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.

Keywords: cancer; epigenetics; inflammatory response; ketogenic diet; ketone bodies; β-hydroxybutyrate.

Figure 1

Metabolism of ketone bodies. (A) Synthesis of ketone bodies in the liver mitochondria. (B/C) Alternative metabolic fates of ketone bodies. (B) Funneling in the Krebs via succinyl-CoA:3-ketoacid coenzyme A transferase (SCOT) in mitochondria of extrahepatic tissues, and (C) their being used as metabolic precursors in cholesterol synthesis or de novo lipogenesis.

Figure 2

The epigenetic effect of ketone bodies on chromatin status. Pathways of modification of chromatin conformation by ketone bodies through histone posttranslational modifications (PTMs): (i) increasing the pool of acetyl-CoA as substrate for HATs, (ii) inducing changes methylation status of histones and (iii) causing β-hydroxybutyrylation per se or hyperacetylation with β-hydroxybutyrate acting as a histone deacetylase inhibitor.

Figure 3

Selective use of ketone bodies by normal, non-cancerous cells can allow bypassing the glucose-induced Warburg effect in cancer cells. (A) In normal cells, glucose is fully oxidized through glycolysis followed by the mitochondrial Krebs cycle coupled to oxidative phosphorylation. (C) In cancer cells, pyruvate (the last metabolic intermediate of glycolysis) is reduced to lactate, which may serve as a precursor to sustain biosynthetic pathways. (B,D) Under conditions of glucose depletion, insulin deficiency, ketogenic diet or prolonged intensive physical activity, glucose becomes limited and cells resort to the use of ketone bodies, including BHB. (B) In normal cells, BHB can sustain extra mitochondrial biosynthetic pathways and serve as a AcCoA source to feed the Krebs cycle. (D) In cancer cells, the replacement of glucose as the primary energy source with ketone bodies (BHB) enables blunting the Warburg effect and tumor cell growth. (GLUT, glucose transporter; MCT monocarboxylate transporter; OxPhos, oxidative phosphorylation; SCOT, Succinyl-CoA: 3-ketoacid CoA transferase; ROS, reactive oxygen species; AcAc, acetoacetate).