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  3. Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration

Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration

  • Dev Cell. 2024 Jul 16:S1534-5807(24)00398-8. doi: 10.1016/j.devcel.2024.06.020.
Xiaoxin Guo 1,  Juanyu Zhou 2,  La Yan 2,  Xingzhu Liu 2,  Yu Yuan 2,  Jinbao Ye 2,  Zehong Zhang 2,  Haiou Chen 2,  Yongxin Ma 3,  Zhendong Zhong 4,  Guanzheng Luo 4,  Haiyang Chen 5
Affiliations

Affiliations

  • 1 West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, National Clinical Research Center for Geriatrics and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China.
  • 2 West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, National Clinical Research Center for Geriatrics and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Department of Medical Genetics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, China.
  • 4 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 5 West China Centre of Excellence for Pancreatitis and Laboratory of Stem Cell and Anti-Aging Research, National Clinical Research Center for Geriatrics and State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: chenhy82@scu.edu.cn.
PMID: 39047737 DOI: 10.1016/j.devcel.2024.06.020
Abstract

Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.

Keywords

VLCFAs; feedback regulation; gut regeneration; intestinal stem cell; peroxisome dynamics.

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