Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters

Abstract

Ketone bodies have emerged as central mediators of metabolic health, and multiple beneficial effects of a ketogenic diet, impacting metabolism, neuronal pathologies and, to a certain extent, tumorigenesis, have been reported both in animal models and clinical research. Ketone bodies, endogenously produced by the liver, act pleiotropically as metabolic intermediates, signaling molecules, and epigenetic modifiers. The endothelium and the vascular system are central regulators of the organism's metabolic state and become dysfunctional in cardiovascular disease, atherosclerosis, and diabetic micro- and macrovascular complications. As physiological circulating ketone bodies can attain millimolar concentrations, the endothelium is the first-line cell lineage exposed to them. While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature, recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell (EC) functioning by modulating the EC inflammatory status, senescence, and metabolism. Here, we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies-at lower concentrations-on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms. We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects. At low concentration, endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies (or their precursors) may prove beneficial to ameliorate endothelial function and, consequently, pathologies in which endothelial damage occurs.

Keywords: Endothelial cells; Histone post-translational modifications; Ketone bodies; Vascular physiology; β-Hydroxybutyrate; β-Hydroxybutyrylation.

Figure 1

Concentration dependency of the biochemical and physiological responses to ketone bodies. Low to medium concentrations of ketone bodies, attained through fasting, ketogenic diet, or physical effort, convey physiologically beneficial effects. Conversely, pathological ketone body concentrations, observed in diabetic ketoacidosis, contribute to the disease morbidity and can be life threatening. HDACs: Histone deacetylases.

Figure 2

Schematic diagram summarizing the main epigenetic alterations induced by β-hydroxybutyrate or a ketogenic diet[7,46,62-67]. BHB: β-Hydroxybutyrate; HDACs: Histone deacetylases; KD: Ketogenic diet.

Figure 3

In vitro and in vivo responses to ketone bodies are dependent of their concentrations, with low to moderate concentrations exerting beneficial effects on the endothelium and the cardiovascular system and high concentrations typical of diabetic ketoacidosis being detrimental. AcAc: Acetoacetate; BHB: β-hydroxybutyrate; HUVECs: Human umbilical vein endothelial cells; ICAM-1: Intercellular-1 adhesion molecule; IL: Interleukin; KB: Ketone bodies; LFA-1: Lymphocyte function-associated antigen-1; MCP1: Monocyte chemotactic protein-1.

Figure 4

Summary of the physiological changes occurring upon assumption of a ketogenic diet that affects cardiovascular function. HbA1c: Hemoglobin A1c; HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipoprotein cholesterol; TG: Triglycerides.