Lecture on Ketone Body Metabolism (Ketolysis)

Overview

• Ketolysis refers to the catabolism of ketone bodies to be used as energy.
• Main ketone bodies: beta-hydroxybutyrate and acetoacetate.
• Ketone bodies are produced in the liver during fasting or intense exercise from the beta-oxidation of fatty acids.
• Utilized by peripheral tissues, primarily the brain and skeletal muscle.

Ketone Body Utilization

• Beta-hydroxybutyrate is the most abundant ketone body.
• During fasting, serum levels of beta-hydroxybutyrate increase:
  • 16-hour fast: several hundred micromolar
  • 48-hour fast: 1-2 millimolar
• Intense exercise (~90 minutes) can also raise beta-hydroxybutyrate levels to 1-2 millimolar.
• Ketogenic diet results in consistently elevated beta-hydroxybutyrate levels (>2 millimolar).

Transport and Metabolism

• Ketone bodies transported from the liver via SLC16A6 transporter.
• Believed to dissolve in blood due to polar groups, not requiring transport proteins.
• Brain: uses monocarboxylate transporters (MCT1, MCT2) to transport ketone bodies across the blood-brain barrier.
• Skeletal Muscle: allows passive diffusion of ketone bodies.

Metabolic Pathway

• Beta-hydroxybutyrate is converted to acetoacetate by beta-hydroxybutyrate dehydrogenase, reducing NAD+ to NADH.
• Reversible reaction influenced by NAD+/NADH levels.
• Acetoacetate can spontaneously degrade to acetone, which is exhaled.
• Major pathway: Acetoacetate is converted to acetoacetyl-CoA by succinyl-CoA:3-ketoacid CoA transferase (OXCT1 or SCOT), bypassing HMG-CoA lyase.
• Liver lacks OXCT1 enzyme, thus cannot perform ketolysis.

Energy Production

• Acetoacetyl-CoA is split into two acetyl-CoA by thiolase, entering the citric acid cycle to produce NADH and FADH2.
• ATP yield:
  • Beta-hydroxybutyrate oxidation: 26 moles of ATP
  • Acetoacetate oxidation: 23 moles of ATP
  • Additional ATP from NADH in beta-hydroxybutyrate metabolism (~2.5 ATP).

Importance of Ketone Utilization

• Spares glucose, maintaining blood glucose levels for glucose-dependent cells (e.g., red blood cells).

Conclusion

• Ketolysis provides an alternative energy source, particularly beneficial during glucose scarcity conditions such as fasting and prolonged exercise.
• Ensures availability of glucose for essential glucose-reliant cells.