Concerted Actions of FoxO1 and Pparα in hepatic gene expression and metabolic adaptation

Several transcription factors regulate the fasting response in the liver. They include FoxO1 and 3, cAMP response element binding protein (CREB), CCAAT enhancer-binding proteins (CEBP α/ β), glucocorticoid receptor (GR), Pparα, FoxA2, HNF4α, and many others. Previous genome-wide chromatin occupancy studies demonstrated an unexpected overlap of FoxO1 and PPARα DNA binding sites at active intergenic and intron enhancers, where approximately half of FoxO1 sites are shared with PPARα. However, the functional significance of these findings remains unknown. To address this gap in knowledge, we performed molecular interaction analyses of these two transcription factors and generated a combined hepatocyte-specific ablation of the respective genes. We found a concerted regulation of genes involved in glucose metabolism, with additive effects on in vivo tests of glucose tolerance. The data reveal a heretofore unexplored functional relay of two critical transcriptional networks in liver metabolism.