Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 339 (6116): 211-214

Copyright © 2013 by the American Association for the Advancement of Science

Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor

Tadahiro Shimazu,1,2 Matthew D. Hirschey,1,2 John Newman,1,2 Wenjuan He,1,2 Kotaro Shirakawa,1,2 Natacha Le Moan,3 Carrie A. Grueter,4,5 Hyungwook Lim,1,2 Laura R. Saunders,1,2 Robert D. Stevens,6 Christopher B. Newgard,6 Robert V. Farese, Jr.,2,4,5 Rafael de Cabo,7 Scott Ulrich,8 Katerina Akassoglou,3 Eric Verdin1,2,*

Abstract: Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body D-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

1 Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA.
2 Department of Medicine, University of California, San Francisco, CA 94143, USA.
3 Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
4 Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
5 Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
6 Sarah W. Stedman Nutrition and Metabolism Center, and Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27704, USA.
7 Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
8 Department of Chemistry, Ithaca College, Ithaca, NY 14850, USA.

* To whom correspondence should be addressed. E-mail: everdin{at}gladstone.ucsf.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Unique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors.
J. A. Gaspar, M. X. Doss, J. G. Hengstler, C. Cadenas, J. Hescheler, and A. Sachinidis (2014)
Circ. Res. 114, 1346-1360
   Abstract »    Full Text »    PDF »
The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis.
N. Turgeon, J. M. Gagne, M. Blais, F.-P. Gendron, F. Boudreau, and C. Asselin (2014)
Am J Physiol Gastrointest Liver Physiol 306, G594-G605
   Abstract »    Full Text »    PDF »
Impaired glucose tolerance in low-carbohydrate diet: maybe only a physiological state.
R. de Oliveira Caminhotto and F. B. Lima (2013)
Am J Physiol Endocrinol Metab 305, E1521
   Full Text »    PDF »
Polyunsaturated fatty acyl-coenzyme As are inhibitors of cholesterol biosynthesis in zebrafish and mice.
S. Karanth, V. M. Tran, B. Kuberan, and A. Schlegel (2013)
Dis. Model. Mech. 6, 1365-1377
   Abstract »    Full Text »    PDF »
Worldwide Dietary Therapies for Adults With Epilepsy and Other Disorders.
M. C. Cervenka, B. Henry, J. Nathan, S. Wood, and J. S. Volek (2013)
J Child Neurol 28, 1034-1040
   Abstract »    Full Text »    PDF »
The Phosphatidylinositol 3,5-Bisphosphate (PI(3,5)P2)-dependent Tup1 Conversion (PIPTC) Regulates Metabolic Reprogramming from Glycolysis to Gluconeogenesis.
B.-K. Han and S. D. Emr (2013)
J. Biol. Chem. 288, 20633-20645
   Abstract »    Full Text »    PDF »
Ketone body metabolism and cardiovascular disease.
D. G. Cotter, R. C. Schugar, and P. A. Crawford (2013)
Am J Physiol Heart Circ Physiol 304, H1060-H1076
   Abstract »    Full Text »    PDF »
When Metabolism and Epigenetics Converge.
P. Sassone-Corsi (2013)
Science 339, 148-150
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882