Chapter 10: Ketone Synthesis and Utilization Defects

NORMAL KETONE BODY METABOLISM

The ketone bodies acetoacetate (AcAc) and 3-hydroxybutyrate (3HB) are four carbon carboxylic acids produced in the liver, mainly from the oxidation of fatty acids. Ketone bodies are transported from the liver to other tissues, where they can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle. 3-Hydroxybutyrate, acetoacetate, and acetone are all colloquially called ketone bodies, but chemically 3-hydroxybutyrate is a carboxylic acid, not a ketone body.

Ketones are a source of energy for extrahepatic tissues such as brain and skeletal and cardiac muscle. They are particularly important for the brain, especially during periods of prolonged fasting or starvation when glucose supply is limited, as the brain has no other substantial non–glucose-derived energy source. Defects in ketone body synthesis (ketogenesis) result in hypoketotic hypoglycemic crises during prolonged fasting or febrile illness, whereas defects in ketone body utilization (ketolysis) result in ketoacidotic crises. While both acetoacetate and 3-hydroxybutyrate can be utilized as fuels, acetone is formed by spontaneous decarboxylation of excess acetoacetate, is volatile, is a metabolic end product, and is eliminated via expiration. Acetone is the cause of the sweet odor on the breath in persons with ketoacidosis. Inherited disorders of ketogenesis include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2) deficiency and HMG-CoA lyase (HMGCL) deficiency. The defects in ketolysis include succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (b-ketothiolase or T2) deficiency. HMGCL deficiency and T2 deficiency also affect leucine and isoleucine catabolism, respectively.¹

Overview of Ketone Body Metabolism

Free fatty acids (FFA) are the source of ketone body synthesis (Figure 10-1). Hepatic mitochondrial b-oxidation of FFA produces acetyl-CoA; during periods of excess acetyl-CoA production, acetoacetyl-CoA is formed from the condensation of two acetyl-CoA molecules. HMGCS2 further catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA. HMG-CoA is then cleaved into AcAc and acetyl-CoA by HMG-CoA lyase (HMGCL). A portion of the AcAc produced is converted into 3HB by the reverse reaction of 3-hydroxybutyrate dehydrogenase. AcAc and 3HB are then exported into blood. Extrahepatic tissues are able to take up these ketone bodies into mitochondria. In extrahepatic tissues, 3HB is first converted back to AcAc. AcAc is then activated to acetoacetyl-CoA by SCOT. Acetoacetyl-CoA is subsequently converted into two molecules of acetyl-CoA by mitochondrial T2 which can be used as an energy source via the Krebs cycle. Of note, an abnormal elevation of the 3HB/AcAc ratio is typically suggestive of a non-oxidized state of the hepatocyte mitochondrial matrix resulting from hypoxia-ischemia or other causes.²

SCOT activity is absent from liver, hence hepatic mitochondria produce ...