Intrahepatic Regulation

There are situations (e.g., stress) where the supply of fatty acids to the liver may be increased, but there is no necessity to increase the availability of ketone bodies to the peripheral tissues. Consequently, there is a requirement that the rate of hepatic keto-genesis should be controlled independently of the supply of fatty acids. However, it must be stressed that without an increase in the supply of fatty acids the rate of ketogenesis cannot increase.

Adipose tissue

Adipose tissue

Figure 3 Role of ketone bodies as feedback regulators.

Much of the current interest is concerned with how the intrahepatic metabolism of fatty acids (Figure 4) is regulated. Long-chain fatty acids entering the liver have three main fates:

1. They can be re-esterified to phospholipids and triacylglycerols and then be secreted as very low-density lipoproteins (VLDL).

2. They can be oxidized via the mitochondrial /3-oxi-dation complex to acetyl-CoA. The latter can combine with another molecule of acetyl-CoA in the reaction catalysed by acetoacetyl-CoA thio-lase and then enter the hydroxymethylglutaryl-CoA pathway to form acetoacetate.

3. The acetyl-CoA derived from the fatty acids can be completely oxidized in the tricarboxylate cycle.

The short- and medium-chain fatty acids cannot be re-esterified to any appreciable extent in mammalian liver and therefore they are either metabolized to ketone bodies or completely oxidized. In addition, unlike the long-chain fatty acids, they are transported directly into the mitochondrial matrix without the need to be converted first to the corresponding acyl-CoA derivatives.

The role of malonyl CoA The entry of free long-chain fatty acids into the hepatocyte is via a specific carrier on the plasma membrane. Once inside the cytosol the long-chain fatty acids are bound to binding proteins, converted to the acyl-CoA derivatives, and then can either be esterified or enter

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