Metabolic disruption exacerbates intestinal damage during sleep deprivation by abolishing HIF1α-mediated repair

  • Cell Rep. 2024 Nov 10;43(11):114915. doi: 10.1016/j.celrep.2024.114915.
Hai-Yi Zhang  1 ,  Ya-Qing Shu  2 ,  Yan Li  1 ,  Ya-Lin Hu  1 ,  Zhi-Hong Wu  1 ,  Zhi-Peng Li  1 ,  Yao Deng  1 ,  Zi-Jian Zheng  1 ,  Xiao-Jing Zhang  1 ,  Liu-Fei Gong  1 ,  Yang Luo  1 ,  Xiao-Yu Wang  1 ,  Hong-Ping Li  3 ,  Xiao-Ping Liao  1 ,  Gong Li  1 ,  Hao Ren  1 ,  Wei Qiu  4 ,  Jian Sun  5
Affiliations
  • 1. State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China; National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • 2. The Third Affiliated Hospital of Sun Yat-sen University, Department of Neurology, Guangzhou, China.
  • 3. Shenzhen Children's Hospital, Shenzhen, China.
  • 4. The Third Affiliated Hospital of Sun Yat-sen University, Department of Neurology, Guangzhou, China. Electronic address: [email protected].
  • 5. State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China; Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China; National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China. Electronic address: [email protected].
PMID: 39527478 DOI: 10.1016/j.celrep.2024.114915
Abstract

Sleep deprivation (SD) has been reported to induce intestinal damage by several mechanisms, yet its role in modulating epithelial repair remains unclear. In this study, we find that chronic SD leads to colonic damage through continuous hypoxia. However, HIF1α, which generally responds to hypoxia to modulate barrier integrity, was paradoxically dysregulated in the colon. Further investigation revealed that a metabolic disruption during SD causes accumulation of α-ketoglutarate in the colon. The excessive α-ketoglutarate degrades HIF1α protein through PHD2 (prolyl hydroxylase 2) to abolish the intestinal repair functions of HIF1α. Collectively, these findings provide insights into how SD can exacerbate intestinal damage by fine-tuning metabolism to abolish HIF1α-mediated repair.

Keywords
CP: Metabolism; CP: Neuroscience; HIF1α; PHD2; intestinal barrier repairing; metabolic dysfunction; sleep deprivation; α-ketoglutarate.
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