Ketone body signaling mediates intestinal stem cell homeostasis and adaptation to diet
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA553549 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9660782.fastq.gz | Fastqsanger.gz | |||
| SRR9660783.fastq.gz | Fastqsanger.gz | |||
| SRR9660784.fastq.gz | Fastqsanger.gz | |||
| SRR9660785.fastq.gz | Fastqsanger.gz | |||
| SRR9660786.fastq.gz | Fastqsanger.gz |
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Project description:Little is known about how metabolites couple tissue stem 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 (ßOHB)—distinguishes the self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes ßOHB levels in Lgr5+ ISCs and skews their differentiation towards secretory cell fates, which can be rescued by exogenous ßOHB and class I histone deacetylases (HDACs) inhibitor treatment. Mechanistically, ßOHB acts by inhibiting HDACs to reinforce Notch signaling in ISCs, thereby instructing self-renewal and lineage decisions. Notably, while a low glucose ketogenic diet elevates ISC function and post-injury regeneration through ßOHB-mediated Notch signaling, a glucose supplemented diet has the opposite effects. These findings reveal how control of ßOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
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Project 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+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5+ 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.
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Project description:Diets characterized by increased blood levels of ketone bodies can protect the brain against a variety of acute and chronic neurological diseases. Moreover, ketone bodies are neuroprotective in many in vitro models of neurological injury. The underlying mechanisms remain unknown however. Recently, we have shown that ketone bodies do not only decrease neuronal injury and death but also protect long-term potentiation in acute hippocampal slices exposed to oxidative stress in the form of exogenous hydrogen peroxide. Elucidating the mechanisms behind the effects of ketone bodies on neuronal survival and function will undoubtedly lead to the development of novel neuroprotective treatments. Our aim is to determine acute changes in gene expression of CA1 pyramidal neurons exposed to various duration of the ketone bodies acetoacetate and beta-hydroxybutyrate. CA1 hippocampal pyramidal neurons exposed to oxidative stress do not display any long-term potention following burst stimulation of Schaffer collaterals. Incubation with the ketone bodies acetoacetate and beta-hydroxybutyrate for at least 20 min prior to hydrogen peroxide application restores long-term potentiation to control levels. We hypothesize that the neuroprotective effects of ketone bodies are mediated by changes in gene expression. Acute hippocampal slices (400 microns in thickness) were obtained from 4 week-old rats and exposed to acetoacetate and beta-hydroxybutyrate (1 mM each) for 1 h and 6 h. A control group was incubated in artificial cerebrospinal fluid only. After treatment, the hippocampal slices were used immediately for RNA isolation. Isolated RNA was sent for analysis. Each sample sent for analysis included tissue from 7 separate animals. Hybridization to an Affymetrix array is being performed 3 times for each experimental condition.
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Project description:Diets characterized by increased blood levels of ketone bodies can protect the brain against a variety of acute and chronic neurological diseases. Moreover, ketone bodies are neuroprotective in many in vitro models of neurological injury. The underlying mechanisms remain unknown however. Recently, we have shown that ketone bodies do not only decrease neuronal injury and death but also protect long-term potentiation in acute hippocampal slices exposed to oxidative stress in the form of exogenous hydrogen peroxide. Elucidating the mechanisms behind the effects of ketone bodies on neuronal survival and function will undoubtedly lead to the development of novel neuroprotective treatments. Our aim is to determine acute changes in gene expression of CA1 pyramidal neurons exposed to various duration of the ketone bodies acetoacetate and beta-hydroxybutyrate. CA1 hippocampal pyramidal neurons exposed to oxidative stress do not display any long-term potention following burst stimulation of Schaffer collaterals. Incubation with the ketone bodies acetoacetate and beta-hydroxybutyrate for at least 20 min prior to hydrogen peroxide application restores long-term potentiation to control levels. We hypothesize that the neuroprotective effects of ketone bodies are mediated by changes in gene expression. Acute hippocampal slices (400 microns in thickness) were obtained from 4 week-old rats and exposed to acetoacetate and beta-hydroxybutyrate (1 mM each) for 1 h and 6 h. A control group was incubated in artificial cerebrospinal fluid only. After treatment, the hippocampal slices were used immediately for RNA isolation. Isolated RNA was sent for analysis. Each sample sent for analysis included tissue from 7 separate animals. Hybridization to an Affymetrix array is being performed 3 times for each experimental condition. Keywords: dose response
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