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Suppression of oxidative stress by ?-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-?-hydroxybutyrate (?OHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous ?OHB, or fasting or calorie restriction, two conditions associated with increased ?OHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by ?OHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with ?OHB 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 ?OHB conferred substantial protection against oxidative stress.

SUBMITTER: Shimazu T

PROVIDER: S-EPMC3735349 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

Shimazu Tadahiro T Hirschey Matthew D MD Newman John J He Wenjuan W Shirakawa Kotaro K Le Moan Natacha N Grueter Carrie A CA Lim Hyungwook H Saunders Laura R LR Stevens Robert D RD Newgard Christopher B CB Farese Robert V RV de Cabo Rafael R de Cabo Rafael R Ulrich Scott S Akassoglou Katerina K Verdin Eric E

Science (New York, N.Y.) 20121206 6116

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 mous ...[more]

PMID: 23223453

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Project description:Butyrate and R-?-hydroxybutyrate are two related short chain fatty acids naturally found in mammals. Butyrate, produced by enteric butyric bacteria, is present at millimolar concentrations in the gastrointestinal tract and at lower levels in blood; R-?-hydroxybutyrate, the main ketone body, produced by the liver during fasting can reach millimolar concentrations in the circulation. Both molecules have been shown to be histone deacetylase (HDAC) inhibitors, and their administration has been associated to an improved metabolic profile and better cellular oxidative status, with butyrate inducing PGC1? and fatty acid oxidation and R-?-hydroxybutyrate upregulating oxidative stress resistance factors FOXO3A and MT2 in mouse kidney. Because of the chemical and functional similarity between the two molecules, we compared here their impact on multiple cell types, evaluating i) histone acetylation and hydroxybutyrylation levels by immunoblotting, ii) transcriptional regulation of metabolic and inflammatory genes by quantitative PCR and iii) cytokine secretion profiles using proteome profiling array analysis. We confirm that butyrate is a strong HDAC inhibitor, a characteristic we could not identify in R-?-hydroxybutyrate in vivo nor in vitro. Butyrate had an extensive impact on gene transcription in rat myotubes, upregulating PGC1?, CPT1b, mitochondrial sirtuins (SIRT3-5), and the mitochondrial anti-oxidative genes SOD2 and catalase. In endothelial cells, butyrate suppressed gene expression and LPS-induced secretion of several pro-inflammatory genes, while R-?-hydroxybutyrate acted as a slightly pro-inflammatory molecule. Our observations indicate that butyrate induces transcriptional changes to a higher extent than R-?-hydroxybutyrate in rat myotubes and endothelial cells, in keep with its HDAC inhibitory activity. Also, in contrast with previous reports, R-?-hydroxybutyrate, while inducing histone ?-hydroxybutyrylation, did not display a readily detectable HDAC inhibitor activity and exerted a slight pro-inflammatory action on endothelial cells.

Dataset Information

Suppression of oxidative stress by ?-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

Publications

Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

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