Kentone Body Types And Importance
Ketone bodies formed in liver to free up CoA for b-oxidation metabolized in other tissues, including brain, as an energy source. The formation of ketone bodies is a consequence of prolonged metabolism of fat. Their formation in the liver actually enables liver to metabolize even more fat by freeing up CoA that would otherwise be tied up as acetyl-CoA waiting to get into the TCA cycle. The liver exports the ketone bodies; and other tissues, particularly the brain, can adapt to use them. With increasing metabolism of fat through b-oxidation, much of the mitochondrial CoA pool may become tied up as acyl- or acetyl-CoA. In such cases, the supply of free CoA can be diminished, and this may limit the rate of b-oxidation. Upon prolonged fasting and heavy reliance on fat for energy, the liver induces the enzymes required for the formation of ketone bodies and brain induces enzymes required for their metabolism. Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. Ketone bodies are utilized in other tissues (but not the liver) by converting the acetoacetate to acetoacetyl-CoA and then converting the acetoacetyl-CoA to 2 acetyl-CoA, which are burned in the muscle mitochondria. Increased fatty acid oxidation is a characteristic of starvation and of diabetes mellitus, leading to ketone body production by the liver (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin.
Ketogenesis occurs when there is a high rate of fatty acid oxidation in the liver
Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and ß-hydroxybutyrate. Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies. Acetoacetate and 3-hydroxybutyrate are interconverted by the mitochondrial enzyme D(ß)-3-hydroxybutyrate dehydrogenase; the equilibrium is controlled by the mitochondrial [NAD+]/ [NADH] ratio, ie, the redox state. The concentration of total ketone bodies in the blood of well-fed mammals does not normally exceed 0.2 mmol/L. Extrahepatic tissues utilize them as respiratory substrates. The net flow of ketone bodies from the liver to the extrahepatic tissues results from active hepatic synthesis coupled with very low utilization. The reverse situation occurs in extrahepatic tissues.
