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

How control of ketone bodies helps to fine-tune stem cell adaptation in homeostasis and injury.

AUG 22, 2019

Written by Chia-Wei Cheng, Moshe Biton, Adam L.Haber, Nuray Gunduz, George Eng, Liam T.Gaynor, Surya Tripathi1, Gizem Calibasi-Kocal, Steffen Rickelt, Vincent L.Butty, MartaMoreno-Serrano, Ameena M.Iqbal, Khristian E.Bauer-Rowe, ShinyaImada, Mehmet Sefa Ulutas, Constantine Mylonas, Mark T.Whary, Stuart S.Levine, Yasemin Basbinar, Richard O.Hynes, Mari Mino-Kenudson, Vikram Deshpande, Laurie A.Boyer, James G.Fox, Christopher Terranova, Kunal Rai, Helen Piwnica-Worms, Maria M.Mihaylova, Aviv Regev, Ömer H.Yilmaz

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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.