Ketone bodies as signaling metabolites

Abstract

Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. We review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism and in diseases of aging.

Keywords: HDAC; acetylation; calorie restriction; epigenetics; longevity.

Figure 1. Outline of ketone body metabolism and regulation

The key irreversible step in ketogenesis is synthesis of 3-hydroxy-3-methylglutaryl-CoA by HMGCS2. Conversely, the rate limiting step in ketolysis is conversion of acetoacetate to acetoacetyl-CoA by OXCT1. HMGCS2 transcription is heavily regulated by FOXA2, mTOR, PPARα, and FGF21. HMGCS2 activity is post-translationally regulated by succinylation and acetylation/SIRT3 deacetylation. Other enzymes are regulated by cofactor availability (e.g., NAD/NADH₂ ratio for BDH1). All enzymes involved in ketogenesis are acetylated and contain SIRT3 deacetylation targets, but the functional significance of this is unclear other than for HMGCS2. Although ketone bodies are thought to diffuse across most plasma membranes, the transporter SLC16A6 may be required for liver export, while several monocarboxylic acid transporters assist with transport across the blood-brain barrier.

Figure 2. Intersection of longevity pathways and regulation of βOHB production

βOHB production is controlled by at least two nutrient-responsible pathways that are implicated in longevity and may be subject to regulation by βOHB via HDAC inhibition. Rapamycin and down-regulation of the mTOR pathway promote ketogenesis; rapamycin and FGF21 enhance mammalian longevity. FOXA2 also enhances ketogenesis, and its activation is regulated by both class III (sirtuins) and class I/II HDACs.

Figure 3. Cellular signaling mediated by βOHB

βOHB is a ligand for at least two cell-surface G-protein-coupled receptors that modulate lipolysis, sympathetic tone, and metabolic rate. In addition, βOHB alters protein acetylation through at least two mechanisms: increasing the cellular pool of acetyl-CoA that is a substrate for histone acetyltransferases, and directly inhibiting the activity of class I histone deacetylases. Abbreviations: CS, citrate synthase. ACLY, ATP-citrate lyase.

Figure 4. HDAC regulation of longevity pathways

HDACs deacetylate both histone and non-histone proteins, regulating gene transcription and the post-translational function of proteins. HDACs regulate a variety of pathways implicated in longevity and age-related disease, and modulation of HDAC activity regulates lifespan in model organisms.