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Ketone bodies as epigenetic modifiers

Ruan, Hai-Bina; Crawford, Peter, A.b,c

Current Opinion in Clinical Nutrition and Metabolic Care: July 2018 - Volume 21 - Issue 4 - p 260–266
doi: 10.1097/MCO.0000000000000475
GENES AND CELL METABOLISM: Edited by George Grimble and Luc A. Cynober

Purpose of review Ketone body metabolism is a dynamic and integrated metabolic node in human physiology, whose roles include but extend beyond alternative fuel provision during carbohydrate restriction. Here we discuss the most recent observations suggesting that ketosis coordinates cellular function via epigenomic regulation.

Recent findings Ketosis has been linked to covalent modifications, including lysine acetylation, methylation, and hydroxybutyrylation, to key histones that serve as dynamic regulators of chromatin architecture and gene transcription. Although it remains to be fully established whether these changes to the epigenome are attributable to ketone bodies themselves or other aspects of ketotic states, the regulated genes mediate classical responses to carbohydrate restriction.

Summary Direct regulation of gene expression may occur in-vivo via through ketone body-mediated histone modifications during adherence to low-carbohydrate diets, fasting ketosis, exogenous ketone body therapy, and diabetic ketoacidosis. Additional convergent functional genomics, metabolomics, and proteomics studies are required in both animal models and in humans to identify the molecular mechanisms through which ketosis regulates nuclear signaling events in a myriad of conditions relevant to disease, and the contexts in which the benefits of ketosis might outweigh the risks.

aDepartment of Integrative Biology and Physiology

bDivision of Molecular Medicine, Department of Medicine

cDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA

Correspondence to Peter A. Crawford, MD, PhD, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. E-mail: crawforp@umn.edu

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