Peroxisome-proliferator-activated receptor (PPAR) γ co-activator 1α (PGC-1α/PPARGC1) plays an important role in energy metabolism by co-ordinating transcriptional programmes of mitochondrial biogenesis, adaptive thermogenesis and fatty acid β-oxidation. PGC-1α 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-1α serves as a co-activator for the liver X receptor (LXR) α, known to contribute to the regulation of cellular cholesterol homoeostasis. In transient transfection studies, PGC-1α amplified the LXR-mediated autoregulation of the LXRα 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-1α in a ligand-dependent manner. Mutational analysis showed that the LXXLL signature motif (L2) of PGC-1α 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-1α from PPARα and the glucocorticoid receptor, and this repressor did not interfere with PGC-1α-mediated co-activation of LXR-dependent gene transcription. Moreover, inhibition of p38 mitogen-activated protein kinase signalling, shown to abolish the co-activation of PPARα by PGC-1α, had only a moderate inhibitory effect on the co-activation of LXR. These results identify PGC-1α as a bona fide LXR co-activator and implicate distinct interfaces of PGC-1α and/or additional cofactors in the modulation of LXR and PPARα transcriptional activities.
- liver X receptor response element
- nuclear hormone receptor
- p38 mitogen-activated protein kinase
- transcriptional co-activator
Abbreviations used: ABC, ATP-binding cassette transporter; CETP, cholesteryl ester transfer protein; 9cRA, 9-cis-retinoic acid; EMSA, electrophoretic mobility-shift assay; GR, glucocorticoid receptor; 22(R)HC, 22(R)-hydroxycholesterol; LXR, liver X receptor; LXRE, LXR response element; MAPK, mitogen-activated protein kinase; PGC-1α, PPARγ co-activator 1α; PPAR, peroxisome-proliferator-activated receptor; RXR, retinoid X receptor; TK, thymidine kinase; UCP, uncoupling protein.
- The Biochemical Society, London ©2003