From chromatin to carbohydrates: bridging the gap with β-hydroxybutyrate


Beta-hydroxybutyrate mediated inhibition of Class I HDACs in vitro and in vivo. Image obtained from: Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E. 2013. Suppression of oxidative stress by βydroxybutyrate, an endogenous histone deacetylases inhibitor. Science 339:211-214.

By Rebecca Golden

Paper: Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylases inhibitor

A cell must be able to adjust its genomic programming in response to changes in cellular metabolism so it can respond dynamically and efficiently to changes in its environment. Epigenetics is one such critical means of regulating gene expression by changing the packaging or structural features of DNA rather than the sequence of the DNA itself. Examples of epigenetic regulation include histone acetylation through histone acetyltransferases (HATS) and histone deacetylation through histone deacetylases (HDACs). Recently, cellular metabolites acetyl-coenzyme A (acetyl-CoA) and nicotinamide adenine dinucleotide (NAD+) have been identified as regulators of HATS and class III HDACs, providing the first known links between epigenetics and metabolism. These metabolites do not provide insight into regulation of class I HDACs, however, which are highly implicated in cell survival and proliferation (Dokmanovic et al. 2007). Now, a study by Shimazu et al. (Science 2013, 339, published online January 11, DOI:10.1126/science.1227166) identifies ketosis product β-hydroxybutyrate (βOHB) as an endogenous inhibitor of class I HDACs at physiological concentrations. Shimazu et al. demonstrate that βOHB-induced HDAC inhibition facilitates changes at epigenetic, transcriptional, translational, and functional levels in response to a metabolic need to reduce oxidative stress during fasting or calorie-restriction.


By assessing in vitro enzymatic activity of human recombinant HDACs in the presence of varying concentrations of βOHB, the authors demonstrate that βOHB exhibits dose-dependent inhibition of class I HDACs at IC50 values consistent with physiological concentrations of βOHB. The authors confirm βOHB inhibition of class I HDACs and a subsequent increase in global histone acetylation levels in vivo by assessing serum βOHB and kidney tissue histone acetylation levels of fasting mice, mice on calorie restricted diets, and mice fed exogenous βOHB in comparison to mice on control diets. To specifically identify βOHB as the source of increases in histone acetylation and HDAC inhibition, the authors also assess the relative contributions of ketosis co-product acetoacetate and of βOHB –catabolism product acetyl-CoA to changes in cellular histone acetylation; neither compound has the capacity to affect the observed epigenetic changes under physiological conditions.

The authors connect these epigenetic changes to a metabolic response to oxidative stress. Microarray analysis and QPCR of fasting, calorie-restricted, and βOHB –fed mouse kidney tissue identify that mRNA levels of genes in the “FOXO3A network” (Shimazu et al. 2013) are up-regulated in the presence of βOHB.  These genes confer resistance to oxidative stress. ChIP analysis of the genes’ promoters demonstrates elevated relative promoter region acetylation, and kidney samples of mice fed βOHB yield significantly lower levels of protein markers of oxidative stress as compared to mice fed control diets, demonstrating the global changes resulting from βOHB inhibition of class I HDACs. Further exploration of physiological effects resulting from βOHB-induced cellular changes in other ketogenic tissues may help elucidate the molecular basis for previously observed neuroprotective effects (Kim et al. 2007), which could be applied towards development of treatments for Mild Cognitive Impairment (MCI) and other neurodegenerative conditions (Krikorian et al. 2012).

One Reply to “From chromatin to carbohydrates: bridging the gap with β-hydroxybutyrate”

  1. As I read through the article I was looking for what the benefit to the study would be. I found it at the end and then when I re-read I understood better what was being said. I would recommend that a little more information be provided earlier to help the reader understand what the critical issue is and why it is important for us to understand.

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