Ketogenesis

Jul 17, 2024

Ketogenesis Lecture Notes

Overview

  • Ketogenesis: Process occurring when there's an excess of acetyl-CoA but not enough oxaloacetate.
  • Trigger: Largely due to a lack of oxaloacetate, which prevents acetyl-CoA from entering the citric acid cycle.

Causes of Excess Acetyl-CoA

  • Diabetes: Body cannot uptake glucose, leading to perceived starvation.
    • Glycogen stores are depleted.
    • Body switches to burning fatty acids.
  • Starvation: Similar pathway as diabetes.
    • Low glucose intake depletes glycogen, necessitating fatty acid burning.
  • Normal Fasting: Even healthy individuals can undergo ketogenesis during fasts or overnight.

Pathway of Ketogenesis

  1. Two molecules of acetyl-CoA combine through a series of steps.
  2. End Products: Acetone and beta-hydroxybutyrate.

Clinical Indicators

  • Acetone Detection: Can be smelled on breath or found in urine of individuals undergoing ketogenesis.
  • Ketone Bodies: Specifically look for acetone and beta-hydroxybutyrate in clinical tests.
  • Diabetic Tests: Amount of ketone bodies/acetone in urine is monitored.

Uses and Metabolism of Beta-Hydroxybutyrate

  • Energy Source: Exported from liver to other tissues, especially the brain.
    • Brain Priority: Brain uses beta-hydroxybutyrate as it is energy-efficient.
    • In diabetics, causes tingling in extremities as energy is diverted to the brain.
  • Conversion Steps:
    1. Beta-hydroxybutyrate is reduced to generate NADH.
    2. Converted to acetoacetate.
    3. Acetoacetate undergoes transferase reaction, accepting a CoA group to form acetoacetyl-CoA.
    4. Acetoacetyl-CoA yields two molecules of acetyl-CoA via thiolase reaction.

Citric Acid Cycle Under Starvation

  • Limited Oxaloacetate: Only the essential oxaloacetate is used for citric acid cycle.
  • Body Preserving Brain: All processes that could divert molecules from the cycle are shut down.
  • ATP Generation: Each acetyl-CoA through the citric acid cycle produces around 10 ATP.

Summary

  • Ketogenesis: Formation of acetone and beta-hydroxybutyrate is a response to excess acetyl-CoA & low oxaloacetate.
    • Normal in fasting, but also a clinical marker in diabetes.
  • Energy Management: Body prioritizes brain energy needs during perceived starvation, limiting ketone bodies to other tissues.