Published January 1, 2019
| Version v1
Journal article
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Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
Creators
- Cheng, Chia-Wei1
- Biton, Moshe
- Haber, Adam L.2
- Gunduz, Nuray
- Eng, George
- Gaynor, Liam T.3
- Tripathi, Surya1
- Calibasi-Koca, Gizem
- Rickelt, Steffen1
- Butty, Vincent L.4
- Moreno-Serrano, Marta1
- Iqbal, Ameena M.1
- Bauer-Rowe, Khristian E.1
- Imada, Shinya
- Ulutas, Mehmet Sefa
- Mylonas, Constantine5
- Whary, Mark T.6
- Levine, Stuart S.4
- Basbinar, Yasemin7
- Hynes, Richard O.
- Hynes, Richard O.
- 1. MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
- 2. Broad Inst Harvard & MIT, Klarman Cell Observ, Cambridge, MA 02142 USA
- 3. Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA
- 4. MIT, Dept Biol, BioMicro Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA
- 5. MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA
- 6. MIT, Dept Biol Engn, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA
- 7. Dokuz Eylul Univ, Inst Oncol, Dept Translat Oncol, Izmir, Turkey
Description
Little is known about how metabolites couple tissuespecific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutarylCoA synthetase 2), the gene encoding the ratelimiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (beta OHB), distinguishes self-renewing Lgr5(+) stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes beta OHB levels in Lgr5(+) ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous beta OHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, beta OHB 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 postinjury regeneration through beta OHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of beta OHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
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