Ketone body use by the peripheral tissues: Ketolysis

Although the liver constantly synthesizes low levels of ketone bodies, their production increases during fasting when ketone bodies are needed to provide energy to the peripheral tissues.

3-Hydroxybutyrate is oxidized to acetoacetate by 3-hydroxybutyrate dehydrogenase, producing NADH (Fig. 1). Acetoacetate is then provided with a CoA molecule taken from succinyl CoA by succinyl CoA:acetoacetate CoA transferase (thiophorase). This reaction is reversible, but the product, acetoacetyl CoA, is actively removed by its cleavage to two acetyl CoA by thiolase. This pulls the reaction forward. Extrahepatic tissues, including the brain but excluding cells lacking mitochondria (for example, RBC), efficiently oxidize acetoacetate and 3-hydroxybutyrate in this manner. In contrast, although the liver actively produces ketone bodies, it lacks thiophorase and, therefore, is unable to use ketone bodies as fuel.

Figure 1: Ketone body synthesis in the liver and use in peripheral tissues. The liver and red blood cells cannot use ketone bodies. [Note: Thiophorase is also known as succinyl CoA:acetoacetate CoA transferase.] CoA = coenzyme A; NAD(H) = nicotinamide adenine dinucleotide; TCA = tricarboxylic acid; CO2 = carbon dioxide.