Ketone Metabolism Overview

Overview

This lecture explains ketone metabolism, including when and why it occurs, the steps of ketone body synthesis (ketogenesis), and how different tissues use ketone bodies for energy, especially under conditions of low glucose.

Conditions Stimulating Ketone Metabolism

• Ketone metabolism occurs during low blood glucose, prolonged starvation, uncontrolled type 1 diabetes, and carbohydrate-restrictive diets (e.g., Atkins).
• The brain primarily uses glucose but switches to ketone bodies when glucose is scarce.
• Muscles can also use ketone bodies, especially during low glucose and high fatty acid oxidation.

Location and Organs Involved

• Ketogenesis primarily occurs in the liver.
• Ketone body utilization for energy occurs in the muscles and brain.

Biochemical Pathways

• Under normal conditions, glucose is oxidized to pyruvate, then to acetyl-CoA, which enters the Krebs cycle.
• Low glucose reduces pyruvate and acetyl-CoA, decreasing Krebs cycle activity.
• The body increases fatty acid breakdown (beta oxidation), generating acetyl-CoA.
• When gluconeogenesis depletes oxaloacetate, excess acetyl-CoA is diverted to ketone body formation.

Ketone Body Synthesis (Ketogenesis)

• Two acetyl-CoA combine (via acetoacetyl-CoA transferase) to form acetoacetyl-CoA.
• Acetoacetyl-CoA plus another acetyl-CoA (via HMG-CoA synthase, the rate-limiting enzyme) forms HMG-CoA.
• HMG-CoA lyase converts HMG-CoA into acetoacetate (a ketone body).
• Acetoacetate is reduced by beta-hydroxybutyrate dehydrogenase (using NADH) to beta-hydroxybutyrate (another ketone body).
• Acetoacetate can also be converted to acetone (non-usable, volatile) by acetoacetate decarboxylase.

Clinical Implications and Diagnostics

• Acetoacetate and beta-hydroxybutyrate are acidic, potentially causing ketoacidosis, indicated by low blood pH and high anion gap (>11 mmol/L).
• Excess ketone bodies can cause acetone (fruity) breath, vomiting, dehydration (hypovolemia), and coma.
• Kussmaul (deep, rapid) breathing is a compensatory response to acidosis.
• Elevated ketone levels in urine (ketonuria) help diagnose ketoacidosis.

Utilization of Ketone Bodies (Ketolysis)

• Ketone bodies are transported to muscles and brain through blood.
• Beta-hydroxybutyrate is converted back to acetoacetate (producing NADH).
• Acetoacetate receives a CoA from succinyl-CoA (via thiophorase) to form acetoacetyl-CoA, then split into two acetyl-CoA.
• Acetyl-CoA enters the Krebs cycle to produce ATP.
• The brain uses ketone bodies during prolonged low glucose because fatty acids cannot cross the blood-brain barrier.

Key Terms & Definitions

• Ketone Bodies — Energy molecules (acetoacetate, beta-hydroxybutyrate, acetone) formed from excess acetyl-CoA.
• Ketogenesis — Liver process of converting acetyl-CoA into ketone bodies.
• Beta Oxidation — Process breaking down fatty acids into acetyl-CoA.
• Ketoacidosis — Acidic blood condition due to excessive ketone bodies.
• Kussmaul Breathing — Deep, rapid respiration to reduce blood acidity.
• Ketonuria — Presence of ketone bodies in urine.
• HMG-CoA Synthase — Rate-limiting enzyme of ketogenesis.

Action Items / Next Steps

• Review gluconeogenesis and Krebs cycle for background context.
• Practice drawing ketogenesis and ketolysis pathways.
• Prepare for questions on diagnostics and consequences of ketoacidosis.