Oberkofler Hannes, Schraml Elisabeth, Krempler Franz, Patsch Wolfgang
Department of Laboratory Medicine, Landeskliniken Salzburg, A-5020 Salzburg, Austria.
Biochem J. 2003 Apr 1;371(Pt 1):89-96. doi: 10.1042/BJ20021665.
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.
过氧化物酶体增殖物激活受体（PPAR）γ共激活因子1α（PGC-1α/PPARGC1）通过协调线粒体生物发生、适应性产热和脂肪酸β氧化的转录程序，在能量代谢中发挥重要作用。PGC-1α还被确定通过共激活肝脏糖异生和肌肉葡萄糖摄取的关键转录因子，在中间代谢中发挥作用。在本研究中，我们表明PGC-1α作为肝脏X受体（LXR）α的共激活因子，已知其有助于调节细胞胆固醇稳态。在瞬时转染研究中，PGC-1α通过先前描述的LXR反应元件，在人棕色脂肪细胞系和3T3-L1细胞中增强了LXR介导的LXRα启动子的自调节。PGC-1α还以配体依赖的方式增强了通过胆固醇酯转移蛋白基因启动子的天然LXR反应元件介导的LXR反式激活。突变分析表明，PGC-1α的LXXLL基序（L2）对于LXR介导的转录反应的共激活至关重要。该基序位于先前描述的假定阻遏物结合区域附近。该阻遏物将PGC-1α与PPARα和糖皮质激素受体隔离，并且该阻遏物不干扰PGC-1α介导的LXR依赖性基因转录的共激活。此外，抑制p38丝裂原活化蛋白激酶信号传导（已证明可消除PGC-1α对PPARα的共激活）对LXR的共激活仅具有中等抑制作用。这些结果确定PGC-1α为真正的LXR共激活因子，并暗示PGC-1α的不同界面和/或其他辅助因子参与调节LXR和PPARα的转录活性。
