Impact of fasting on intestinal stem cells and cancer

禁食对肠道干细胞和癌症的影响

• 批准号: 10238167
• 负责人: Omer Yilmaz
• 金额: $ 38.56万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238167
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; APC gene; Acetyl Coenzyme A; Affect; Agonist; Colon; Colon Carcinoma; Diet; Engineering; Enzymes; Fasting; Health; Health Promotion; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Injury; Intestinal Cancer; Intestinal Neoplasms; Intestines; Ketone Bodies; Ketones; LGR5 gene; Ligase; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Natural regeneration; Nonesterified Fatty Acids; Organoids; PPAR alpha; PPAR delta; Pathway interactions; Physiological; Process; Production; Regimen; Role; Secretory Cell; Signal Transduction; Small Intestines; Source; Testing; Therapeutic; Tissues; Whole Organism; Work; adult stem cell; base; beta-Hydroxybutyrate; biosynthetic product; fatty acid oxidation; gene repression; improved; in vivo; insight; intestinal tumorigenesis; ketogentic; mouse model; novel; novel therapeutics; oxidation; prevent; programs; repaired; response; stem cell aging; stem cell function; stem cells; stemness; tissue repair; transplant model; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY Fasting regimens can increase lifespan, improve health or both in diverse species including mammals. Fasting also has an emerging role in inhibiting tumor growth, yet little is known about how it impacts tumor initiation or how fasting-imposed metabolism can be therapeutically exploited to treat established tumors. Given that adult stem cells coordinate tissue adaptation and drive tumorigenesis, understanding the mechanism(s) that mediate their response to fasting has important implications for enhancing tissue repair after injury or aging where stem cell function declines, and may provide new therapeutic inroads for cancer. In the mouse intestine, where LGR5+ intestinal stem cells (ISCs) drive the rapid renewal of the intestinal lining, we showed that fasting augments ISC function by inducing a peroxisome proliferator-activated receptor delta (PPARd) driven fatty acid oxidation (FAO) program, which breaks down free fatty acids into acetyl-CoA units. This work raises the critical question of how fasting functions through the FAO pathway to regulate intestinal stemness. We hypothesize that beta-hydroxybutyrate (βOHB), a ketone body and biosynthetic product of FAO generated acetyl- CoA, functions as a signaling metabolite and energetic substrate that mediates the ISC fasting response. In support of this idea, we recently found that the LGR5+ ISCs strongly express enzymes of the ketogenic pathway that produce βOHB, including its rate-limiting enzyme HMGCS2 (3-hydroxy-3- methylglutaryl-CoA synthetase 2), compared to non-stem cell populations and that fasting strongly elevates HMGCS2 and βOHB levels in ISCs. HMGCS2 loss in the small intestine reduces βOHB levels in LGR5+ ISCs and skews their differentiation towards secretory cell fates, which we showed can be rescued by exogenous βOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, βOHB acts as a signaling metabolite to reinforce the NOTCH program in ISCs by inhibiting HDAC-mediated transcriptional repression. Dynamic control of βOHB levels in ISCs, therefore, could enable the rapid adaptation of the intestine to diverse physiological states like fasting. Many important questions that form the basis of our aims remain regarding the role ketone bodies as effectors of the fasting response in ISCs such as understanding the in vivo signaling (Aim 1) and energetic (Aim 2) roles of βOHB in this process. Another critical question is to decipher how the fasting-induced FAO program in ISCs influences tumor initiation and progression (Aim 3). !

项目摘要 禁食方案可以提高寿命，改善包括哺乳动物在内的潜水员物种。禁食 在抑制肿瘤生长中也具有新兴的作用，但对于它如何影响肿瘤感染或 如何热探索禁食的代谢如何治疗已建立的肿瘤。鉴于那个成年人 干细胞协调组织适应并驱动肿瘤发生，了解介导的机制 它们对禁食的反应对增强受伤或衰老后的组织修复具有重要意义 细胞功能会下降，并可能为癌症提供新的治疗性侵害。在鼠标肠中，其中 LGR5+肠干细胞（ISC）驱动肠壁的快速更新，我们表明禁食 通过诱导过氧化物组增殖物激活的受体三角洲（PPARD）驱动脂肪酸来增强ISC功能 氧化（FAO）程序，该程序将游离脂肪酸分解为乙酰辅酶A单元。这项工作提高了关键 关于禁食如何通过FAO途径进行调节肠干的问题。我们假设 那个β-羟基丁酸（βOHB）是粮农组织的酮体和生物合成产物产生的乙酰基 - COA，用作介导ISC禁食的信号代谢产物和能量底物 回复。为了支持这一想法，我们最近发现LGR5+ ISC强烈表达 生成βHb的生酮途径，包括其限制速率酶HMGCS2（3-羟基-3-- 与非茎细胞群体相比，甲基戊二酰-COA合成酶2），禁食强烈升高 ISC中的HMGCS2和βHb水平。小肠中的HMGCS2损失降低了LGR5+ ISC中的βHb水平 并偏向于秘密细胞命运的分化，我们表明可以通过外源性来救出这些命运 βHB和I类组蛋白脱乙酰基酶（HDACS）抑制剂治疗。从机械上讲，βHb充当 信号代谢产物通过抑制HDAC介导的转录，以增强ISC中的Notch程序 抑制。因此，对ISC中βHb水平的动态控制可以使得能够快速适应 肠道对潜水员的物理状态，例如禁食。构成我们目标基础的许多重要问题 仍然涉及酮体的作用作为禁食反应在ISC中的影响，例如了解 βHb在此过程中的体内信号传导（AIM 1）和能量（AIM 2）作用。另一个关键问题是 破译禁食诱导的ISC中的粮农组织计划如何影响肿瘤倡议和进展（AIM 3）。 呢