Dynamic repression by BCL6 controls the genome-wide liver response to fasting and steatosis

Transcription is tightly regulated to maintain energy homeostasis during periods of feeding or fasting, but the molecular factors that control these alternating gene programs are incompletely understood. Here, we find that the B cell lymphoma 6 (BCL6) repressor is enriched in the fed state and converges genome-wide with PPARα to potently suppress the induction of fasting transcription. Deletion of hepatocyte Bcl6 enhances lipid catabolism and ameliorates high-fat-diet-induced steatosis. In Ppara-null mice, hepatocyte Bcl6 ablation restores enhancer activity at PPARα-dependent genes and overcomes defective fasting-induced fatty acid oxidation and lipid accumulation. Together, these findings identify BCL6 as a negative regulator of oxidative metabolism and reveal that alternating recruitment of repressive and activating transcription factors to shared cis-regulatory regions dictates hepatic lipid handling.