Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Chia Wei Cheng; M. Biton; Adam L. Haber; N. Gunduz; George Eng; Liam T. Gaynor; S. Tripathi; G. Calibasi-Kocal; Steffen Rickelt; Vincent L. Butty; M. Moreno-Serrano; Ameena M. Iqbal; Khristian E. Bauer-Rowe; Shinya Imada; Mehmet Sefa Ulutas; Constantine Mylonas; Mark T. Whary; Stuart S. Levine; Yasemin Basbinar; Richard O. Hynes; Mari Mino-Kenudson; Vikram Deshpande; Laurie A. Boyer; James G. Fox; Christopher Terranova; K. Rai; H. Piwnica-Worms; Maria M. Mihaylova; Aviv Regev; Ömer H. Yilmaz

doi:10.1016/j.cell.2019.07.048

Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Chia Wei Cheng, M. Biton, Adam L. Haber, N. Gunduz, George Eng, Liam T. Gaynor, S. Tripathi, G. Calibasi-Kocal, Steffen Rickelt, Vincent L. Butty, M. Moreno-Serrano, Ameena M. Iqbal, Khristian E. Bauer-Rowe, Shinya Imada, Mehmet Sefa Ulutas, Constantine Mylonas, Mark T. Whary, Stuart S. Levine, Yasemin Basbinar, Richard O. HynesMari Mino-Kenudson, Vikram Deshpande, Laurie A. Boyer, James G. Fox, Christopher Terranova, K. Rai, H. Piwnica-Worms, Maria M. Mihaylova, Aviv Regev, Ömer H. Yilmaz

Research output: Contribution to journal › Article › peer-review

201 Scopus citations

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⁺ 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. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.

Original language	English (US)
Pages (from-to)	1115-1131.e15
Journal	Cell
Volume	178
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2019.07.048
State	Published - Aug 22 2019

Keywords

HDAC
Hmgcs2
Intestinal stem cell
Notch
beta-hydroxybutyrate
ketogenic diet
ketone bodies

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2019.07.048

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Cheng, C. W., Biton, M., Haber, A. L., Gunduz, N., Eng, G., Gaynor, L. T., Tripathi, S., Calibasi-Kocal, G., Rickelt, S., Butty, V. L., Moreno-Serrano, M., Iqbal, A. M., Bauer-Rowe, K. E., Imada, S., Ulutas, M. S., Mylonas, C., Whary, M. T., Levine, S. S., Basbinar, Y., ... Yilmaz, Ö. H. (2019). Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell, 178(5), 1115-1131.e15. https://doi.org/10.1016/j.cell.2019.07.048

Cheng, CW, Biton, M, Haber, AL, Gunduz, N, Eng, G, Gaynor, LT, Tripathi, S, Calibasi-Kocal, G, Rickelt, S, Butty, VL, Moreno-Serrano, M, Iqbal, AM, Bauer-Rowe, KE, Imada, S, Ulutas, MS, Mylonas, C, Whary, MT, Levine, SS, Basbinar, Y, Hynes, RO, Mino-Kenudson, M, Deshpande, V, Boyer, LA, Fox, JG, Terranova, C , Rai, K , Piwnica-Worms, H, Mihaylova, MM, Regev, A & Yilmaz, ÖH 2019, 'Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet', Cell, vol. 178, no. 5, pp. 1115-1131.e15. https://doi.org/10.1016/j.cell.2019.07.048

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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+ 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. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.",

keywords = "HDAC, Hmgcs2, Intestinal stem cell, Notch, beta-hydroxybutyrate, ketogenic diet, ketone bodies",

author = "Cheng, {Chia Wei} and M. Biton and Haber, {Adam L.} and N. Gunduz and George Eng and Gaynor, {Liam T.} and S. Tripathi and G. Calibasi-Kocal and Steffen Rickelt and Butty, {Vincent L.} and M. Moreno-Serrano and Iqbal, {Ameena M.} and Bauer-Rowe, {Khristian E.} and Shinya Imada and Ulutas, {Mehmet Sefa} and Constantine Mylonas and Whary, {Mark T.} and Levine, {Stuart S.} and Yasemin Basbinar and Hynes, {Richard O.} and Mari Mino-Kenudson and Vikram Deshpande and Boyer, {Laurie A.} and Fox, {James G.} and Christopher Terranova and K. Rai and H. Piwnica-Worms and Mihaylova, {Maria M.} and Aviv Regev and Yilmaz, {{\"O}mer H.}",

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doi = "10.1016/j.cell.2019.07.048",

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AU - Cheng, Chia Wei

AU - Biton, M.

AU - Haber, Adam L.

AU - Gunduz, N.

AU - Eng, George

AU - Gaynor, Liam T.

AU - Tripathi, S.

AU - Calibasi-Kocal, G.

AU - Rickelt, Steffen

AU - Butty, Vincent L.

AU - Moreno-Serrano, M.

AU - Iqbal, Ameena M.

AU - Bauer-Rowe, Khristian E.

AU - Imada, Shinya

AU - Ulutas, Mehmet Sefa

AU - Mylonas, Constantine

AU - Whary, Mark T.

AU - Levine, Stuart S.

AU - Basbinar, Yasemin

AU - Hynes, Richard O.

AU - Mino-Kenudson, Mari

AU - Deshpande, Vikram

AU - Boyer, Laurie A.

AU - Fox, James G.

AU - Terranova, Christopher

AU - Rai, K.

AU - Piwnica-Worms, H.

AU - Mihaylova, Maria M.

AU - Regev, Aviv

AU - Yilmaz, Ömer H.

PY - 2019/8/22

Y1 - 2019/8/22

N2 - 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. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.

AB - 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. Ketone body metabolites inform intestinal stem cell decisions in response to diverse diets.

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KW - beta-hydroxybutyrate

KW - ketogenic diet

KW - ketone bodies

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JO - Cell

JF - Cell

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ER -

Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

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Keywords

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