Liver X receptor controls a bifurcated transcriptional program where lipogenesis genes overshoot upon refeeding while cholesterol biosynthesis genes return to pre-fasting levels [lxr_chip]

Transitions from a fed to a fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) were never explored. We aimed to inspect the transcriptional and chromatin events occurring upon refeeding, their kinetic behavior and their molecular drivers. We found that the refeeding response is temporally-organized with an early response focused on ramping up protein translation while later stages of refeeding drive a bifurcated lipid synthesis program. While both lipid synthesis pathways were inhibited during fasting, cholesterol biosynthesis genes returned to their basal levels upon refeeding while lipogenesis genes significantly overshoot above pre-fasting levels. Lipogenic gene overshoot is dictated by Liver X Receptor alpha (LXRα) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot. ChIP-Seq floxed mice fasted for 24h followed by refeeding of 24h and LXR dko mice fasted for 24h followed by refeeding of 24h