During the absorptive period following a carbohydrate-rich meal, glycolysis becomes more significant in the liver. This increase is driven by the elevated insulin/glucagon ratio, which stimulates the conversion of glucose to pyruvate. The regulated enzymes of glycolysis, such as glucokinase, PFK-1, and pyruvate kinase (PK), are produced in larger quantities. Fructose 2,6-bisphosphate, generated by the active kinase domain of bifunctional PFK-2, allosterically activates PFK-1. Additionally, PK becomes dephosphorylated and active. Pyruvate dehydrogenase (PDH), responsible for converting pyruvate to acetyl CoA, is also active due to the inhibition of PDH kinase by pyruvate. The resulting acetyl CoA is either used for fatty acid (FA) synthesis or oxidized for energy in the tricarboxylic acid (TCA) cycle. In contrast, during this absorptive state, the liver inhibits gluconeogenesis and glycogenolysis, pathways that generate glucose. Pyruvate carboxylase (PC), which initiates gluconeogenesis, is mostly inactive due to low levels of acetyl CoA, its allosteric activator. The high insulin/glucagon ratio also promotes the inactivation of other gluconeogenic enzymes like fructose 1,6-bisphosphatase. Glycogenolysis is inhibited by the dephosphorylation of glycogen phosphorylase and phosphorylase kinase. In terms of fat metabolism, the liver experiences increased fatty acid synthesis during the absorptive period. This is favored by the availability of acetyl CoA and NADPH, as well as the activation of ACC through dephosphorylation and the presence of citrate, its allosteric activator. ACC plays a crucial role in catalyzing the formation of malonyl CoA, which is a rate-limiting step in fatty acid synthesis. Furthermore, citrate directly activates fatty acid synthesis and indirectly inhibits fatty acid degradation by inhibiting carnitine palmitoyltransferase-I (CPT-I). The cytosolic acetyl coenzyme A is sourced from pyruvate, which enters the mitochondria and is decarboxylated by PDH. The resulting acetyl CoA combines with oxaloacetate (OAA) to form citrate, which then leaves the mitochondria and enters the cytosol. In the cytosol, citrate is cleaved by ATP citrate lyase, induced by insulin, to produce the acetyl CoA substrate for ACC and OAA.
Increased glycolysis: In the liver, glycolysis is significant only during the absorptive period following a carbohydrate-rich meal. The conversion of glucose to pyruvate is stimulated by the elevated insulin/glucagon ratio that results in increased amounts of the regulated enzymes of glycolysis: glucokinase, PFK-1, and pyruvate kinase ([PK] see p. 105). Additionally, PFK-1 is allosterically activated by fructose 2,6bisphosphate generated by the active (dephosphorylated) kinase domain of bifunctional PFK-2. PK is dephosphorylated and active. Pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl CoA, is active (dephosphorylated) because pyruvate inhibits
PDH kinase (see Fig. 24.3, ). The acetyl CoA either is used as a substrate for fatty acid (FA) synthesis or is oxidized for energy in the tricarboxylic acid (TCA) cycle. (See Fig. 24.4 for the central role of glucose 6-phosphate.) 5. Decreased glucose production: While glycolysis and glycogenesis (pathways that promote glucose storage) are being stimulated in the liver in the absorptive state, gluconeogenesis and glycogenolysis (pathways that generate glucose) are being inhibited. Pyruvate carboxylase (PC), which catalyzes the first step in gluconeogenesis, is largely inactive because of low levels of acetyl CoA, its allosteric activator (see p. 119). [Note: The acetyl CoA is being used for FA synthesis.] The high insulin/glucagon ratio also favors inactivation of other gluconeogenic enzymes such as fructose 1,6-bisphosphatase (see Fig. 8.17, p. 100). Glycogenolysis is inhibited by dephosphorylation of glycogen phosphorylase and phosphorylase kinase. [Note: The increased uptake and decreased production of blood glucose in the absorptive period prevents hyperglycemia.]
B. Fat metabolism 1. Increased fatty acid synthesis: Liver is the primary site of de novo synthesis of FA (see Fig. 24.3, ). FA synthesis, a cytosolic process, is favored in the absorptive period by availability of the substrates acetyl CoA (from glucose and amino acid metabolism) and NADPH (from glucose metabolism in the pentose phosphate pathway) and by the activation of ACC, both by dephosphorylation and by the presence of its allosteric activator, citrate. [Note: Inactivity of AMPK favors dephosphorylation.] ACC catalyzes the formation of malonyl CoA from acetyl CoA, the rate-limiting reaction for FA synthesis (see p. 183). [Note: Malonyl CoA inhibits carnitine palmitoyltransferase-I (CPT-I) of FA oxidation (see p. 191). Thus, citrate directly activates FA synthesis and indirectly inhibits FA degradation.] a.
Source of cytosolic acetyl coenzyme A: Pyruvate from aerobic glycolysis enters mitochondria and is decarboxylated by PDH. The acetyl CoA product is combined with oxaloacetate (OAA) to form citrate via citrate synthase of the TCA cycle. Citrate leaves the mitochondria (as a result of the inhibition of isocitrate dehydrogenase by ATP) and enters the cytosol. Citrate is cleaved by ATP citrate lyase (induced by insulin), producing the acetyl CoA substrate of ACC plus OAA.
b.