ketolysis

Ketolysis is the metabolic process by which ketone bodies, primarily acetoacetate and beta-hydroxybutyrate, are oxidized to acetyl-CoA to fuel energy production in tissues outside the liver. Ketone bodies are produced in the liver during states of low carbohydrate availability or fasting and are transported to other tissues for use as an energy source. The liver itself cannot perform ketolysis because it lacks the key enzyme responsible for ketone body activation.

In peripheral tissues, beta-hydroxybutyrate is converted to acetoacetate by beta-hydroxybutyrate dehydrogenase, generating NADH. Acetoacetate is then activated to acetoacetyl-CoA by succinyl-CoA:3-oxoacid CoA transferase (SCOT) using succinyl-CoA as the CoA donor. The thiolase enzyme then cleaves acetoacetyl-CoA into two acetyl-CoA molecules, which enter the citric acid cycle to produce energy.

Ketolysis occurs in the mitochondria of tissues such as the heart, skeletal muscle, and brain (after adaptation), and its activity is upregulated during prolonged fasting or carbohydrate restriction. It is suppressed when insulin levels are high or dietary carbohydrate is abundant. The brain increases ketone body utilization after several days of fasting or during a ketogenic diet, reducing its need for glucose.

Clinical aspects are centered on rare defects in ketolysis, such as SCOT deficiency caused by mutations in the OXCT1 gene. This condition impairs ketone body utilization and can lead to metabolic crises during fasting or illness, characterized by ketoacidosis. Ketolysis remains an essential energy pathway during periods of energy scarcity when ketone bodies are abundant.