title: Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.
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.
authors.affiliation: Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, USA.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shimazu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.forename: John
authors.initials: J
authors.lastname: Newman
authors.forename: Wenjuan
authors.initials: W
authors.lastname: He
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shirakawa
authors.forename: Natacha
authors.initials: N
authors.lastname: Le Moan
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Grueter
authors.forename: Hyungwook
authors.initials: H
authors.lastname: Lim
authors.forename: Laura R
authors.initials: LR
authors.lastname: Saunders
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Scott
authors.initials: S
authors.lastname: Ulrich
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000107:Acetylation; D000818:Animals; D031204:Caloric Restriction; D002374:Catalase / Q000378:metabolism; D005215:Fasting; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D013482:Superoxide Dismutase / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C491054:Mt2 protein, mouse; D034741:RNA, Small Interfering; D008668:Metallothionein; D002374:Catalase; D013482:Superoxide Dismutase; D006655:Histone Deacetylases; D020155:3-Hydroxybutyric Acid