Ketone Bodies and Their Metabolism

Ketone Bodies

In the fasted state, the liver converts excess acetyl CoA (from beta oxidation of fatty acids) into ketone bodies:
- Acetoacetate
- 3-hydroxybutyrate (beta-hydroxybutyrate)
These ketone bodies can be used for energy by various tissues.
Tissues such as cardiac and skeletal muscle, and the renal cortex can metabolize acetoacetate and 3-hydroxybutyrate to acetyl CoA.
During fasting, muscle metabolizes ketones as rapidly as the liver releases them, preventing accumulation in the bloodstream.
After about a week of fasting, ketone concentrations in the blood become high enough for the brain to begin metabolizing them.

Location: Occurs in the mitochondria of liver cells.
Trigger: Excess acetyl CoA accumulation in the fasted state.
Process:
- HMG CoA synthase forms HMG CoA.
- HMG CoA lyase breaks down HMG CoA into acetoacetate.
- Acetoacetate can be subsequently reduced to 3-hydroxybutyrate.
- Acetone is a minor side product that is volatile and not used for energy.

Acetoacetate is picked up from the blood and activated in the mitochondria.
Succinyl CoA acetoacetyl CoA transferase (thiophorase) catalyzes the reaction.
- This enzyme is present only in tissues outside the liver.
During this reaction, acetoacetate is converted to acetyl CoA.
The liver lacks thiophorase, so it cannot catabolize the ketone bodies that it produces.

During a prolonged fast (longer than one week), the brain derives up to two-thirds of its energy from ketone bodies.
When ketones are metabolized to acetyl CoA in the brain, pyruvate dehydrogenase is inhibited.
Glycolysis and glucose uptake in the brain decrease.
This switch spares essential protein in the body, which would otherwise be catabolized to form glucose by gluconeogenesis in the liver.
This allows the brain to indirectly metabolize fatty acids as ketone bodies.