美国麻省理工学院的Ömer H. Yilmaz研究组发现酮体信号调控肠道干细胞的稳态以及对饮食的适应。2019年8月22日，国际知名学术期刊《细胞》发表了这一成果。
研究人员发现，在哺乳动物小肠中，Hmgcs2（3-hydroxy-3-methylglutaryl-CoA synthetase 2）的表达能够区分自我更新的Lgr5阳性干细胞（ISC）与分化细胞类型；Hmgcs2是一个编码限速酶的基因，用于生产酮体，包括β-羟基丁酸酯（βOHB）。Hmgcs2缺失消耗Lgr5阳性 ISC中的βOHB水平并且使它们向分泌细胞命运的分化倾斜，这可以通过外源βOHB和I类组蛋白去乙酰化酶（HDAC）抑制剂处理来挽救。从机制上讲，βOHB通过抑制HDAC来强化Notch信号传导，指导ISC自我更新和谱系决定。值得注意的是，尽管高脂肪生酮饮食通过βOHB介导的Notch信号传导提升ISC功能和损伤后再生，但补充葡萄糖的饮食具有相反的效果。这些发现揭示了如何通过饮食控制ISC中βOHB激活的信号传导有助于微调体内平衡和损伤中的干细胞适应。
研究人员表示，对于代谢物如何将组织特异性干细胞的功能与生理结合起来，人们知之甚少。
附：英文原文
Title: Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
Author: Chia-Wei Cheng,Moshe Biton ,Adam L. Haber ,Nuray Gunduz,George Eng,Liam T. Gaynor,Surya Tripathi,Gizem Calibasi-Kocal,Steffen Rickelt,Vincent L. Butty,Marta Moreno-Serrano,Ameena M. Iqbal,Khristian E. Bauer-Rowe,Shinya Imada,Mehmet Sefa Ulutas,Constantine Mylonas,Mark T. Whary,Stuart S. Levine,Yasemin Basbinar,Richard O. Hynes,Mari Mino-Kenudson,Vikram Deshpande,Laurie A. Boyer,James G. Fox,Christopher Terranova,Kunal Rai,Helen Piwnica-Worms,Maria M. Mihaylova,Aviv Regev,Ömer H. Yilmaz
Issue&Volume: Volume 178 Issue 5
Abstract: Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5 + stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5 + ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
DOI: https://doi.org/10.1016/j.cell.2019.07.048
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30848-7