Why a d-β-hydroxybutyrate monoester?

Abstract

Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-β-hydroxybutyrate (βHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate βHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible βHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The βHB monoester is a salt-free βHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the βHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the βHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.

Keywords: Ketone monoester; ketone bodies; ketosis.

Conflict of interest statement

The intellectual property covering the uses of ketone bodies and ketone esters are owned by BTG Plc, Oxford University Innovation Ltd and the US National Institutes of Health. Professor Kieran Clarke, as an inventor, will receive a share of the royalties under the terms prescribed by each institution. Professor Clarke is a director of TdeltaS Ltd, a company spun out of the University of Oxford to develop products based on the science of ketone bodies in human nutrition. The other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper.

© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Figures

Figure 1.. In hepatocytes, acetyl-coenzyme A acetyltransferase (ACAT: 1) combines two acetyl-CoA molecules into acetoacetyl-CoA (AcAc-CoA).

AcAc-CoA is combined with another acetyl-CoA by HMG-CoA synthase (2) to form 3-hydroxymethylglutaryl-CoA (HMG-CoA). HMG-CoA lyase (3) cleaves HMG-CoA, releasing acetyl-CoA and the ketone body, acetoacetate (AcAc). AcAc can then be reduced to βHB by βHB dehydrogenase (4). βHB, the main transport ketone, exits hepatocytes via monocarboxylate transporters (MCT) and travels through the circulation to peripheral tissues. Once there, βHB is oxidised back into AcAc by βHB dehydrogenase (4). In the rate-limiting step of ketolysis, succinyl-CoA-3-oxaloacid CoA transferase (SCOT) (5) converts AcAc and succinyl-CoA into AcAc-CoA and succinate. AcAc-CoA is then cleaved by ACAT (1) to yield two molecules of acetyl-CoA that can enter the Krebs cycle.

Figure 2.. The βHB monoester bond is cleaved by gut esterases, yielding βHB and butanediol, which enter the portal circulation.

In the liver, alcohol dehydrogenase (ADH) converts butanediol converted into βHB, which leaves via the monocarboxylate transporters (MCT). Each monoester molecule thus yields two βHB equivalents.