Concerted Actions of FoxO1 and PPARα in Hepatic Gene Expression and Metabolic Adaptation.

Several transcription factors regulate the fasting response in liver. They include FoxO1 and FoxO3, CREB, C/EBP α/β, glucocorticoid receptor (GR), peroxisome proliferator-activated receptor-α (PPARα), FoxA2, hepatocyte nuclear factor-α (HNF4α), and others. Genome-wide chromatin occupancy studies revealed an unexpected overlap of FoxO1 and PPARα DNA binding sites at active intergenic and intron enhancers, yet their functional significance remains unknown. To address this gap in knowledge, we conducted molecular interaction analyses of these transcription factors and generated combined hepatocyte-specific ablation of the respective genes. Integrated analysis of hepatic RNA sequencing from these mice by FoxO1 and PPARα chromatin immunoprecipitation sequencing revealed a concerted regulation of glucose metabolism, with additive effects on in vivo glucose tolerance. Synergistic effects on glycogenesis were observed when PPARα was ablated in the absence of FoxO1, particularly following a high-fat diet. Free fatty acids increased following FoxO1 and were normalized by PPARα ablation, while liver triglyceride content increased in PPARα knockouts and was normalized by FoxO1 ablation. The findings highlight a functional relay between FoxO1 and PPRAα, linking insulin signaling with hepatic lipid metabolism, and offer insight into potential therapeutic strategies for metabolic diseases. ARTICLE HIGHLIGHTS: FoxO1 and PPARα share significant DNA binding sites, regulating a coordinated transcriptional network in hepatic metabolism. FoxO1 and PPARα orchestrate distinct yet overlapping roles in gluconeogenesis and fatty acid/lipid metabolism. High-fat diet amplifies the metabolic interplay between FoxO1 and PPARα, with implications for insulin resistance management. Targeting the FoxO1-PPARα interplay offers novel strategies for treating selective insulin resistance and metabolic disorders.