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

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dc.authoridRickelt, Steffen/0000-0002-5224-7764
dc.authoridCalibasi Kocal, Gizem/0000-0002-3201-4752
dc.authoridRai, Kunal/0000-0003-2321-6894
dc.authoridBiton, Moshe/0000-0001-8330-1674
dc.authoridMihaylova, Maria/0000-0002-2725-767X
dc.authoridLevine, Stuart/0000-0001-7363-562X
dc.authoridButty, Vincent/0000-0003-1173-2429
dc.authorid/0000-0003-1088-923X
dc.authoridBasbinar, Yasemin/0000-0001-9439-2217
dc.authoridGunduz, Nuray/0000-0003-3477-2888
dc.contributor.authorCheng, Chia-Wei
dc.contributor.authorBiton, Moshe
dc.contributor.authorHaber, Adam L.
dc.contributor.authorGunduz, Nuray
dc.contributor.authorEng, George
dc.contributor.authorGaynor, Liam T.
dc.contributor.authorTripathi, Surya
dc.date.accessioned2024-12-24T19:25:24Z
dc.date.available2024-12-24T19:25:24Z
dc.date.issued2019
dc.departmentSiirt Üniversitesi
dc.description.abstractLittle 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.
dc.description.sponsorshipNIH [R00 AG054760, R00 AG045144, R01CA211184, R01CA034992, U54CA224068]; V Foundation V scholar award; Sidney Kimmel scholar award; Pew-Stewart Trust scholar award; Kathy and Curt Marble Cancer Research Fund; Bridge grant; American Federation of Aging Research (AFAR); MIT Stem Cell Initiative through Fondation MIT; Ludwig postdoctoral fellowship; Helen Hay Whitney postdoctoral fellowship; TUBITAK-BIDEB 2214-A fellowship; TUBITAK 2219 international postdoctoral research fellowship; MIT Ludwig Center for Molecular Oncology Research, NIH [U54CA163109]; Howard Hughes Medical Institute; Klarman Cell Observatory; HHMI
dc.description.sponsorshipWe thank Fang Wang for providing beta OHB oligomers. We thank Dr. Julien Sage and Dr. Spyros Artavanis-Tsakonas for the generous gift of Hes1-GFP reporter mice. We thank Sven Holder for histology support, the Whitehead Institute Metabolite profiling core facility, and the Koch Institute Flow Cytometry, Histology, and ES Cell and Transgenics core facilities. We thank Leah Bury for illustration assistance, members of the Yilmaz laboratory for discussions, and Kerry Kelley for laboratory management. O.H.Y. is supported by NIH R00 AG045144, R01CA211184, R01CA034992, and U54CA224068; a V Foundation V scholar award; a Sidney Kimmel scholar award; a Pew-Stewart Trust scholar award; the Kathy and Curt Marble Cancer Research Fund; a Bridge grant; the American Federation of Aging Research (AFAR); and the MIT Stem Cell Initiative through Fondation MIT. C.W.C. is supported by a Ludwig postdoctoral fellowship and a Helen Hay Whitney postdoctoral fellowship. N.G is supported by a TUBITAK-BIDEB 2214-A fellowship. G. C.-K. is supported by a TUBITAK 2219 international postdoctoral research fellowship. We thank the members of The Hope Babette Tang (1983) Histology Facility at the Koch Institute. S. R. was supported by a postdoctoral fellowship from the MIT Ludwig Center for Molecular Oncology Research, NIH grant U54CA163109, and the Howard Hughes Medical Institute (to R. O. H.). A. R. is supported by the Klarman Cell Observatory and HHMI. M. M. M. is supported by NIH R00 AG054760. A. R. is a SAB member of Thermo Fisher Scientific, Driver Group, and Syros Pharmaceuticals and a co-founder of Celsius Therapeutics. We would like to thank Kerry Kelly for excellent lab management.
dc.identifier.doi10.1016/j.cell.2019.07.048
dc.identifier.endpage+
dc.identifier.issn0092-8674
dc.identifier.issn1097-4172
dc.identifier.issue5
dc.identifier.pmid31442404
dc.identifier.scopus2-s2.0-85070720035
dc.identifier.scopusqualityQ1
dc.identifier.startpage1115
dc.identifier.urihttps://doi.org/10.1016/j.cell.2019.07.048
dc.identifier.urihttps://hdl.handle.net/20.500.12604/6398
dc.identifier.volume178
dc.identifier.wosWOS:000482191000010
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherCell Press
dc.relation.ispartofCell
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_20241222
dc.titleKetone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
dc.typeArticle

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