Mechanisms driving fasting-induced protection from genotoxic injury in the small intestine.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Kali Deans-Fielder, Timothy Wu, Thanh Nguyen, Sarah To, Yang-Zhe Huang, Steven J Bark, Jason C Mills, Noah F Shroyer
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引用次数: 0

Abstract

Genotoxic agents such as doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mechanistic target of rapamycin complex 1 (mTORC1) in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting after DXR prevented the mTORC1 spike and damage reduction. Surprisingly, the mTORC1 inhibitor, rapamycin, did not block fasting/refeeding-induced reduction in DNA damage, suggesting that increased mTORC1 is dispensable for protection against the initial DNA damage response. In Ddit4-/- mice [DDIT4 (DNA-damage-inducible transcript 4) functions to regulate mTORC1 activity], fasting reduced DNA damage and increased intestinal crypt viability vs. ad libitum-fed Ddit4-/- mice. Fasted/refed Ddit4-/- mice maintained body weight, with increased crypt proliferation by 5 days post-DXR, whereas ad libitum-fed Ddit4-/- mice continued to lose weight and displayed limited crypt proliferation. Genes encoding epithelial stem cell and DNA repair proteins were elevated in DXR-injured, fasted vs. ad libitum Ddit4-/- intestines. Thus, fasting strongly reduced intestinal damage when normal dynamic regulation of mTORC1 was lost. Overall, the results confirm that fasting protects the intestines against DXR and suggests that fasting works by pleiotropic - including both mTORC1-dependent and independent - mechanisms across the temporally dynamic injury response.NEW & NOTEWORTHY New findings are 1) DNA damage reduction following a 24-h fast depends on the timing of postfast refeeding in relation to chemotherapy initiation; 2) fasting/refeeding-induced upregulation of mTORC1 activity is not required for early (6 h) protection against DXR-induced DNA damage; and 3) fasting increases expression of intestinal stem cell and DNA damage repair genes, even when mTORC1 is dysregulated, highlighting fasting's crucial role in regulating mTORC1-dependent and independent mechanisms in the dynamic recovery process.

空腹诱导小肠免受基因毒性损伤的机制
多柔比星(DXR)等基因毒性药物会对肠道造成损害,而禁食可以减轻这种损害。禁食如何起到保护作用以及禁食和进食的最佳时机仍不清楚。在这里,我们对禁食/进食诱导的全局性肠道转录变化进行了分析,发现了新陈代谢的变化,并发现细胞能量中枢 mTORC1 与保护免受 DXR 诱导的 DNA 损伤有关。我们对肠道组织和组织提取物中的特定转录本和蛋白质进行的分析表明,在服用 DXR 时禁食后再进食可减少损伤,并导致 mTORC1 活性激增。然而,在服用 DXR 后继续禁食则会阻止 mTORC1 活性的飙升和损伤的减轻。令人惊讶的是,mTORC1抑制剂雷帕霉素并不能阻止禁食/进食诱导的DNA损伤减少,这表明mTORC1的增加对于保护DNA免受最初的损伤反应是不可或缺的。与自由进食的 Ddit4-/- 小鼠相比,在 Ddit4-/- 小鼠中(DDIT4 具有调节 mTORC1 活性的功能),禁食可减少 DNA 损伤并提高肠隐窝存活率。禁食/进食的 Ddit4-/- 小鼠体重保持不变,DXR 后 5 天隐窝增殖增加,而自由进食的 Ddit4-/- 小鼠体重持续下降,隐窝增殖有限。编码上皮干细胞和DNA修复蛋白的基因在DXR损伤的禁食肠道与Ddit4-/-禁食肠道中都有所升高。因此,当 mTORC1 失去正常动态调控时,禁食能有效减少肠道损伤。总之,研究结果证实了禁食能保护肠道免受 DXR 的伤害,并表明禁食是通过多效应(包括依赖于 mTORC1 和独立于 mTORC1 的机制)在时间动态损伤反应中发挥作用的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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