The Conversion of Glucose to Fatty Acids Is an Irreversible Process

The synthesis of fatty acids from glucose begins with gly­colysis. 'Γhis pathway leads to the production of two pyruvate molecules for each molecule of glucose consumed. Pyruvate can then enter the mitochondria to be activated to acetyl coenzyme A (acetyl CoA) for entry into the Krebs cycle.

FIGURE 32-4 ■ Hepatic synthesis of fatty acid from carbohydrate requires the passage of carbohydrate carbons through the mitochondria. Citrate forms a shuttle to transport the carbons of acetyl coenzyme A (acetyl CoA) out of the mitochondria because acetyl CoA cannot pass directly through the mitochondrial membrane.The formation of citrate from Oxaloacetate and acetyl CoA is the first reaction ofthe Krebs cycle; thus fatty-acid formation is an alternative to Krebs cycle oxidation when there is more than enough acetyl CoA to provide cellular energy through Krebs cycle activity.

However, the Krebs cycle is for energy generation, and during the absorptive period, there is more than enough acetyl CoA and Krebs cycle activity to provide for energy needs; therefore the excess acetyl CoA must be shunted away from the Krebs cycle. The excess acetyl CoA combines with oxαloαcetαte to form citrate in what is essentially the first reaction of the Krebs cycle. Instead of continuing through the Krebs cycle reactions, however, during the absorptive period much of the citrate is transported out of the mitochondria into the cytosol. Once in the cytosol, each citrate molecule contributes two carbons toward the synthesis of fatty acids. The remaining portion of the citrate molecule cycles back into the mitochondria for further use. Citrate serves as a carrier molecule to transport two-carbon units out of the mitochondria because acetyl CoA cannot pass the mitochondrial membrane directly (Figure 32-4).

Several important steps in this conversion of glucose to fatty acids are promoted by insulin and are discussed in detail later. It is important to recognize that the conversion of glu­cose to fatty acids is irreversible; thus carbohydrate can form fat, but fat cannot form carbohydrate. The discussion here concerns hepatic metabolism, and the liver is an important site of fatty-acid synthesis in several species. Direct synthesis of fatty acids also occurs in adipose tissue. The relative impor­tance of liver and adipose tissue as sites of fatty-acid synthesis varies with species, as discussed later.