{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cheng CW"],"funding":["TUBITAK-BIDEB","Helen Hay Whitney","NIA NIH HHS","Howard Hughes Medical Institute","Ludwig","NIH","TUBITAK","American Federation of Aging Research","V Foundation","Pew-Stewart Trust","NIDDK NIH HHS","Fondation MIT","Kathy and Curt Marble Cancer Research Fund","Sidney Kimmel","NCI NIH HHS","MIT Ludwig Center for Molecular Oncology Research","HHMI","Bridge","Klarman Cell Observatory","MIT Stem Cell Initiative"],"pagination":["1115-1131.e15"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6732196"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["178(5)"],"pubmed_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<sup>+</sup> stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5<sup>+</sup> 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."],"journal":["Cell"],"pubmed_title":["Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet."],"pmcid":["PMC6732196"],"funding_grant_id":["R01CA034992","R01 CA211184","T32 CA009216","U54CA224068","U54 CA163109","K99 AG054760","R01CA211184","R01 CA034992","U54 CA224068","R00 AG045144","R00 AG054760","U54-CA163109","P30 DK043351","K99 DK123407","R01 CA207236","2214-A","2219"],"pubmed_authors":["Whary MT","Boyer LA","Mino-Kenudson M","Fox JG","Mihaylova MM","Bauer-Rowe KE","Piwnica-Worms H","Gunduz N","Ulutas MS","Gaynor LT","Rai K","Yilmaz OH","Eng G","Calibasi-Kocal G","Mylonas C","Imada S","Butty VL","Biton M","Rickelt S","Tripathi S","Levine SS","Hynes RO","Deshpande V","Basbinar Y","Regev A","Cheng CW","Terranova C","Moreno-Serrano M","Haber AL","Iqbal AM"],"additional_accession":[]},"is_claimable":false,"name":"Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.","description":"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<sup>+</sup> stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5<sup>+</sup> 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.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Aug","modification":"2024-11-12T13:27:25.128Z","creation":"2020-08-24T07:07:05Z"},"accession":"S-EPMC6732196","cross_references":{"pubmed":["31442404"],"doi":["10.1016/j.cell.2019.07.048"]}}