biostudies-literatureCheng CWTUBITAK-BIDEBHelen Hay WhitneyNIA NIH HHSHoward Hughes Medical InstituteLudwigNIHTUBITAKAmerican Federation of Aging ResearchV FoundationPew-Stewart TrustNIDDK NIH HHSFondation MITKathy and Curt Marble Cancer Research FundSidney KimmelNCI NIH HHSMIT Ludwig Center for Molecular Oncology ResearchHHMIBridgeKlarman Cell ObservatoryMIT Stem Cell Initiative1115-1131.e15https://www.ebi.ac.uk/biostudies/studies/S-EPMC6732196biostudies-literatureUnknown178(5)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.CellKetone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.PMC6732196R01CA034992R01 CA211184T32 CA009216U54CA224068U54 CA163109K99 AG054760R01CA211184R01 CA034992U54 CA224068R00 AG045144R00 AG054760U54-CA163109P30 DK043351K99 DK123407R01 CA2072362214-A2219Whary MTBoyer LAMino-Kenudson MFox JGMihaylova MMBauer-Rowe KEPiwnica-Worms HGunduz NUlutas MSGaynor LTRai KYilmaz OHEng GCalibasi-Kocal GMylonas CImada SButty VLBiton MRickelt STripathi SLevine SSHynes RODeshpande VBasbinar YRegev ACheng CWTerranova CMoreno-Serrano MHaber ALIqbal AMfalseKetone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.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.2019-01-01T00:00:00Z2019 Aug2024-11-12T13:27:25.128Z2020-08-24T07:07:05ZS-EPMC67321963144240410.1016/j.cell.2019.07.048