Cheng, Chia-WeiBiton, MosheHaber, Adam L.Gunduz, NurayEng, GeorgeGaynor, Liam T.Tripathi, Surya2024-12-242024-12-2420190092-86741097-4172https://doi.org/10.1016/j.cell.2019.07.048https://hdl.handle.net/20.500.12604/6398Little 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.eninfo:eu-repo/semantics/openAccessArticle17851115+Q1WOS:000482191000010Q12-s2.0-850707200353144240410.1016/j.cell.2019.07.048