Overview
This lecture covers ketone metabolism, including the conditions that trigger ketogenesis, the biochemical pathway for ketone body formation, and the use and clinical significance of ketones in the body.
Triggers for Ketone Metabolism
- Ketone metabolism is activated during low blood glucose, prolonged starvation, uncontrolled diabetes (especially type 1), or low-carbohydrate diets (e.g., Atkins diet).
- The brain and muscles are the main organs that use ketone bodies as alternative energy sources when glucose is scarce.
Sites and Pathway of Ketogenesis
- Ketogenesis occurs in the liver, where fatty acids are broken down to acetyl CoA via beta-oxidation.
- When glucose is low, oxaloacetate is diverted for gluconeogenesis, limiting acetyl CoA entry into the Krebs cycle.
- Excess acetyl CoA is converted into ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone.
Key Steps in Ketone Body Formation
- Two acetyl CoA molecules combine to form acetoacetyl CoA (via acetyl CoA acyl transferase).
- Acetoacetyl CoA + another acetyl CoA form HMG CoA (via HMG CoA synthase, the rate-limiting enzyme).
- HMG CoA is split into acetoacetate (via HMG CoA lyase).
- Acetoacetate can be reduced to beta-hydroxybutyrate (via beta-hydroxybutyrate dehydrogenase) or spontaneously decarboxylated to acetone (via acetoacetate decarboxylase).
Utilization of Ketone Bodies
- Acetoacetate and beta-hydroxybutyrate enter the blood, taken up by muscles and the brain for energy.
- In tissues, beta-hydroxybutyrate is oxidized back to acetoacetate, which is then converted to acetoacetyl CoA (using succinyl CoA) and further split into two acetyl CoA molecules to enter the Krebs cycle for ATP production.
Clinical and Diagnostic Considerations
- Ketone bodies are acidic (pKa ≈ 4-5), leading to metabolic acidosis (ketoacidosis) if produced excessively.
- Signs include fruity (acetone) breath, high anion gap, vomiting, dehydration, and Kussmaul breathing (deep, rapid breathing).
- Excess ketones can be detected in urine (ketonuria); severe cases can lead to hypovolemia and coma.
Key Terms & Definitions
- Ketogenesis — Formation of ketone bodies from acetyl CoA in the liver.
- Beta-oxidation — Breakdown of fatty acids to generate acetyl CoA.
- Gluconeogenesis — Creation of glucose from non-carbohydrate sources, consuming oxaloacetate.
- HMG CoA Synthase — Rate-limiting enzyme for ketone body synthesis.
- Ketoacidosis — Metabolic acidosis caused by excessive ketone bodies.
Action Items / Next Steps
- Review glycolysis, the Krebs cycle, and electron transport chain.
- Practice drawing the ketogenesis pathway.
- Prepare notes on clinical signs of ketoacidosis.