Ketone Bodies Summary

Ketone Bodies

Ketone bodies include acetone, acetoacetate, and β-hydroxybutyrate.
Synthesized primarily in the liver mitochondria and serve as fuel for tissues like the brain, heart, and skeletal muscle.
During starvation, they become a major energy source for the brain, providing acetyl-CoA when glucose is scarce.
Acetoacetate and β-hydroxybutyrate are normal substrates for kidney cortex and heart muscle.

Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, catalyzed by thiolase in reverse (same enzyme as in β-oxidation).
Another acetyl-CoA molecule is added to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
HMG-CoA lyase converts HMG-CoA to acetoacetate and acetyl-CoA via a mixed aldol-Claisen ester cleavage.
Acetoacetate can be reduced to β-hydroxybutyrate by β-hydroxybutyrate dehydrogenase.
Acetoacetate and β-hydroxybutyrate are transported from the liver to target tissues, where they are converted to acetyl-CoA.

Acetoacetate: The first ketone produced; can be used directly or converted to other ketones; a true ketone.
β-Hydroxybutyrate: Most prevalent ketone; formed from acetoacetate; not a true ketone but considered a ketone body.
Acetone: Formed as a side product of acetoacetate; undergoes rapid breakdown; exits the body via breath and urine.

Keto esters are used as performance enhancers by athletes and those on ketogenic diets.
Research focuses on ketone esters, including their potential to fuel the brain in Alzheimer’s disease.

Type 1 diabetes: Inadequate insulin leads to high blood glucose.
Type 2 diabetes: Cells are not responsive to insulin.
Reduced glucose transport causes cells to rely on increased gluconeogenesis and catabolism of fat and protein.
In type 1 diabetes, excess acetyl-CoA from fat breakdown is used to produce large amounts of ketone bodies due to oxaloacetate shortage.
Acetone can be detected in the breath of type 1 diabetics, indicating high ketone body levels.