Browsing by Subject "Hmgcs2"

Filter results by typing the first few letters
Now showing 1 - 1 of 1
  • Thumbnail Image
    ItemOpen Access
    Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet
    (Cell Press, 2019) Cheng, C.-W.; Biton, M.; Haber, A. L.; Gündüz, Nuray; Eng, G.; Gaynor, L. T.; Tripathi, S.; Çalıbaşı-Koçal, G.; Rickelt, S.; Butty, V. L.; Moreno-Serrano, M.; Iqbal, A. M.; Bauer-Rowe, K. E.; Imada, S.; Ulutaş, M. S.; Mylonas, C.; Whary, M. T.; Levine, S. S.; Başbınar, Y.; Hynes, R. O.; Mino-Kenudson, M.; Deshpande, V.; Boyer, L. A.; Fox, J. G.; Terranova, C.; Rai, K.; Piwnica-Worms, H.; Mihaylova, M. M.; Regev, A.; Yılmaz, Ö. H.
    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. Graphical Abstract