Hepatic Ketone Body Formation Is Promoted by Low Glucose Availability, a High Glucagon/lnsulin Ratio, and a Ready Supply of Fatty Acids
Ketone body formation occurs within the hepatic mitochondria, and the rate of ketone body synthesis is controlled by the regulated transport of fatty acids across the mitochondrial membrane (Figure 32-16).
Fatty acids enter mitochondria in combination with a molecule known as carnitine, and transport depends on an enzyme known as carnitine palmitoyltransferase / (CPT-I). The activity of this enzyme, along with the availability of fatty acid, is the primary determinant of the rate of ketone body formation. CPT-I activity is regulated in an interesting manner, being inhibited by an intermediate of the fatty-acid synthesis pathway, malonyl CoA. Malonyl CoA concentrations are high when the liver is responding to insulin and glucose is being used for fatty-acid synthesis. When glucagon concentrations are high relative to insulin, little fatty acid is synthesized in the liver. Thus, malonyl CoA concentrations are low, and CPT-I is fully active when the insulin/glucagon ratio is low. Ketene body synthesis is stimulated under these hormonal conditions.Under conditions when CPT-I is active, most available fatty acid is transported into the mitochondria for ketone body synthesis. This well-orchestrated but somewhat complex regulatory system is important because the liver can both produce and consume fatty acids. If there were not a way of “turning off” fatty-acid destruction during periods of
FIGURE 32-15 During prolonged periods of food deprivation or energy deficiency, the ketone bodies (K), fatty acids (FA), and triglycerides (TG) become the major fuels. Glucose oxidation becomes minor, thus sparing muscle protein that otherwise would be needed for gluconeogenesis.
FIGURE 32-16 The liver is a site of both destruction and synthesis of fatty acids.To keep both processes from occurring simultaneously, fatty-acid destruction is inhibited during periods of fatty-acid synthesis.
Solid lines, Pathway of fatty-acid synthesis; irregular broken line, fatty-acid destruction. Oxidative destruction is suppressed by the action of malonyl CoA, an intermediate in the synthesis of fatty acid. Malonyl CoA blocks the transport of fatty acids into the mitochondria at the translocation enzyme carnitine palmitoyltransferase I (CPT I).synthesis, a futile cycle of synthesis and destruction would occur. The inhibition of CPT-I by malonyl CoA provides a system that blocks the metabolic destruction of newly synthesized fatty acid while still providing a mechanism for the utilization of fatty acids derived from adipose tissue. The overall pattern of metabolism results in a reciprocal relationship between glucose availability and ketone body production. Although ketone bodies are produced in the liver, they cannot be used there for energy production. Therefore, all ketone bodies are transported to peripheral tissues for utilization. When the concentration of ketone bodies in the blood becomes abnormally high, some are excreted in urine.