Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
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; Ulutas, Mehmet Sefa; Mylonas, Konstantinos; Whary, Mark T.; Hynes, Richard O; Boyer, Laurie Ann; Fox, James G; Regev, Aviv; Yilmaz, Omer H.; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Biological Engineering
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)
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