“What is a Histone Deacetylase?”
Histone deacetylases (HDACs) are a category of protein that performs post-translational DNA modifications. Specifically, these proteins are known for their ability to remove acetyl groups from the histones of DNA, and thereby alter gene expression. A histone is a water-soluble protein that is attached to the DNA nucleosomes (groups of nucleotides). These histone proteins control the folding of the chromatin, and therefore the space available for enzymes that unzip and copy DNA into RNA, thereby affecting the translation rate. Histone acetylation, or the binding of acetyl groups to histones, is one of the important factors in determining this conformation and is an important component of the epigenome. The epigenome is the regulation of the genome, or the information that determines what genes are expressed in a given cell.
“Why are HDACs relevant?”
HDACs are important due to their ability to affect the translation of DNA. In our case, we want to look at ketosis and the relevance of HDACs to the effects of ketosis. First, we must note that beta-hydroxy-butyrate (BHB) is one of the so-called ketone bodies which increase during fasting and is associated with the metabolic state called ketosis (though not actually a ketone). BHB exerts numerous metabolic effects, and at least some of these may be due to its status as an inhibitor of HDACs. BHB is highly analogous to butyrate, also known as butyric acid, which is reported to act as an endogenous inhibitor of class 1 HDACs. The authors of “Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor” determined that BHB reduces oxidative stress and suggest this effect was likely due to an increase in Fox3a and Mt2 mRNA, which have been previously demonstrated to impart resistance to oxidative stress [1].
Further BHB’s potential ability to inhibit class 1 HDACs, specifically HDAC 2 and 3, may have other important effects. Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal survival and synaptic plasticity [4]. One paper reports that BHB facilitates the exercise-induced increase in BDNF - at least in mice - and that this effect is contingent on the inhibition of HDAC 2 and 3 [2]. At this time BHB is the only elucidated mechanistic mediator by which exercise induces BDNF expression and has significant implications for the benefits of ketogenic diets.
Other effects of inhibiting HDAC 3 include an increase in fibroblast growth factor 21 (FGF-21) and peroxisome-proliferator activated receptor-alpha (PPARa) [3]. FGF-21 appears to be an anti-aging factor associated with fasting, but also anti-anabolic effects [5]. PPARa is a transcriptional regulator of fatty acid metabolism and autophagy, with beneficial effects in mouse models of Alzheimer’s like disease [6]. I will go into detail on the PPAR genes in later posts as they are a notable topic of interest.
Other forms of histone regulation.
Though I spent most of this entire blog post talking about histone acetylation, this is merely a tiny slice of the research on HDACs. And that is nothing compared to trying to figure out the confusing mess that is other forms of histone regulation. Histones are proteins, and these proteins are composed of reactive amino acids. These amino acids can react with many regulatory molecules. When they react with BHB, the process is called beta-hydroxy-butyrylation. Beta-hydroxy-butyrylation also causes conformational changes the way that acetylation does, and some authors postulate this is BHB’s primary mode of epigenetic regulation not acting as a direct HDAC inhibitor. The number of biochemicals that can bind to histones is astoundingly large and the lack of adequate research in this area makes it even more difficult to fully cover such a topic so it will have to wait for another day to get its own blog post.
The Next Topic - HCAR2?
My most likely next topic for a post will be an overview of the hydroxycarboxylic acid receptor 2 (HCAR2). This receptor responds to one of our favorite endogenous molecules, BHB.
Sources:
[1] Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor | Pubmed Free Full Text
[2] Exercise promotes the expression of brain-derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate | Pubmed Free Full Text
[3] Sodium Butyrate Stimulates Expression of Fibroblast Growth Factor 21 in Liver by Inhibition of Histone Deacetylase 3 | Pubmed Free Full Text
[4] Brain-derived neurotrophic factor | Pubmed Free Full Text
[5] The starvation hormone, fibroblast growth factor-21, extends lifespan in mice | Pubmed Free Full Text
[6] Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model | Pubmed Free Full Text