Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
PLoS Biol. 2024 Sep 6;22(9):e3002735. doi: 10.1371/journal.pbio.3002735. eCollection 2024 Sep.
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.
哺乳动物在进食和禁食状态之间转换是很常见的。肝脏通过转录调控能量使用和储存的代谢途径来协调对进食/禁食的适应性反应。进食停止（重新进食）后的转录和增强子动态尚未被探索。我们研究了在重新进食时在小鼠中发生的转录和染色质事件，包括动力学行为和分子驱动因素。我们发现，重新进食反应具有时间组织性，早期反应集中在提高蛋白质翻译的速度，而重新进食的后期阶段则推动分叉的脂质合成程序。虽然在禁食期间胆固醇生物合成和脂肪生成途径都受到抑制，但大多数胆固醇生物合成基因在重新进食时恢复到基础水平，而大多数脂肪生成基因明显超过禁食前的水平。基因敲除、增强子动力学和 ChIP-seq 分析表明，脂肪生成基因的过表达是由 LXRα 决定的。这些来自无偏分析的发现揭示了长期以来已知的重新进食脂肪过冲现象背后的机制。
