Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review

Abstract

Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.

Keywords: NAFLD; SIRT1; epigenetic regulators; ketogenic diet; ketone bodies; obesity; visceral fat; β-OH-butyrate.

Figure 1

Schematic representation of the epigenetic activity of ketone bodies and SIRT1 in response to starvation or to the ketogenic diet. Synergistically, KBs and SIRT1 target both histone and nonhistone proteins and alter cellular metabolic programs. NAD, nicotinamide adenine dinucleotide; PTMs, post-translational modifications.

Figure 2

Schematic representation of the epigenetic control of KBs and SIRT1 on their targets. Post-translational modifications (PTMs) are key mechanisms for epigenetic regulation, which alters the activity of metabolic modulators. Abbreviations: NAD, nicotinamide adenine dinucleotide; AMPK, AMP-activated protein kinase; PPAR-alpha, peroxisome proliferator-activated receptor-α; PPAR-gamma, peroxisome proliferator-activated receptor-γ; PGC1-α, PPARγ-coactivator1-α; FOXO, Forkhead Box O; CRTC2, cAMP response element-binding (CREB)-regulated transcription coactivator 2; UCPs, uncoupling proteins; LXR, liver X receptor; FGF-21, fibroblast growth factor-21.