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Transcription factor GATA-6 recruits PPARα to cooperatively activate Glut4 gene expression

机译:转录因子GATA-6募集PPARα协同激活Glut4基因表达

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摘要

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.
机译:过氧化物酶体增殖物激活受体α(PPARα)是调节能量代谢的核激素受体,但其确切机制尚不清楚。在这里,我们证明了PPARα激动剂非诺贝特激活了葡萄糖转运蛋白Glut4的表达。此外,在非诺贝特刺激心肌细胞后,PPARα通过GATA位点与Glut4启动子相关。这种占有是通过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的相互作用激活了Glut4基因的表达,改善了葡萄糖的消耗,并增强了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)的两个突变体均不能在Glut4激活中协同作用。因此,GATA-6是由PPARα介导的能量代谢所必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。

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