Transcription Factor GATA-6 Recruits PPARα to Cooperatively Activate Glut4 Gene Expression

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear hormone receptor that regulates energy metabolism, but its precise mechanisms remain unknown. Here, we demonstrate that the PPAR alpha agonist fenofibrate activated expression of the glucose transporter Glut4. Moreover, PPAR alpha 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 PPAR alpha with amino acids 276-443 of the cardiac transcription factor GATA-6. In addition, the interaction of PPAR alpha with GATA-6 activated Glut4 gene expression, improved glucose consumption, and enhanced activity of mitochondrial citrate synthase in C2C12 myoblasts; both mutants of PPAR alpha (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 PPAR alpha, and these findings provide a molecular basis for understanding the role of GATA-6 proteins in muscle development and disease. (C) 2011 Elsevier Ltd. All rights reserved.