LXR-dependent enhancer activation regulates the temporal organization of the liver's response to refeeding leading to lipogenic gene overshoot.
Noga KorenfeldTali GorbonosMaria C Romero FlorianDan RotaroDana GoldbergTalia Radushkevitz-FrishmanMeital Charni-NatanMeirav Bar-ShimonCarolyn L CumminsIdo GoldsteinPublished in: PLoS biology (2024)
Transitions between the fed and 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) have not been explored. We examined the transcriptional and chromatin events occurring upon refeeding in mice, including kinetic behavior and molecular drivers. We found that the refeeding response is temporally organized with the early response focused on ramping up protein translation while the later stages of refeeding drive a bifurcated lipid synthesis program. While both the cholesterol biosynthesis and lipogenesis pathways were inhibited during fasting, most cholesterol biosynthesis genes returned to their basal levels upon refeeding while most lipogenesis genes markedly overshoot above pre-fasting levels. Gene knockout, enhancer dynamics, and ChIP-seq analyses revealed that lipogenic gene overshoot is dictated by LXRα. These findings from unbiased analyses unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.
Keyphrases
- genome wide
- transcription factor
- genome wide identification
- blood glucose
- insulin resistance
- binding protein
- copy number
- gene expression
- dna methylation
- high fat diet induced
- single cell
- genome wide analysis
- type diabetes
- blood pressure
- low density lipoprotein
- high throughput
- metabolic syndrome
- circulating tumor cells
- single molecule
- skeletal muscle
- heat shock
- bioinformatics analysis
- heat stress