Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Liver
The Role of the Liver in Carbohydrate Metabolism

The primary role of the Liver in Carbohydrate METABOLISM is to maintain a constant Blood glucose concentration. This is achieved by regulating the balance between the Synthesis and Breakdown of Glycogen stored in the liver.

In the liver, glycogen synthesis and its regulation are largely analogous to the processes occurring in other Organs and Tissues, particularly Skeletal Muscle. The synthesis of glycogen from glucose normally provides a temporary carbohydrate reserve, which is essential for maintaining blood glucose levels whenever supply drops significantly (for example, in humans, this occurs during inadequate dietary carbohydrate intake or overnight fasting).

It is important to emphasize the crucial role of the enzyme glucokinase in hepatic glucose utilization. Much like hexokinase, glucokinase catalyzes the phosphorylation of glucose to yield glucose-6-phosphate; however, The activity of glucokinase in the liver is nearly 10 times higher than that of hexokinase. A key difference between the two Enzymes is that, unlike hexokinase, glucokinase has a high K_M for glucose and is not inhibited by glucose-6-phosphate.

Following a meal, glucose levels in the portal vein rise sharply, accompanied by a proportional increase in intrahepatic glucose concentration*. This elevation in hepatic glucose concentrations significantly boosts glucokinase activity, automatically driving up glucose uptake by the liver (the resulting glucose-6-phosphate is then either channeled into glycogen synthesis or degraded).

* During the intestinal absorption of CARBOHYDRATES, the Blood Glucose Level in the portal vein can rise up to 20 mmol/L, whereas peripheral blood typically contains no more than 5 mmol/L.

It is widely held that the liver's primary role in glucose breakdown is essentially to supply precursor metabolites required for the Biosynthesis of Fatty acids and glycerol, rather than to oxidize glucose to CO₂ and H₂O. Under normal conditions, triglycerides synthesized in the liver are released into the bloodstream as Lipoproteins and transported to adipose tissue for more long-term storage.

The Reactions of the Pentose Phosphate Pathway in the liver generate NADPH, which is utilized for reductive biosynthesis in The production of Fatty acids, Cholesterol, and Other Steroids. Additionally, this pathway produces pentose phosphates, which are essential for nucleic acid synthesis.

Alongside glucose utilization, the liver is also actively involved in glucose production. The immediate source of glucose in the liver is glycogen, The breakdown of which occurs primarily via a phosphorolytic pathway. Cyclic nucleotide systems play a major role in regulating The rate of hepatic Glycogenolysis. Furthermore, glucose is synthesized in the liver via Gluconeogenesis.

The primary substrates for gluconeogenesis are lactate, glycerol, and Amino Acids. It is generally accepted that virtually all amino acids, with the exception of leucine, can replenish the pool of gluconeogenic precursors.

When evaluating the carbohydrate function of the liver, one must bear in mind that the balance between glucose utilization and production is regulated primarily through neurohumoral mechanisms involving Endocrine glands.

Glucose-6-phosphate plays a central role in glucose transformations and the autoregulation of Carbohydrate Metabolism in the liver. It strongly inhibits the phosphorolytic breakdown of glycogen, activates the enzymatic transfer of glucose from uridine diphosphate glucose to the growing glycogen chain, serves as a substrate for subsequent glycolytic transformations as well as glucose oxidation (including The pentose phosphate pathway), and finally, the dephosphorylation of glucose-6-phosphate by phosphatase releases free glucose into the bloodstream for delivery to all organs and tissues (Fig. 16.1).

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Fig. 16.1. The Role of glucose-6-phosphate in carbohydrate metabolism.

Fig. 16.2. Hormonal Regulation of the fructose-2,6-bisphosphate (F-2,6-P₂) system in the liver via cAMP-dependent protein Kinases.

As noted earlier, the most potent allosteric activator of Phosphofructokinase-1 and inhibitor of hepatic fructose-1,6-bisphosphatase is fructose-2,6-bisphosphate (F-2,6-P₂). An increase in hepatocellular F-2,6-P₂ levels enhances Glycolysis while suppressing the rate of gluconeogenesis. F-2,6-P₂ diminishes the inhibitory effect of ATP on phosphofructokinase-1 and increases the enzyme's affinity for fructose-6-phosphate. Conversely, when inhibiting fructose-1,6-bisphosphatase, F-2,6-P₂ raises the K_M value for fructose-1,6-bisphosphate. The concentration of F-2,6-P₂ in the liver, Heart, skeletal muscle, and other tissues is regulated by a bifunctional enzyme that catalyzes both the synthesis of F-2,6-P₂ from fructose-6-phosphate and ATP, and its Hydrolysis back to fructose-6-phosphate and P_i—meaning the enzyme exhibits both kinase and bisphosphatase activities simultaneously. The bifunctional enzyme (phosphofructokinase-2/fructose-2,6-bisphosphatase) isolated from rat liver consists of two identical subunits, each with a Molecular Weight of 55,000, and contains two distinct catalytic centers. The kinase domain is located at the N-terminus, whereas the bisphosphatase domain resides at the C-terminus of each polypeptide chain. Furthermore, the hepatic bifunctional enzyme serves as an excellent substrate for cAMP-dependent protein kinase A. Protein kinase A-mediated phosphorylation of Serine residues in each subunit of the bifunctional enzyme leads to a decrease in its kinase activity and an increase in its bisphosphatase activity. Notably, Hormones—specifically Glucagon—play a vital role in regulating the activity of this bifunctional enzyme (Fig. 16.2).

Numerous pathological conditions, particularly Diabetes Mellitus, are accompanied by significant alterations in the function and Regulation of the F-2,6-P₂ system. Studies have shown that in experimental (streptozotocin-induced) diabetes in rats, concurrent with a sharp surge in blood and urine glucose levels, hepatocellular F-2,6-P₂ concentrations are significantly reduced. Consequently, the rate of glycolysis drops while gluconeogenesis is amplified. This phenomenon has a clear explanation: the hormonal imbalances arising in diabetic rats—namely, elevated glucagon and decreased Insulin levels—drive up intracellular cAMP concentrations in liver tissue, thereby enhancing cAMP-dependent phosphorylation of the bifunctional enzyme, which in turn suppresses its kinase activity and boosts its bisphosphatase activity. This mechanism likely accounts for the drop in F-2,6-P₂ levels in hepatocytes during experimental diabetes. Evidently, other mechanisms also contribute to lowering F-2,6-P₂ levels in streptozotocin-induced diabetes. It has been demonstrated that experimental diabetes leads to reduced glucokinase activity (and potentially a lower enzyme content) in liver tissue. This results in a decreased rate of glucose phosphorylation, followed by a decline in fructose-6-phosphate—the substrate for the bifunctional enzyme. Finally, recent studies have revealed that streptozotocin-induced diabetes decreases The amount of mRNA encoding the bifunctional enzyme in hepatocytes, resulting in diminished F-2,6-P₂ levels in liver tissue and enhanced gluconeogenesis. All of this further reinforces the premise that F-2,6-P₂ acts as a critical component in hormonal signaling cascades, functioning as a tertiary messenger in hormone action, particularly regarding the Regulation of glycolysis and gluconeogenesis.

When examining intermediary carbohydrate metabolism in the liver, the metabolism of FRUCTOSE AND GALACTOSE must also be considered. Fructose entering the liver can be phosphorylated at the C-6 position to yield fructose-6-phosphate by hexokinase, an enzyme with relative Specificity that catalyzes the phosphorylation of mannose In addition to glucose and fructose. However, an alternative pathway exists in the liver: fructose can be phosphorylated via a more specific enzyme, fructokinase, yielding fructose-1-phosphate. This reaction is not inhibited by glucose. Subsequently, fructose-1-phosphate is cleaved by aldolase into two trioses: dihydroxyacetone phosphate and glyceraldehyde. Under the action of a specific kinase (triokinase) and in the presence of ATP, glyceraldehyde is phosphorylated to glyceraldehyde-3-phosphate. The latter (which readily equilibrates with dihydroxyacetone phosphate) undergoes standard metabolic transformations, including The formation of pyruvic acid as an intermediate product.

It should be noted that in cases of genetically determined fructose intolerance or hereditary fructose-1,6-bisphosphatase deficiency, fructose-induced hypoglycemia occurs despite abundant hepatic glycogen reserves. This is presumably due to allosteric inhibition of liver phosphorylase by fructose-1-phosphate and fructose-1,6-bisphosphate.

Furthermore, the glycolytic metabolism of fructose in the liver proceeds much more rapidly than that of glucose. Glucose metabolism features a rate-limiting step catalyzed by phosphofructokinase-1, which serves as the principal Metabolic control point for the rate of Glucose Catabolism. Because fructose bypasses this regulatory step, it rapidly accelerates hepatic metabolic pathways leading to fatty acid synthesis, their Esterification, and the secretion of very-low-density lipoproteins, which can ultimately elevate plasma triglyceride levels.

Galactose is initially phosphorylated in the liver in the presence of ATP and galactokinase to form galactose-1-phosphate. In fetal and infant livers, galactokinase exhibits K_M and V_max values approximately 5 times higher than those found in adults. The majority of galactose-1-phosphate in the liver is converted via a reaction catalyzed by hexose-1-phosphate uridylyltransferase:

UDP-glucose + Galactose-1-phosphate —> UDP-galactose + Glucose-1-phosphate.

This represents a unique transferase reaction that channels galactose back into the main pathway of carbohydrate metabolism. Hereditary deficiency of hexose-1-phosphate uridylyltransferase leads to galactosemia, a condition characterized by mental retardation and cataract formation. In this disorder, the newborn's liver loses its ability to metabolize D-galactose, a component of milk lactose.