Concerted Actions of FoxO1 and Ppara 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 a/ ß), glucocorticoid receptor (GR), Ppara, FoxA2, HNF4a, and many others. Previous genome-wide chromatin occupancy studies demonstrated an unexpected overlap of FoxO1 and PPARa DNA binding sites at active intergenic and intron enhancers, where approximately half of FoxO1 sites are shared with PPARa. 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. Overall design: mRNA profiles of liver tissues from liver specific FoxO1 and/or PPARa knockout mice during 4h fasted. For constitutive liver-specific FoxO1 knockouts, we crossed FoxO1lox/lox or PPARa lox/lox and Albumin-cre transgenic mice. We also collected the samples after 3 weeks high-fat diet feeding.