Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d-3-hyroxybutyrate (3-hydroxybutyrate or β-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three sub stances are collectively known as theketone bodies (also called acetone bodies or [incorrectly*] “ketones”) (Figure 1). Acetoacetate and 3-hydroxybutyrate are interconverted by the mitochondrial enzyme d-3-hydroxybutyrate dehydrogenase; the equilibrium is controlled by the mitochondrial [NAD+]/ [NADH] ratio, that is, the redox state. The concentration of total ketone bodies in the blood of well-fed mammals does not normally exceed 0.2 mmol/L. However, in ruminants, 3-hydroxybutyrate is formed continuously from butyric acid (a product of ruminal fermentation) in the rumen wall. In nonruminants, the liver appears to be the only organ that adds significant quantities of ketone bodies to the blood. Extra hepatic tissues utilize acetoacetate and 3-hydroxybutyrate as respiratory substrates. Acetone is a waste product which, as it is volatile, can be excreted via the lungs. Because there is active synthesis but little utilization of ketone bodies in the liver, while they are used but not produced in extrahepatic tissues, there is a net flow of the compounds to the extrahepatic tissues (Figure 2).

Fig1. Interrelationships of the ketone bodies. d-3-Hydroxybutyrate dehydrogenase is a mitochondrial enzyme.

Fig2. Formation, utilization, and excretion of ketone bodies. (The main pathway is indicated by the solid arrows.)

Acetoacetyl-CoA Is the Substrate for Ketogenesis

The enzymes responsible for ketone body formation (ketogenesis) are associated mainly with the mitochondria. Acetoacetyl-CoA is formed when two acetyl-CoA molecules produced via fatty acid breakdown condense to form acetoacetyl-CoA by a reversal of the thiolase reaction , and may also arise directly from the terminal four carbons of a fatty acid during β-oxidation (Figure 3). Condensation of acetoacetyl-CoA with another molecule of acetyl-CoA by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase forms HMG-CoA. HMG-CoA lyase then causes acetyl-CoA to split off from the HMG-CoA, leaving free acetoacetate. Both enzymes must be present in mitochondria for ketogenesis to take place. In mammals, ketone bodies are formed solely in the liver and in the rumen epithelium. 3-Hydroxybutyrate is formed from acetoacetate (see Figure 3) and is quantitatively the predominant ketone body present in the blood and urine in ketosis.

Fig3. Pathways of ketogenesis in the liver. (FFA, free fatty acids.)

Ketone Bodies Serve as a Fuel for Extrahepatic Tissues

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed can only be reactivated by linkage to CoA directly in the cytosol, where it is used in a different, much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver.

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate-CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl CoA (Figure 4). In a reaction requiring the addition of a CoA, two acetyl-CoA molecules are formed by the splitting of acetoacetyl-CoA by thiolase and these are oxidized in the citric acid cycle. 3-Hydroxybutyrate is utilized by conversion to acetoacetate by the reversal of the reaction by which it is formed in the liver, generating an NADH in the process (see Figure 4). Thus, 1 mol of acetoacetate or 3-hydroxbutyrate yields 19 or 21.5 mol of ATP, respectively, by these pathways. If the blood level of ketone bodies rises to a concentration of ~12 mmol/L, the oxidative machinery becomes saturated and at this stage, a large proportion of oxygen consumption may be accounted for by their oxidation.

Fig4. Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahepatic tissues. CoA transferase, succinyl-CoA-acetoacetate-CoA transferase. The breakdown of acetoacetyl-CoA by thiolase produces two acetyl-CoA molecules and requires the addition of one CoA (not shown).

In moderate ketonemia, the loss of ketone bodies via the urine is only a few percent of the total ketone body production and utilization. Since there are renal threshold-like effects (there is not a true threshold) that vary between species and individuals, measurement of the ketonemia, not the ketonuria, is the preferred method of assessing the severity of ketosis.

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