Pyruvic acid gluconeogenesis from

Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting. As a result of excessive lipolysis in adipose tis sue, the liver is flooded with fatty acids (see p. 328). The rate of for mation of acetyl CoA by p-oxidation of these fatty acids exceeds the capacity of the liver to oxidize it to C02 and H20. As a result, acetyl CoA accumulates and leads to activation of pyruvate carboxylase. [Note Acetyl CoA inhibits pyruvate dehydrogenase (see p. 108). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle.]... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

In addition, hepatic fatty acid oxidation is also required to sustain gluconeogenesis. These fatty acids may be obtained from exogenous feeding or metabolism of fatty acids released from endogenous lipid stores. (3-Oxidation of fatty acids provides the acetyl-CoA needed to activate mitochondrial pyruvate carboxylase and the NADH used as the substrate in the reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase in the direction of gluconeogenesis (see Fig. 10-1). 

Pyruvate Carboxylase Pyruvate carboxylase catalyzes the car-boxylation of pyruvate to oxaloacetate - both the first committed step of gluconeogenesis from pyruvate and also an important anaplerotic reaction, permitting repletion of tricarboxylic acid cycle intermediates and hence fatty acid synthesis. The mammalian enzyme is activated aUosterically by acetyl CoA, which accumulates when there is a need for increased activity of pyruvate carboxylase to synthesize oxaloacetate to permit increased citric acid cycle activity or for gluconeogenesis (Attwood, 1995 Jitrapakdee and Wallace, 1999). 

As discussed in section 5.4.4.2 and section 9-3.2, many of the products of amino acid metabolism can also be used for gluconeogenesis, as they are sources of pyruvate or one of the intermediates in the citric acid cycle, and hence give rise to oxaloacetate. The requirement for gluconeogenesis from amino acids in order to maintain a supply of glucose explains why there is often a considerable loss of muscle in prolonged fasting or starvation, even if there are apparently adequate reserves of adipose tissue to meet energy needs. 

Biomolecules are synthesized as well as degraded, but the pathways for anabolism and catabolism are not the exact reverse of one another. Fatty acids are biosynthesized from acetate by an 8-step pathway, and carbohydrates are made from pyruvate by the 11-step gluconeogenesis pathway. 

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