Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

Abstract

Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies’ biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies’ consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD’s application on cardiovascular health and on physical performance.

Short-Term Physiological Effects of a Very Low-Calorie Ketogenic Diet: Effects on Adiponectin Levels and Inflammatory States

“…A low-calorie diet is a balanced diet characterized by 45%-55% carbohydrates, 15%-25% proteins, and 25%-35% fat, with the additional dose of 30 g of fiber in the form of fruit and vegetables [15]. On the contrary, the ketogenic diet is low in carbohydrates (<50 g daily from vegetables) and lipids (only 10 g of olive oil per day) [16].…”

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

“…Several different mechanisms of PTMs of SIRT1 have been described, including, but not limited to, phosphorylation, ubiquitination, and methylation [ 80 , 83 ]. A new PTM in the presence of high concentrations of the ketone body–ßHB has been described called lysine beta-hydroxybutyrylation [ 84 ]. Although this PTM has not been directly described in the context of sirtuins, it may provide valuable insights into the function of sirtuins in mediating the therapeutic effect of KD.…”

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

“…Ketogenesis also represents a metabolic pathway required for the development of memory CD8+ T cells where BHB promotes β-hydroxybutyrylation of Lys9 in H3 (H3K9bhb) and this is associated to upregulation in the gene expression of Foxo1 and Ppargc1a, which cooperatively upregulate Pck1 expression [50]. Furthermore, BHB regulates the inflammasome and the expression of associated inflammatory genes through histone Kbhb, reducing inflammatory responses and blood pressure [51]. Finally, BHB induces β-hydroxybutyrylation in histone H3 (H3K9bhb) of the adiponectin gene and adiponectin expression in adipocytes [52].…”