You are here

Cell DOI:10.1016/j.cell.2019.07.048

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

Publication TypeJournal Article
Year of Publication2019
AuthorsCheng, C-W, Biton, M, Haber, AL, Gunduz, N, Eng, G, Gaynor, LT, Tripathi, S, Calibasi-Kocal, G, Rickelt, S, Butty, VL, Moreno-Serrano, M, Iqbal, AM, Bauer-Rowe, KE, Imada, S, Ulutas, MSefa, Mylonas, C, Whary, MT, Levine, SS, Basbinar, Y, Hynes, RO, Mino-Kenudson, M, Deshpande, V, Boyer, LA, Fox, JG, Terranova, C, Rai, K, Piwnica-Worms, H, Mihaylova, MM, Regev, A, Yilmaz, ÖH
Date Published2019 Aug 22

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.


Alternate JournalCell
PubMed ID31442404
PubMed Central IDPMC6732196
Grant ListR00 AG045144 / AG / NIA NIH HHS / United States
R01 CA034992 / CA / NCI NIH HHS / United States
R01 CA211184 / CA / NCI NIH HHS / United States
U54 CA163109 / CA / NCI NIH HHS / United States