fbpx

SCIENCE JOURNAL

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

The effects of ketone body on intestinal stem cell by diet.

AUG 22, 2019

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

View full article HERE.

 01


ABSTRACT

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.