Carnitine shuttle inhibition

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

The carnitine shuttle is the rate-determining step in mitochondrial fatty acid degradation. Malonyl CoA, a precursor of fatty acid biosynthesis, inhibits carnitine acyltransferase (see p. 162), and therefore also inhibits uptake of fatty acids into the mitochondrial matrix. 

The fatty acids must be transported into the mitochondrion where P-oxidation occurs. Transport of fatty acids through the inner mitochondrial membrane involves the carnitine shuttle (Chapter 21). The carnitine shuttle is inhibited by malonyl CoA which inactivates carnitine acyltransferase I (CAT I). Malonyl CoA is produced when fatty acids are being synthesised during the fed state, and by inhibiting the carnitine shuttle it prevents the futile destruction by P-oxidation of the brand-new fatty acids as they are formed. 

THE FED STATE Two to four hours after a meal, the body is in the absorptive (fed) state. This is a period of anabolism, where there is a high insulin gfucagon ratio in the circulation. In the liver, glycolysis is increased, and glycogen synthesis is favoured. There is no gluconeogenesis. Surplus amino acids are used for protein synthesis or deaminated in the liver to pyruvate, acetyl CoA or oxaloacetate, which enter the TCA cycle. FA synthesis is favoured sinc e excess acetyl CoA is converted to malonyl CoA (by acetyl CoA carboxylase). Malonyl CoA inhibits the carnitine shuttle which transports FAs to be oxidized in the mitochondria, therefore they have to be stored as TAG in the periphery. 

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