β-hydroxybutyrate: much more than a metabolite

Abstract

The ketone body β-hydroxybutyrate (βOHB) is a convenient carrier of energy from adipocytes to peripheral tissues during fasting or exercise. However, βOHB is more than just a metabolite, having important cellular signaling roles as well. βOHB is an endogenous inhibitor of histone deacetylases (HDACs) and a ligand for at least two cell surface receptors. In addition, the downstream products of βOHB metabolism including acetyl-CoA, succinyl-CoA, and NAD+ (nicotinamide adenine dinucleotide) themselves have signaling activities. These regulatory functions of βOHB serve to link the outside environment to cellular function and gene expression, and have important implications for the pathogenesis and treatment of metabolic diseases including type 2 diabetes.

Keywords: Acetylation; Epigenetics; HDAC; Ketone bodies; Low carbohydrate.

Figure 1. Cellular signaling functions of the ketone body βOHB

βOHB itself is an endogenous inhibitor of histone deacetylase enzymes, thereby altering gene expression to regulate resistance to oxidative stress and possibly many other cellular functions. βOHB is also a ligand for at least two cell-surface G-protein-coupled receptors that modulate lipolysis, sympathetic tone, and metabolic rate.

Figure 2. Cellular signaling functions of βOHB downstream metabolites

Metabolism of βOHB increases cellular levels of acetyl-CoA and reduces levels of succinyl-CoA and NAD+. These secondary effects can further increase mitochondrial protein acetylation and reduce mitochondrial protein succinylation, potentially regulating the function of many metabolic enzymes. The relative sparing of cytoplasmic NAD levels with utilization of BOHB rather than glucose can alter the activity of NAD-dependent enzymes such as sirtuins. Finally, acetyl-CoA generated in mitochondria can be transported into the nucleus via the citrate shuttle to serve as substrate for histone acetyltransferases, a secondary mechanism by which BOHB might increase histone acetylation and alter gene expression.