The DOI matches its Crossref record; 85 of the 85 references it cites were found in a registry or an index.
Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
Open accessAbstract
SUMMARY 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 the self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5+ ISCs and skews their differentiation towards secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, thereby instructing ISC self-renewal and lineage decisions. Notably, while 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.
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Metadata
- Authors
- Cheng, C.-W., Biton, M., Haber, A. L., Gunduz, N., Eng, G., Gaynor, L. T., Tripathi, S., Calibasi-Kocal, G., Rickelt, S., Butty, V. L., Moreno-Serrano, M., Iqbal, A. M., Bauer-Rowe, K. E., Imada, S., Ulutas, M. S., Mylonas, C., Whary, M. T., Levine, S. S., Basbinar, Y., Hynes, R. O., Mino-Kenudson, M., Deshpande, V., Boyer, L. A., Fox, J. G., Terranova, C., Rai, K., Piwnica-Worms, H., Mihaylova, M. M., Regev, A., & Yilmaz, Ö. H.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 178
- Issue
- 5
- Pages
- 1115-1131.e15
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2969784858
- Cited by
- 373
- References
- 85
- FWCI
- 18.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 387 d)
- Funders
- American Federation for Aging Research
- V Foundation for Cancer Research
- Pew Charitable Trusts
- Howard Hughes Medical Institute (R00 AG054760)
- Helen Hay Whitney Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Klarman Cell Observatory, Broad Institute
- Sidney Kimmel Foundation
- National Institutes of Health (R00 AG054760, R00 AG045144, R01CA211184, R01CA034992, U54CA224068)
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- Cheng, C.-W., Biton, M., Haber, A. L., Gunduz, N., Eng, G., Gaynor, L. T., Tripathi, S., Calibasi-Kocal, G., Rickelt, S., Butty, V. L., Moreno-Serrano, M., Iqbal, A. M., Bauer-Rowe, K. E., Imada, S., Ulutas, M. S., Mylonas, C., Whary, M. T., Levine, S. S., Basbinar, Y., . . . Yilmaz, Ö. H. (2019). Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell. https://doi.org/10.1016/j.cell.2019.07.048
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
