#Ketones

#Describe ketone bodies including their synthesis and metabolism

#Ketone Bodies

The three main ketone bodies are:

• Acetoacetic acid
• β-hydroxybutyric acid
• Acetone

These molecules act as an alternative energy substrate, particularly during periods of reduced glucose availability.

#Ketogenesis

Ketogenesis occurs primarily in the liver.

Fatty acids undergo β-oxidation to generate large amounts of acetyl-CoA.
When acetyl-CoA accumulates, two molecules combine to form acetoacetic acid.

Acetoacetic acid can then be:

• Reduced to β-hydroxybutyric acid (the predominant circulating ketone), or
• Spontaneously converted to acetone (a minor byproduct)

These ketone bodies are released into the bloodstream, where they are rapidly taken up by peripheral tissues and utilised in the citric acid cycle (CAC) for energy production.

Under normal conditions, serum ketone concentrations remain very low due to rapid utilisation.

#Drivers of Ketogenesis

#1. Oxaloacetate deficiency

Oxaloacetate is a key member of the citric acid cycle. It reacts with acetyl-CoA to form citrate, allowing the cycle to begin again. A reduction in oxaloacetate therefore limits entry of acetyl-CoA into the CAC, resulting in diversion of acetyl-CoA toward ketone synthesis.

This most commonly occurs due to reduced glucose availability:

• ↓ glycolysis → ↓ pyruvate → ↓ oxaloacetate

Seen in:

• Starvation
• Low/no carbohydrate (ketogenic) diets
• Diabetes mellitus (due to to decreased uptake of glucose)

Alcohol metabolism can also cause oxaloacetate deficiency. Ethanol metabolism requires conversion of NAD+ → NADH. In an effort to restore NAD+, pyruvate is metabolised to lactate instead of being used to generate oxaloacetate. This results in functional oxaloacetate depletion.

#2. Increased Fatty Acid Metabolism

When glucose utilisation is reduced, the body relies more heavily on fat as an energy source.

β-oxidation of fatty acids produces a large quantity of acetyl-CoA. For example, a 12-carbon fatty acid generates 6 acetyl-CoA molecules. Excess acetyl-CoA is diverted towards ketone synthesis.

#3. Ketogenic Amino Acids

Ketone production is also supported (to a lesser extent) by ketogenic amino acids, particularly:

• Leucine
• Lysine

These amino acids are metabolised directly into acetyl-CoA which may be diverted towards ketone synthesis.

#Hormonal Control

#Insulin

Insulin suppresses ketogenesis primarily by inhibiting hormone-sensitive lipase, preventing the breakdown of stored fat.

This results in:

• Reduced lipolysis
• Decreased free fatty acid availability
• Reduced β-oxidation
• Increased glycolysis

#Glucagon

Glucagon stimulates ketogenesis by activating hormone-sensitive lipase, increasing the breakdown of stored fat.

This leads to:

• Increased lipolysis
• Increased free fatty acids
• Increased β-oxidation
• Reduced glycolysis

#Glucagon : Insulin ratio

The glucagon : insulin ratio correlates well with ketone production.

• A high ratio promotes a ketogenic state
• A low ratio suppresses ketogenesis

#Other Hormones

Both cortisol and adrenaline contribute to increased ketogenesis by stimulating lipolysis.

#References

Laffel, L. (1999), Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab. Res. Rev., 15: 412-426.