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

By Tadahiro Shimazu, M. Hirschey, John Newman, Wenjuan He, Kotaro Shirakawa, Natacha Le Moan, Carrie A. Grueter, H. Lim, L. Saunders, Robert D. Stevens and 6 more. Science, 2012

1,531 citations recorded by the source corpus.

Stress Protector During prolonged fasting, the oxidation of fatty acids leads to increased accumulation of d-β-hydroxybutyrate (βOHB) in the bloodstream. Such increased concentrations of βOHB inhibit class I histone deacetylases. Histone acetylation in turn influences transcriptional activity at various genes. Shimazu et al. (p. 211, published online 6 December; see the Perspective by Sassone-Corsi) found that among the genes showing increased transcription in animals treated with high concentrations of βOHB were two genes implicated in cellular responses to oxidative stress. When treated ahead of time with βOHB, mice were protected from the toxic effects of the oxidative stress causing poison paraquat. Ketone bodies, metabolites that accumulate during fasting, change gene expression by inhibiting histone deacetylases. [Also see Perspective by Sassone-Corsi] 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.

Subfields: Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/9c29180abb3d8ee42dfa5217c17caa0fa537da29

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Citations in the corpus

Mechanisms of ROS Regulation of Plant Development and Stress Responses (2019, positive): “In mammals, histone deacetylases (HDACs) function in epigenetic regulation in connection with oxidative stress (Shimazu et al., 2013).”
Acetyl coenzyme A: a central metabolite and second messenger. (2015, positive): “…2015; Takahashi et al., 2006), but also for the preferential transactivation of genes involved in cell growth and replication (Cai et al., 2011; Donohoe et al., 2012; Lee et al., 2014; Shi and Tu, 2013), glycolysis (Wellen et al., 2009), and resistance to oxidative stress (Shimazu et al., 2013).”
Promoting Health and Longevity through Diet: from Model Organisms to Humans (2015, positive): “Treatment of cells and mice with βOHB, an endogenous histone deacetylase inhibitor powerfully induced by fasting, protects against oxidative stress (Shimazu et al., 2013).”
Metabolic Regulation of Gene Expression by Histone Lysine β-hydroxybutyrylation (2016, positive): “Recently, β-hydroxybutyrate was reported to repress oxidative stress in mouse kidney by inhibiting endogenous class I HDAC activity (Shimazu et al., 2013).”
The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? (2016, background): “body DHB was found to have systemic HDAC inhibitory effects, potentially related to beneficial health effects of autophagy, the removal of surplus or damaged intracellular components, associated with intermitted fasting, caloric restriction or a ketogenic diet (Shimazu et al., 2013).”
Metabolic Control of Longevity. (2016, positive): “…effects by promoting the release of cortisol in the bloodstream (Yang et al., 2016), by increasing the circulating concentrations of ketone bodies including b-hydroxybutyrate, which activates FOXO3A (Shimazu et al., 2013), and by directly inhibiting the NLRP3 inflammasome (Youm et al., 2015).”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, background): “D-bOHB induces the canonical antioxidant proteins FOXO3a, SOD, MnSOD, and catalase prospectively through HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).”
Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate (2016, positive): “In addition, DBHB also has been shown to act as a class I HDAC inhibitor in non-neuronal tissues (Shimazu et al., 2013).”