Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
Name
nihms-1536380.pdf
Description
Accepted version
Size
3.65 MB
Format
Adobe PDF
Checksum (MD5)
b1f035ce32c498a795bed527a9b23ace
Author(s)
Cheng, Chia-Wei
Gunduz, Nuray
Eng, George M
Tripathi, Surya
Calibasi Kocal, Gizem
Rickelt, Steffen
Moreno, Marta
Iqbal, Ameena M.
Bauer-Rowe, Khristian E.
Imada, Shinya
Date Issued
August 2019
Journal
Cell
Publisher
Elsevier BV
Citation
Cheng, Chia-Wei et al. “Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.” Cell, 178, 5 (August 2019): 1115–1131.e15 © 2019 The Author(s)
Version
Author's final manuscript
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. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Biological Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CELL.2019.07.048
