Coordinated Regulation of Glycogen Synthesis and Breakdown:- Allosteric and Hormonal Signals Coordinate Carbohydrate Metabolism
Having looked at the mechanisms that regulate individual enzymes, we can now consider the overall shifts in carbohydrate metabolism that occur in the well-fed state, during fasting, and in the fight-or-flight response—signaled by insulin, glucagon, and epinephrine, respectively. We need to contrast two cases in which regulation serves different ends: (1) the role of hepatocytes in supplying glucose to the blood, and (2) the selfish use of carbohydrate fuels by nonhepatic tissues, typified by skeletal muscle (the myocyte), to support their own activities. After ingestion of a carbohydrate-rich meal, the elevation of blood glucose triggers insulin release (Fig. 15–31, top). In a hepatocyte, insulin has two immediate effects: it inactivates GSK3, acting through the cascade shown in Figure 15–29, and activates a protein phosphatase, perhaps PP1. These two actions fully activate glycogen synthase. PP1 also inactivates glycogen phos phorylase a and phosphorylase kinase by dephosphorylating both, effectively stopping glycogen breakdown. Glucose enters the hepatocyte through the high-capacity transporter GLUT2, always present in the plasma mem brane, and the elevated intracellular glucose leads to dis sociation of hexokinase IV (glucokinase) from its nuclear regulator protein. Hexokinase IV enters the cytosol and phosphorylates glucose, stimulating glycolysis and sup plying the precursor for glycogen synthesis. Under these conditions, hepatocytes use the excess glucose in the blood to synthesize glycogen, up to the limit of about 10% of the total weight of the liver.
FIGURE 15–31 Regulation of carbohydrate metabolism in the hepatocyte. Arrows indicate causal relationships between the changes they connect. ↓A→↑B means that a decrease in A causes an increase in B. Pink arrows connect events that result from high blood glucose; blue arrows connect events that result from low blood glucose.
Between meals, or during an extended fast, the drop in blood glucose triggers the release of glucagon, which, acting through the cascade shown in Figure 15–25, activates PKA. PKA mediates all the effects of glucagon (Fig. 15–31, bottom). It phosphorylates phosphorylase kinase, activating it and leading to the activation of glycogen phosphorylase. It phosphorylates glycogen synthase, inactivating it and blocking glycogen synthesis. It phosphorylates PFK-2/FBPase-2, leading to a drop in the con centration of the regulator fructose 2,6-bisphosphate, which has the effect of inactivating the glycolytic enzyme PFK-1 and activating the gluconeogenic enzyme FBPase 1. And it phosphorylates and inactivates the glycolytic enzyme pyruvate kinase. Under these conditions, the liver produces glucose 6-phosphate by glycogen break down and by gluconeogenesis, and it stops using glucose to fuel glycolysis or make glycogen, maximizing the amount of glucose it can release to the blood. This re lease of glucose is possible only in liver, because other tissues lack glucose 6-phosphatase (Fig. 15–6). The physiology of skeletal muscle differs from that of liver in three ways important to our discussion of metabolic regulation (Fig. 15–32): (1) muscle uses its stored glycogen only for its own needs; (2) as it goes from rest to vigorous contraction, muscle undergoes very large changes in its demand for ATP, which is supported by glycolysis; (3) muscle lacks the enzymatic machinery for gluconeogenesis. The regulation of carbohydrate metabolism in muscle reflects these differences from liver. First, myocytes lack receptors for glucagon. Second, the muscle isozyme of pyruvate kinase is not phosphorylated by PKA, so glycolysis is not turned off when [cAMP] is high. In fact, cAMP increases the rate of glycolysis in muscle, probably by activating glycogen phos phorylase. When epinephrine is released into the blood in a fight-or-flight situation, PKA is activated by the rise in [cAMP], and phosphorylates and activates glycogen phosphorylase kinase. The resulting phosphorylation and activation of glycogen phosphorylase results in faster glycogen breakdown. Epinephrine is not released under low-stress conditions, but with each neuronal stimulation of muscle contraction, cytosolic [Ca2+] rises briefly and activates phosphorylase kinase through its calmodulin subunit. Elevated insulin triggers increased glycogen syn thesis in myocytes by activating PP1 and inactivating GSK3. Unlike hepatocytes, myocytes have a reserve of GLUT4 sequestered in intracellular vesicles. Insulin triggers their movement to the plasma membrane, where they allow increased glucose uptake. In response to insulin, therefore, myocytes help to lower blood glucose by increasing their rates of glucose uptake, glycogen synthesis, and glycolysis.
