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

Cheng, Chia-Wei, Biton, Moshe, Haber, Adam L., Gunduz, Nuray, Eng, George, Gaynor, Liam T., Tripathi, Surya, Calibasi-Kocal, 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., Mino-Kenudson, Mari, Deshpande, Vikram, Boyer, Laurie A., Fox, James G., Terranova, Christopher, Rai, Kunal, Piwnica-Worms, Helen, Mihaylova, Maria M., Regev, Aviv, Yilmaz, Ömer H.
Cell 2019 v.178 no.5 pp. 1115-1131.e15
3-hydroxybutyric acid, genes, histone deacetylase, homeostasis, hydroxymethylglutaryl-CoA synthase, ketogenic diet, ketone bodies, mammals, small intestine, stem cells
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.