| Literature DB >> 31442404 |
Chia-Wei Cheng1, Moshe Biton2, Adam L Haber3, Nuray Gunduz4, George Eng5, Liam T Gaynor6, Surya Tripathi1, Gizem Calibasi-Kocal7, Steffen Rickelt1, Vincent L Butty8, Marta Moreno-Serrano1, Ameena M Iqbal1, Khristian E Bauer-Rowe1, Shinya Imada9, Mehmet Sefa Ulutas10, Constantine Mylonas11, Mark T Whary12, Stuart S Levine8, Yasemin Basbinar13, Richard O Hynes14, Mari Mino-Kenudson15, Vikram Deshpande15, Laurie A Boyer11, James G Fox12, Christopher Terranova16, Kunal Rai16, Helen Piwnica-Worms17, Maria M Mihaylova18, Aviv Regev19, Ömer H Yilmaz20.
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.Entities:
Keywords: HDAC; Hmgcs2; Intestinal stem cell; Notch; beta-hydroxybutyrate; ketogenic diet; ketone bodies
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Year: 2019 PMID： 31442404 PMCID： PMC6732196 DOI： 10.1016/j.cell.2019.07.048
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582