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.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Biological Engineering; Koch Institute for Integrative Cancer Research at MIT
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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