Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou City, Henan 450001, China.
J Mol Biol. 2012 Jan 6;415(1):143-58. doi: 10.1016/j.jmb.2011.11.011. Epub 2011 Nov 12.
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that regulates energy metabolism, but its precise mechanisms remain unknown. Here, we demonstrate that the PPARα agonist fenofibrate activated expression of the glucose transporter Glut4. Moreover, PPARα was associated with the Glut4 promoter through GATA sites upon fenofibrate stimulation in cardiomyocytes. This occupancy is achieved through an interaction between amino acids 1-136 of PPARα with amino acids 276-443 of the cardiac transcription factor GATA-6. In addition, the interaction of PPARα with GATA-6 activated Glut4 gene expression, improved glucose consumption, and enhanced activity of mitochondrial citrate synthase in C2C12 myoblasts; both mutants of PPARα (1-101 aa) and GATA-6 (227-331 aa) were unable to cooperate in Glut4 activation. Thus, GATA-6 is an important component of the transcription network required for energy metabolism mediated by PPARα, and these findings provide a molecular basis for understanding the role of GATA-6 proteins in muscle development and disease.
过氧化物酶体增殖物激活受体α（PPARα）是一种核激素受体，可调节能量代谢，但确切的机制尚不清楚。在这里，我们证明 PPARα 激动剂非诺贝特可激活葡萄糖转运蛋白 Glut4 的表达。此外，在心肌细胞中，非诺贝特刺激后，PPARα 通过 GATA 位点与 Glut4 启动子结合。这种占据是通过 PPARα 的氨基酸 1-136 与心脏转录因子 GATA-6 的氨基酸 276-443 之间的相互作用实现的。此外，PPARα 与 GATA-6 的相互作用可激活 Glut4 基因表达，增加葡萄糖消耗，并增强 C2C12 成肌细胞中线粒体柠檬酸合酶的活性；PPARα（1-101 aa）和 GATA-6（227-331 aa）的突变体均无法在 Glut4 激活中发挥作用。因此，GATA-6 是由 PPARα 介导的能量代谢所需的转录网络的重要组成部分，这些发现为理解 GATA-6 蛋白在肌肉发育和疾病中的作用提供了分子基础。
