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reactions. In one, pyruvate is decarboxylated via the pyruvate dehydrogenase complex, yielding acetyl-CoA. Lipogenic tissues also contain another mitochondrial enzyme, pyruvate carboxylase, which converts pyruvate to the four-carbon acid oxaloacetate (OAA). Acetyl-CoA and oxaloacetate condense to form the six-carbon acid citrate. As citrate accumulates within the mitochondrion, it is exported to the cytoplasm, where it is converted back to oxaloace-tate and acetyl-CoA. Cytoplasmic acetyl-CoA is the fundamental building block for de novo synthesis of fatty acids.

The first enzyme unique to fatty-acid synthesis is acetyl-CoA carboxylase, which converts the two-carbon substrate acetyl-CoA into the three-carbon product malonyl-CoA. Citrate, in addition to being the precursor of cytoplasmic acetyl-CoA, has a regulatory role. Citrate is an allosteric activator of acetyl-CoA carboxylase and serves as a signal that there is an ample carbon supply for fatty-acid synthesis. As noted above, malonyl-CoA is a potent inhibitor of CPT1. Cytoplasmic malonyl-CoA levels will be high only when there is significant flux through glycolysis, indicative of a high cellular energy state. Under these conditions, entry of fatty acids into the mitochondria (and subsequent ^-oxidation) is prevented. Interestingly, there are two isoforms of acetyl-CoA carboxylase. One is found in the above-named lipogenic tissues. The other is found in many tissues that are not capable of synthesizing fatty acids, e.g., the heart. It is thought that the primary role of the second isozyme is to regulate mitochondrial fatty-acid ^-oxidation by synthesizing malonyl-CoA when cellular energy needs are being met by carbohydrate metabolism.

The subsequent reactions of fatty-acid synthesis in humans are catalyzed by a multienzyme

Table 1 Distinctions between fatty-acid p-oxidation and fatty-acid synthesis
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