Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta-Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons

The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)-a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites-beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both-BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.