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World J Diabetes. Dec 15, 2020; 11(12): 584-595
Published online Dec 15, 2020. doi: 10.4239/wjd.v11.i12.584
Effects of ketogenic diet and ketone bodies on the cardiovascular system: Concentration matters
Souad Nasser, Varvara Vialichka, Marta Biesiekierska, Aneta Balcerczyk, Luciano Pirola
Souad Nasser, Luciano Pirola, Carmen Laboratory, INSERM Unit 1060—Lyon 1 University, Pierre Benite 69310, France
Varvara Vialichka, Marta Biesiekierska, Aneta Balcerczyk, Faculty of Biology and Environmental Protection, Department of Molecular Biophysics, University of Lodz, Lodz 90-236, Poland
Varvara Vialichka, The University of Lodz Doctoral School of Exact and Natural Sciences, Lodz 90-237, Poland
Author contributions: All authors contributed to the writing of the manuscript; Pirola L and Balcerczyk A supervised the project and generated the final version of the paper.
Supported by Polish National Science Centre, Project Grant NCN Harmonia, No. 2019/30/M/NZ3/00682; and NAWA/Campusfrance Polonium, No. PPN/X/RJ/1876/2019.
Conflict-of-interest statement: The authors have declared no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Luciano Pirola, PhD, Senior Scientist, Carmen Laboratory, INSERM Unit 1060—Lyon 1 University, South Lyon Medical Faculty Sector 2, CENS ELI-2D Building, 165 Chemin du Grand Revoyet, Pierre Benite 69310, France. luciano.pirola@univ-lyon1.fr
Received: July 31, 2020
Peer-review started: July 31, 2020
First decision: September 24, 2020
Revised: September 29, 2020
Accepted: October 19, 2020
Article in press: October 19, 2020
Published online: December 15, 2020
Processing time: 131 Days and 17.9 Hours
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; Ketone bodies; Vascular physiology; β-Hydroxybutyrate; β-Hydroxybutyrylation; Histone post-translational modifications

Core Tip: Ketone bodies, acting as fuel molecules, signaling molecules, and epigenetic regulators, improve metabolic health and lifespan. The endothelium and the vascular system are central regulators of the organism’s metabolic state and become dysfunctional in cardiovascular disease and diabetic complications. While in diabetic ketoacidosis high ketone bodies concentrations are detrimental to the vasculature, ketone bodies in the low millimolar range may exert beneficial effects on the vascular system. At low concentrations, ketone bodies may prove beneficial to ameliorate vascular function and alleviate cardiovascular disease.