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

IF 10.7 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2024-07-23 DOI:10.1016/j.devcel.2024.06.020

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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.

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肠道再生过程中，极长链脂肪酸通过肠道干细胞的反馈回路控制过氧物酶体动力学

过氧物酶体动力学对肠干细胞（ISC）分化和肠道再生至关重要。然而，肠道再生过程中支配肠干细胞内过氧物酶体动态的确切机制仍然未知。利用小鼠结肠炎和果蝇肠道模型，我们发现了一种涉及过氧化物酶体增殖激活受体（PPARs）和SOX21转录因子的负反馈控制机制。这种反馈机制能有效调节肠道再生过程中过氧化物酶体的丰度。肠道损伤后，释放的游离超长链脂肪酸（VLCFAs）通过刺激 PPARs-PEX11s 信号，增加过氧物酶体的丰度。PPARs 的作用是刺激过氧化物酶体裂变并抑制pexophagy。在 ISC 分化过程中，作用于过氧物酶体下游的 SOX21 在抑制 PPAR 表达的同时，通过吞噬作用诱导过氧物酶体消亡。因此，PPAR 和 SOX21 构成了一个调节过氧化物酶体动态的微调负反馈环。这些发现揭示了 ISC 中过氧物酶体调控的复杂分子机制，有助于我们了解肠道更新和修复。

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来源期刊

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.