How metabolism alters epigenetics

CNS metabolism Neuronal activity accounts for 80% of the brain’s energy consumption. Blood-borne glucose is an essential energy source for the adult human brain. Both neurons and astrocytes take up glucose via the cell-specific transporters GLUT1 and GLUT3. Upon increased demand neurons ability to take up glucose is limited and lactate provided by astrocytes becomes the primary oxidative fuel. Under certain conditions the brain can also utilize acetoacetate, b-hydroxybutyrate and acetone (ketone bodies) derived from fatty acids as alternative energy source. Neurons metabolize ketone bodies to Acetyl-CoA, which is further oxidized through the TCA cycle. High circulating levels of ketone bodies are known to protect the brain. Ketone bodies also prevent seizures in GLUT1 difficiency syndrome and are important for brain development, but cellular and molecular mechanisms underlying the protective effect of ketone bodies are not yet fully clear. In the following I discuss the presumable link of metabolism with epigenetic changes and implications in brain function.

Balancing the epigenome Epigenetic marks are initiated, perpetuated, and removed via the activity of numerous enzymes (e.g. DNMTs, HATs, HDACs, HMTs, HDMs among many others). Histone and DNA modifying enzymes are able to sense metabolic changes, because they depend on cofactors from numerous biochemical pathways to power their effort. Histone acetyltransferases (HATs) catalyze the acetylation of lysine residues in the N-terminal tails of core histone proteins. With acetyl-CoA as cofactor they link glycolysis, fatty acid and amino acid metabolism with epigenetic gene regulation. HDACs are the natural counterpart of HATs and are implicated in gene silencing. The peculiar Sirtuin family of HDACs uses NAD+ as cofactor to break the bond between lysine and acetyl group. Seizure activity can lead to energy failure. Vice versa, mutations affecting metabolic genes implicated in the maintenance of cellular energy homeostasis often result in an epileptic phenotype. TCA cycle deficits seem to be particularly involved in generating seizures.

Metabolism and epigeneticsMetabolites as endogenous HDAC inhibitors When glycolysis exceeds the cell’s aerobic metabolic capacity lactate accumulates and can enter the nucleus, where it acts as endogenous HDAC inhibitor. Although weaker than other HDAC inhibitors, lactate induces hyperacetylation and increased gene expression. β-Hydroxybutyrate is the major source of energy for mammals during prolonged exercise or starvation and has selective inhibitory function for a subtype of HDACs. Inhibition of HDACs by β-hydroxybutyrate may contribute to the beneficial effect of the ketogenic diet in epilepsy treatment.

The special role of α-ketoglutarate By the conversion of isocitrate and as anaplerotic carbon source under hypoxic conditions (by synthesis from glutamate), α-ketoglutarate is a particularly important intermediate of the TCA cycle. It is further an essential co-factor of histone demethylases (HDMs) and of the Ten-eleven translocation (TET) protein family members. TET enzymes are thought to be involved in active DNA demethylation as they convert DNA methylation (5-mC) to DNA hydroxymethylation (5-hmC). DNA hydroxymethylation is essential during postnatal development and aging, as well as higher order brain function including learning and memory. Experimental evidence clearly supports an involvement of oxidative stress in seizure generation and it can be anticipated that α-ketoglutarate availability perturbs gene activity via epigenetic mechanisms in the epileptic brain.

Oxidative stress Changes in redox homeostasis and oxidative stress can further alter DNA and histone methylation levels through regulation of a key enzyme in the transmethylation cycle. Any methylation reaction in the cell requires S-adenosylmethionine (SAM) as methyl group donor. After transfer of the methyl group to an acceptor molecule SAM needs to be regenerated via the transmethylation pathway, which is sensitive to changes in redox homeostasis. A reducing environment increases SAM production and supports e.g. DNA methylation. Conversely, a more oxidized environment has been proposed to decrease SAM levels and inhibit methylation reactions. Disturbances in folate or adenosine metabolism, which are both directly linked to the transmethylation pathway, have been associated with seizures in humans and rodents.

Lessons learned There is growing evidence that disruption in the production and availability of metabolic intermediaries like S-adenosylmethionine, α‑ketoglutarate, β-hydroxybutyrate, lactate, NAD+, and acetyl-CoA can modify the epigenotype of neuronal and glial cells. Redox biology can change epigenetic events through oxidation of enzymes and alterations of metabolic cofactors that affect epigenetic events like DNA methylation. Combined, these metabolic and redox changes serve as the foundation for altering the epigenotype of normal cells and may help create the epigenetic progenitor of any pathological condition including epilepsy. 

3 thoughts on “How metabolism alters epigenetics

  1. Great summation of these mechanisms. I was wondering, do you have links to the publications done on metabolism and epigenetics? I’ve been having a hard time tracking down the studies to sight. I’m especially interested in carbohydrate & keytone effects on epigenetic methylation. :0)

  2. Pingback: SLC25A22, migrating seizures and mitochrondial glutamate deficiency | Beyond the Ion Channel

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