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

Chia-Wei Cheng; Moshe Biton; Adam L Haber; Nuray Gunduz; George Eng; Liam T Gaynor; Surya Tripathi; Gizem Calibasi-Kocal; Steffen Rickelt; Vincent L Butty; Marta 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; Kunal Rai; Helen 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

Cell. 2019 Aug 22;178(5):1115-1131.e15. doi: 10.1016/j.cell.2019.07.048.

Authors

Chia-Wei Cheng¹, Moshe Biton², Adam L Haber³, Nuray Gunduz⁴, George Eng⁵, Liam T Gaynor⁶, Surya Tripathi¹, Gizem Calibasi-Kocal⁷, Steffen Rickelt¹, Vincent L Butty⁸, Marta Moreno-Serrano¹, Ameena M Iqbal¹, Khristian E Bauer-Rowe¹, Shinya Imada⁹, Mehmet Sefa Ulutas¹⁰, Constantine Mylonas¹¹, Mark T Whary¹², Stuart S Levine⁸, Yasemin Basbinar¹³, Richard O Hynes¹⁴, Mari Mino-Kenudson¹⁵, Vikram Deshpande¹⁵, Laurie A Boyer¹¹, James G Fox¹², Christopher Terranova¹⁶, Kunal Rai¹⁶, Helen Piwnica-Worms¹⁷, Maria M Mihaylova¹⁸, Aviv Regev¹⁹, Ömer H Yilmaz²⁰

Affiliations

¹ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
² Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁴ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, 06800 Ankara, Turkey.
⁵ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA.
⁶ Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
⁷ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey.
⁸ BioMicro Center at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
⁹ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
¹⁰ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, Siirt University, Science and Arts Faculty, 56100 Siirt, Turkey.
¹¹ Department of Biology, MIT, Cambridge, MA 02139, USA.
¹² Division of Comparative Medicine, Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
¹³ Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey.
¹⁴ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
¹⁵ Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA.
¹⁶ Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁷ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁸ Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210 USA.
¹⁹ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
²⁰ Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].

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.

Keywords: HDAC; Hmgcs2; Intestinal stem cell; Notch; beta-hydroxybutyrate; ketogenic diet; ketone bodies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid / blood
3-Hydroxybutyric Acid / pharmacology
Aged, 80 and over
Animals
Cell Differentiation / drug effects
Cell Self Renewal
Diet, High-Fat*
Female
Histone Deacetylase Inhibitors / pharmacology
Humans
Hydroxymethylglutaryl-CoA Synthase / deficiency
Hydroxymethylglutaryl-CoA Synthase / genetics
Hydroxymethylglutaryl-CoA Synthase / metabolism
Intestines / cytology
Intestines / pathology
Ketone Bodies / metabolism*
Male
Mice
Mice, Knockout
Receptors, G-Protein-Coupled / metabolism
Receptors, Notch / metabolism
Signal Transduction / drug effects
Stem Cells / cytology
Stem Cells / metabolism*
Young Adult

Substances

Histone Deacetylase Inhibitors
Ketone Bodies
Lgr5 protein, mouse
Receptors, G-Protein-Coupled
Receptors, Notch
HMGCS2 protein, mouse
Hydroxymethylglutaryl-CoA Synthase
3-Hydroxybutyric Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding