatty acid beta-oxidation. PGC-1alpha 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-1alpha 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-1alpha amplified the LXR-mediated autoregulation of the LXRalpha 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-1alpha in a ligand-dependent manner. Mutational analysis showed that the LXXLL signature motif (L2) of PGC-1alpha was essential for coactivation 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-1alpha from PPARalpha and the glucocorticoid receptor, and this repressor did not interfere with PGC-1alpha-mediated co-activation of LXR-dependent gene transcription. Moreover, inhibition of p38 mitogen-activated protein kinase signalling, shown to abolish the co-activation of PPARalpha by PGC-1alpha, had only a moderate inhibitory effect on the co-activation of LXR. These results identify PGC-1alpha as a bona fide LXR co-activator and implicate distinct interfaces of PGC-1alpha and/or additional cofactors in the modulation of LXR and PPARalpha transcriptional activities.