The below mentioned article provides a note on the process of ketogeneis, explained with the help of a suitable diagram.
In vertebrates, the acetyl-coenzyme A originating from the β-oxidation can leave the mitochondrion in the form of citrate. However a notable part of this acetyl-coA is used for the synthesis of ketone substances: acetoacetic acid, β-hydroxy-butyric acid and acetone. This process, called ketogenesis, takes place in the mitochondrion.
The first steps are similar to those of cholesterol synthesis (see fig. 5-24). The β-hydroxy-β-methyl-glutaryl-coenzyme A formed is split into acetyl-coenzyme A and free acetoacetic acid.
The acetoacetic acid can be:
(i) Either spontaneously decarboxylated to acetone:
CH3-CO-CH2-COOH → CO2 + CH3-CO-CH3
(ii) Or reduced to β-hydroxybutyric acid:
CH3— CO—CH2—COOH + NADH + H+ → CH3—CHOH—CH2—COOH + NAD+
Acetoacetic acid and β-hydroxybutyric acid, which are produced in large quantities, are utilized as energy source by various tissues like muscles, kidney and the brain. Ketone substances do indeed diffuse freely across the cell membranes.
Furthermore, these tissues, contrary to the liver, are capable of reactivating acetoacetic acid by the following reaction:
Acetoacetic acid + Succinyl — coA → Succinic acid + Acetoacetyl — coA
The latter can be split by thiolysis into two molecules of acetyl-coA which will enter the Krebs cycle. Ketogenesis is a very important physiological process. It is exclusively hepatic. The regulation of ketogenesis depends mainly on the concentration of 2 hormones: insulin and glucagon. In mammals a decrease in blood glucose concentration depresses insulin and increases glucagon.
A change in the concentration of these hormones has the following main consequences in the liver: arrest of glycolysis (a very minor process in the liver), increase of neoglucogenesis, inhibition of the synthesis of fatty acids at the level of acetyl-coA carboxylase. The same hormonal change brings about in the adipose tissue, a hydrolysis of triglycerides by action on the hormone-dependent lipase.
The fatty acids thus liberated will be transported to the liver. The inhibition of acetyl-coA carboxylase depresses malonyl-coenzyme A concentration. The latter compound is a repressor of acylcarnitine synthetase, enzyme which will therefore be activated. The penetration of fatty acids into the mitochondrion will be favoured and they will be catabolized by oxidation.
This will increase the NADH/NAD ratio which will result in a reduction of oxaloacetate (originating mainly from the aspartate by transamination) to malate, which can leave the mitochondrion (and will participate in neoglucogenesis).
The reduction of oxaloacetate will prevent the transformation into citrate of the acetyl-coenzyme A resulting from the β-oxidation. The only possible fate of the latter will therefore be the synthesis of ketone substances which will freely leave the hepatocyte to be captured by the other tissues capable of utilizing them.