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Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

2019    Cheng, Chia-Wei; Biton, Moshe; Haber, Adam L.; Gunduz, Nuray; Eng, George; Gaynor, Liam T.; Tripathi, Surya; Calibasi-Koca, Gizem; Rickelt, Steffen; Butty, Vincent L.; Moreno-Serrano, Marta; Iqbal, Ameena M.; Bauer-Rowe, Khristian E.; Imada, Shinya; Ulutas, Mehmet Sefa; Mylonas, Constantine; Whary, Mark T.; Levine, Stuart S.; Basbinar, Yasemin; Hynes, Richard O.; Hynes, Richard O.

Little is known about how metabolites couple tissuespecific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutarylCoA synthetase 2), the gene encoding the ratelimiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (beta OHB), distinguishes self-renewing Lgr5(+) stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes beta OHB levels in Lgr5(+) ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous beta OHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, beta OHB 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 postinjury regeneration through beta OHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of beta OHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.