Biochemistry · MU Pleven

30. Ketogenesis and Ketolysis. Intertissue Connections in Ketone Substances Metabolism. Ketoacidosis. Importance of Ketone Substances.

Covers the three ketone bodies and their formation in liver mitochondria from fatty acids and acetyl-CoA, with the enzymatic steps including the rate-limiting HMG-CoA synthase. It then explains how extrahepatic tissues such as brain, muscle and heart use ketones via thiophorase, and traces the inter-tissue link between adipose tissue, liver and peripheral organs. The note closes with ketoacidosis, its causes, mechanism and clinical signs, and the overall importance of ketone bodies during fasting.

Inside: 4 sections · 4 labelled pictures · 10 flashcards · 3 min

Topic 30 of 76 in the MU Pleven syllabus for Biochemistry (Medicine, Year 2). The free AceMed note covers it in 4 sections, about 389 words (3 min of reading), with 10 flashcards.

In this note

  1. Ketogenesis and Ketolysis. Intertissue Connections in Ketone Substances Metabolism.
  2. Ketogenesis and Ketolysis
  3. Ketolysis (Utilization of Ketone Bodies)
  4. Ketoacidosis

Ketogenesis and Ketolysis

1. What Are Ketone Bodies?

  • Ketone bodies are water-soluble molecules made from acetyl-CoA in the liver.
  • The three ketone bodies are:
  • Acetoacetate
  • β-Hydroxybutyrate
  • Acetone (non-metabolizable → exhaled, fruity breath smell)
  • They serve as an alternative energy source when glucose is limited.

2. When Does Ketogenesis Occur?

  • Low carbohydrate availability:
  • Fasting
  • Prolonged exercise
  • Starvation
  • Low-carb diet
  • Uncontrolled diabetes mellitus (insulin deficiency → excessive ketone formation).
  • When β-oxidation of fatty acids increases, acetyl-CoA accumulates in the liver.

3. Location of Ketogenesis

  • Occurs in the mitochondria of liver hepatocytes.
  • The liver produces ketone bodies but cannot use them (lacks the enzyme thiophorase).

4. Steps of Ketogenesis

  • Fatty acids → Acetyl-CoA (via β-oxidation).
  • Two acetyl-CoA combine → Acetoacetyl-CoA.
  • Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (via HMG-CoA synthase — rate limiting enzyme).
  • HMG-CoA → Acetoacetate.
  • Acetoacetate is converted into:
  • β-Hydroxybutyrate (reversible) depending on NADH level.
  • Acetone (spontaneous decarboxylation).

Ketolysis (Utilization of Ketone Bodies)

1. Organs that Use Ketone Bodies

  • Brain (during fasting > 2–3 days) — reduces glucose requirement.
  • Skeletal muscle (especially during exercise).
  • Heart muscle (prefers ketones over glucose).
  • Kidneys.

The liver cannot use ketones → lacks enzyme thiophorase.

2. Steps of Ketolysis

  • β-Hydroxybutyrate → Acetoacetate.
  • Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA (via Thiophorase).
  • Acetoacetyl-CoA → 2 Acetyl-CoA.
  • Acetyl-CoA enters the Citric Acid Cycle → ATP production.

Intertissue Connections in Ketone Metabolism

  • Adipose tissue breaks down triglycerides → releases free fatty acids into blood.
  • Liver converts these fatty acids → ketone bodies.
  • Ketone bodies are transported via blood to brain, muscle, heart.
  • These tissues convert ketones → acetyl-CoA for energy.
  • This spares glucose, especially for RBCs, which can only use glucose.

This is crucial during starvation to preserve life.

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