| First Author | Cheng CW | Year | 2019 |
| Journal | Cell | Volume | 178 |
| Issue | 5 | Pages | 1115-1131.e15 |
| PubMed ID | 31442404 | Mgi Jnum | J:280699 |
| Mgi Id | MGI:6369472 | Doi | 10.1016/j.cell.2019.07.048 |
| Citation | Cheng CW, et al. (2019) Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell 178(5):1115-1131.e15 |
| abstractText | 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 (betaOHB), distinguishes self-renewing Lgr5(+) stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes betaOHB levels in Lgr5(+) ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous betaOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, betaOHB 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 betaOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of betaOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury. |
