1. Glucose in the blood is transported into the hepatocyte by the GLUT 2 transporter and is converted to glucose 6-phosphate by glucokinase.

2. Phosphoglucomutase then catalyzes the readily reversible reaction that converts glucose 6-phosphate to glucose 1-phosphate.

3. The glucose 1-phosphate is further activated to UDP-glucose by glucose 1-phosphate uridylyltransferase in a reaction that consumes UTP and produces inorganic pyrophosphate. This reaction is thermodynamically favored by the hydrolysis of pyrophosphate by pyrophosphatase, which also makes the formation of UDP-glucose an irreversible reaction.

4. Glycogen synthase catalyzes the addition of a glucosyl residue to a glycogen molecule using UDP-glucose as the substrate, forming an α(1→4) glycosidic bond and releasing UDP. Since glycogen synthase cannot create an α(1→6) linkage, an additional enzyme is required to form branches. When a chain of at least 11 glucosyl residues has been synthesized, 1,4-α-glucan branching enzyme removes a chain of about seven glucosyl residues and transfers it to another chain, creating an α(1→6) glycosidic bond. This new branch point must be at least four glucosyl residues away from another branch point.

Since the synthesis and mobilization of glycogen together form a potential futile cycle, the competing processes must be regulated to prevent waste of ATP/UTP. This is accomplished by hormonal as well as allosteric controls. The enzymatic cascade, that is promulgated when glucagon or epinephrine bind to their respective receptors on the liver cells, is presented in Figure 44-2. The cAMP that is produced by activation of adenylate cyclase binds to PKA and activates it so that it can phosphorylate its target proteins. These include phosphorylase kinase, glycogen synthase, and inhibitor 1. Phosphorylation of glycogen synthase converts it to an inactive form, whereas phosphorylation of phosphorylase kinase and inhibitor 1 activate them. The phosphorylated inhibitor 1 is then able to bind strongly to protein phosphatase 1, but it is a poor substrate and is hydrolyzed slowly. Although the phosphorylated inhibitor 1 is bound to the phosphatase, it will inhibit it from acting on other phosphorylated proteins. Thus, while protein phosphatase 1 is inhibited, those proteins that are activated by phosphorylation remain active, and those that are inhibited by phosphorylation stay in their inactive form.

The mobilization of glycogen in the liver in response to hormonal signals. Binding of the hormones glucagon and/or epinephrine causes the activation of adenylate cyclase resulting in the production of cyclic AMP, which activates protein kinase A. By phosphorylation reactions, protein kinase A inactivates glycogen synthase, activates a cascade that results in active glycogen phosphorylase, and produces an active inhibitor of protein phosphatase 1.

Phosphorylation of phosphorylase kinase partially activates it so that it can phosphorylate phosphorylase b to its active form. Phosphorylase kinase is also partially activated by Ca2+; full activation is obtained when it both binds Ca2+ and is phosphorylated. Conversion of phosphorylase b to phosphorylase a enables glucose 1-phosphate to be released from glycogen. Thus, glucagon and epinephrine start a cascade that mobilizes glucose from glycogen and at the same time inhibits the storage of glucose as glycogen.

When blood glucose levels are elevated, insulin is secreted from the pancreatic cells. When insulin binds to hepatic insulin receptors, it results in the activation of a complex series of kinases that leads to the activation of protein phosphatase 1. Protein phosphatase 1 dephosphorylates phosphorylase kinase, phosphorylase, and inhibitor 1, thus inactivating them and inhibiting the phosphorolysis of glycogen. It also dephosphorylates glycogen synthase, converting it to its active form and enabling the storage of glucose as glycogen. In addition, the liver form of phosphorylase a is inhibited by elevated intracellular concentrations of glucose. Thus insulin favors the storage of glycogen and inhibits its mobilization.

Although the etiology of the AFLP syndrome is unclear, it does appear to be a defect affecting mitochondrial processes. Liver biopsy usually will show mitochondrial disruption and microvesicular fat deposits, indicating decreased β-oxidation of fatty acids. The fatty acids, since they cannot be efficiently oxidized in the mitochondria, are converted to triglycerides, which build up in the hepatocyte. The fat infiltration decreases the amount of glycogen that can be stored and mobilized to maintain blood glucose levels. Gluconeogenesis is also depressed because ATP is not available from the oxidation of fatty acids. Thus, blood glucose levels decline.

As noted above, there have been reports that link some cases of AFLP with a defect in fatty acid metabolism in the fetus. These include fetal deficiencies of long chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD), carnitine-palmitoyl transferase 1 (CPT 1), and medium chain acyl-coenzyme A dehydrogenase (MCAD). The mechanism by which defective fetal fatty acid oxidation causes maternal illness is not known. However, since the fetus uses primarily glucose metabolism for its energy needs, it is likely that toxic products from the placenta, which does use fatty acid oxidation, cause the maternal liver failure.

Transport and Fate of Major Carbohydrates and Amino Acids. [Reproduced with permission from Murray RA, et al.: Harper's Illustrated Biochemistry, 28th edition, McGraw-Hill, 2009.]