Most tissues have a limited capacity for fatty acid oxidation and in the fasting state cannot meet their energy requirements from fatty acid oxidation alone. By contrast, the liver is capable of forming considerably more acetyl CoA from fatty acids than is required for its own metabolism. It takes up fatty acids from the circulation and oxidizes them to acetyl CoA, then synthesizes and exports the four-carbon ketone
fatty acyl Co A dehydrogenase enoyl CoA hydratase
SCoA hydroxy acyl CoA
SCoA fatty acyl CoA
5 Co A oxo-acyl CoA
SCoA acetyl CoA
Figure 5.24 ^-Oxidation offatty acids.
bodies formed from acetyl CoA to other tissues (especially muscle) for use as a metabolic fuel.
The reactions involved are shown in Figure 5.25. Acetoacetyl CoA is formed by reaction between two molecules of acetyl CoA. This is essentially the reverse of the final reaction of fatty acid P-oxidation (see Figure 5.23). Acetoacetyl CoA then reacts with a further molecule of acetyl CoA to form hydroxymethyl-glutaryl CoA, which then undergoes cleavage to release acetyl CoA and acetoacetate.
Acetoacetate is chemically unstable, and undergoes a non-enzymic reaction to yield acetone, which is only poorly metabolized. Most of it is excreted in the urine and in exhaled air — a waste of valuable metabolic fuel reserves in the fasting state. To avoid this, much of the acetoacetate is reduced to P-hydroxybutyrate before being released from the liver.
The pathway for the utilization of P-hydroxybutyrate and acetoacetate in tissues other than the liver is shown in Figure 5.26. The first step is oxidation of P-hydroxybutyrate to acetoacetate, yielding NADH. The synthesis of P-hydroxybutyrate in the liver can thus be regarded not only as a way of preventing loss of metabolic fuel as acetone, but also effectively as a means of exporting NADH (and therefore effectively ATP) to extrahepatic tissues.
The utilization of acetoacetate is controlled by the activity of the citric acid cycle. The reaction of acetoacetate succinyl CoA transferase provides an alternative to the reaction of succinyl CoA synthase (see Figure 5.18), and there will only be an adequate supply of succinyl CoA to permit conversion of acetoacetate to acetoacetyl CoA as long as the rate of citric acid cycle activity is adequate.
Acetoacetate, P-hydroxybutyrate and acetone are collectively known as the ketone bodies, and the occurrence of increased concentrations of these three compounds in the bloodstream is known as ketosis. Actetoacetate and P-hydroxybutyrate are also acids, and will lower blood pH, potentially leading to metabolic acidosis. Although acetone and acetoacetate are chemically ketones, having a —C = O grouping, P-hydroxybutyrate is not chemically a ketone. It is classified with the other two because of its metabolic relationship. See section 10.7 for a discussion of the problems of ketoacidosis in uncontrolled diabetes mellitus.
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