Ketone Bodies as Metabolites and Signalling Molecules at the Crossroad between Inflammation and Epigenetic Control of Cardiometabolic Disorders

Abstract

For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor.

Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization

“…Following adherence to a ketogenic diet, there was a notable enhancement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators, and an increase in the activity of neurotrophic factors [ 55 ]. Consequently, this dietary approach offers a potential nutritional remedy for alleviating diseases instigated by inflammatory conditions [ 56 ]. Additionally, ketone bodies play a crucial role in anti-senescence.…”

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue

“…Summarizing, ketone bodies, β-OHB, and acetoacetate, synthesized in the liver, are excreted by the liver cell through the MCT 1 and, via the circulation, arrive at extrahepatic tissues, including the heart, where they can be utilized as energy fuel [ 6 ]. Peripherally, β-OHB is reconverted into acetoacetate and then, as said, into acetoacetyl-CoA, which gets access into the Krebs cycle.…”

“…Ketone bodies comprise a family of three small low-molecular-weight hydrosoluble molecules, acetoacetate (AcAc), beta-hydroxybutyrate (β-OHB) (also known as 3-hydroxybutyrate), and acetone, which are synthesized mainly in the hepatic mitochondria and constitute a form of alternate fat-derived metabolic energy source for vital organs, including the heart, in states of nutrient shortage when glucose availability is low [ 5 , 6 ]. Ketone bodies are low-chain organic molecules with four (AcAc and β-OHB) or three carbon atoms (acetone), with β-OHB and acetone being the principal circulating ketone bodies; β-OHB accounts for ~70% of the total circulating ketones [ 7 ].…”

Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer’s disease

“…Three types of KBs, including beta-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone, are generated from the hydrolyzation of fatty acids ( Watanabe et al, 2020 ). These KBs are produced in the liver as the primary site of ketone synthesis, albeit they cannot be utilized by hepatocytes as the liver does not have ketolysis-related enzymes (enzyme Oxct1/SCOT1) to metabolize Acetoacetyl-CoA (AcAc-CoA) ( Bendridi et al, 2022 ). The newly synthesized KBs flow to the extra-hepatic tissues, including brain ( Bendridi et al, 2022 ).…”