{"doi":"10.1016/j.cell.2019.07.048","title":"Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet","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","year":2019,"id":6821,"datarank":0.8882367629465725,"base_score":5.921578419643816,"endowment":5.921578419643816,"self_citation_contribution":0.8882367629465725,"citation_network_contribution":0.0,"self_endowment_contribution":0.8882367629465725,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":372,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.036,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2019-08-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":3189,"name":"Moshe Biton","orcid":"0000-0001-8330-1674","position":1,"is_corresponding":false},{"id":3191,"name":"Adam L. 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