Formation of Ketone Bodies
The acetyl CoA from fatty acid oxidation enters the TCA cycle only if fat and carbohydrate digestion are appropriately balanced. Acetyl CoA must combine with oxaloacetate to enter the TCA cycle, thereby forming citrate. However, the availability of oxaloacetate is dependent upon an adequate supply of carbohydrate. (Remember, oxaloacetate is normally formed from pyruvate, catalyzed by pyruvate carboxylase). Therefore, if carbohydrate is not available or is improperly utilized, the concentration of oxaloacetate is lowered, and acetyl CoA cannot enter the TCA cycle.
In fasting or diabetes, oxaloacetate is consumed to produce glucose via gluconeogenesis, and thus is unavailable to condense with acetyl CoA. Under these conditions, acetyl CoA is diverted to form ketone bodies. Acetoacetate is formed from acetyl CoA is three steps:
(1) Thiolase catalyzes the condensation of two molecules of acetyl CoA.
(2) Acetoacetyl CoA then reacts with another acetyl CoA to give HMG-CoA.
(3) HMG-CoA is then cleaved to acetyl CoA and acetoacetate.
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The major site of production of ketone bodies is in the liver. Ketone bodies can be transported out of the liver mitochondria into the blood and to peripheral tissues. Heart muscle and the renal cortex use ketone bodies in preference to glucose. Also, the brain can adapt to the utilization of acetoacetate during starvation and diabetes.
Acetoacetate is converted to acetyl CoA in two steps. Acetoacetate is converted to acetoacetyl CoA by CoA transferase. Second, acetoacetyl CoA is cleaved by thiolase into two molecules of Acetyl CoA. The liver has acetoacetate to supply to other organs because it lacks the CoA transferase.
D-3-hydroxybutyrate must first be oxidized to acetoacetate by reducing NAD+ to NADH.
High levels of acetoacetate in blood signify sufficient amounts of acetyl units and thus lead to a decrease in the rate of lipolysis.
