The Synthesis and Utilization of Ketone Bodies

The Synthesis and Utilization of Ketone bodies

Ketone bodies are two molecules, acetoacetate and b-hydroxybutyrate. The term "ketone body" is historical: only acetoacetate is an actual ketone. Ketone bodies are synthesized in the liver from acetyl-CoA. The brain is an important organ. It is metabolically active and metabolically privileged. The brain generally uses 60-70% of total body glucose requirements, and always requires some glucose for normal functioning. Under most conditions, glucose is essentially the sole energy source of the brain. The brain cannot use fatty acids, which cannot cross the blood-brain barrier. Because animals cannot synthesize significant amounts of glucose from fatty acids, as glucose availability decreases, the brain is forced to use either amino acids or ketone bodies for fuel.

Individuals eating diets extremely high in fat and low in carbohydrates, or starving, or suffering from a severe lack of insulin (Type I diabetes mellitus) therefore increase the synthesis and utilization of ketone bodies. Ketone body synthesis occurs normally under all conditions. However, the formation of ketone bodies increases dramatically during starvation. This seems to be due to a combination of factors. Prolonged low levels of insulin result in both increased fatty acid release from adipose tissue, and increased amounts of the enzymes required to synthesize and utilize ketone bodies. In addition, in the liver, increased demand for gluconeogenesis results in depletion of oxaloacetate, and therefore in decreased capacity for the TCA cycle. This causes a rise in the levels of acetyl-CoA, the substrate for ketone body production.

The first enzyme in the ketone body synthesis pathway is thiolase (the same enzyme that is responsible for the cleavage step in b-oxidation). In ketone body biosynthesis, thiolase catalyzes the condensation of two acetyl CoA molecules to form acetoacetyl-CoA. The next enzyme, HMG-CoA synthase adds a third acetyl CoA molecule, to form b-hydroxy-b-methylglutaryl-CoA (usually abbreviated HMGCoA). HMG-CoA is an important biosynthetic intermediate; however, in the mitochondria, it is only used for ketone body synthesis. The third enzyme, HMGCoA lyase, releases an acetyl-CoA from HMG-CoA to form acetoacetate.

The final enzyme in ketone body synthesis, βhydroxybutyrate dehydrogenase, reduces acetoacetate to b-hydroxybutyrate. The b-hydroxybutyrate dehydrogenase reaction has two functions: 1) it stores energy equivalent to an NADH in the ketone body for export to the tissues, and 2) it produces a more stable molecule. Acetoacetate is a b-ketoacid, and like many such compounds may spontaneously decarboxylate. The product of the decarboxylation reaction, acetone, is a volatile waste product, and is largely excreted via the lungs. "Acetone-breath" has been used as a crude method of diagnosing individuals with untreated Type