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

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 (LXRa) which directly binds and activates lipogenic enhancers. These findings unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot. Overall design: Males, 8 weeks-old mice (C57BL/6J) were randomly assigned to either group (6 mice per group). The experiment started after 1 week of acclimation. The Adlib group had ad libitum access to food (Teklad TD2018) and water throughout the experiment. For the rest of the groups, food was removed at the beginning of the inactive phase (shortly after lights on, zeitgeber time 1). For the Refed groups, food was put back in the cage 24 h later while the fasted group was anesthetized and euthanized. The Refed groups were euthanized 3 h, 10 h and 24 h after food reintroduction. At each group endpoint, mice were anesthetized and euthanized (ketamine:xylazine 30:6 mg/ml) and the liver was excised.