Overview of Fat Metabolism

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b-Oxidation of Fatty Acids and Ketogenesis

Fats (triacylglycerides) are stored mainly in adipose tissue. Lipolysis breaks down fats into the constituent fatty acids and glycerol. Fatty acids can be oxidized via the ^-oxidation pathway in the mito-chondrial matrix. In this process, a cyclical series of reactions removes the last two carbon atoms from the carboxyl end of the fatty acyl-CoA, with the addition of another CoA to form a new fatty acyl-CoA that is two carbon atoms shorter plus acetyl-CoA. In muscle, the acetyl-CoA is metabolized via the TCA cycle to produce reduced coenzymes for the production of ATP. In the liver, it is shunted largely to the synthesis of ketone bodies (ketogen-esis), which, like glucose, are exported for use in other tissues.

On the outer face of the mitochondrial membrane, fatty acids are esterified to CoA to form fatty acyl-CoA, which cannot enter the matrix of the mitochondria, the site of the enzymes for /3-oxida-tion. This function is performed by the carnitine shuttle. On the outer mitochondria membrane, fatty acyl is transferred onto carnitine to form fatty acyl-carnitine that is transported across the inner and outer mitochondrial membranes on a counter-current transporter system, in exchange for transporting free carnitine into the intermembrane space. Once in the matrix, the fatty acyl is esterified to CoA, thus releasing free carnitine. There is no dietary requirement for carnitine because it is readily synthesized from the amino acids lysine and methionine.

Most tissues have a limited capacity for ,3-oxida-tion. However, the liver can produce large amounts of acetyl-CoA by ^-oxidation and can then convert some of this into four-carbon ketone bodies that can be easily transported to other tissues for use as a metabolic fuel. Acetoacetate is formed by the combination of 2 acetyl-CoA and the removal of the CoA molecules. This is unstable and undergoes a nonenzymic reaction to acetone, which is poorly metabolized, most of it being excreted in urine and exhaled air. Hence, most of the acetoacetate is reduced to /3-hydroxybutyrate before being released from the liver. ^-Hydroxybutyrate is metabolized by extrahepatic tissues by adding a CoA via succinate-CoA to form succinate and acetoacetyl-CoA that is then broken down into 2 acetyl-CoA by /3-ketothiolase and CoA (Figure 7).

Synthesis of Fatty Acids and Triacylglycerides

The majority of fatty acids are supplied by the diet, but many tissues are capable of de novo synthesis, including the liver, brain, kidney, mammary glands, and adipose tissue. The de novo synthesis of fatty acids occurs in conditions of excess energy intake.

Fatty acid synthesis occurs in the cytosol but is essentially the reverse of ^-oxidation of fatty acids (although it employs a separate set of enzymes), whereby fatty acids are synthesized from the successive additions of 2C acetyl-CoA followed by reduction.

Acetyl-CoA is formed in the mitochondrial matrix, but it cannot pass across the mitochondrial inner membrane. Hence, the source of acetyl-CoA for fatty acid synthesis is citrate, which can pass out of the mitochondria, where, with CoA, it is cleaved to produce acetyl-CoA and oxaloacetate. The oxalo-acetate is returned indirectly to the mitochondrial matrix via its oxidation to pyruvate, which is linked to the generation of reduced NADP, required for fatty acid synthesis. Once in the mitochondrial matrix, the pyruvate is converted back to oxaloace-tate and thus returned into the TCA cycle.

P-Ketothiolase

2 x acetyl-CoA

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