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 (?OHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ?OHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous ?OHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, ?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 post-injury regeneration through ?OHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of ?OHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.

SUBMITTER: Cheng CW 

PROVIDER: S-EPMC6732196 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature