Abstract
Glucose occupies a unique position in intermediary metabolism for two reasons:
1. it is the substrate of glycolysis which is the only pathway to produce ATP in anaerobic life
2. it is the major and usually the unique substrate for brain metabolism.
The second reason is by far the most important in the human body and one major role of the liver is to maintain a normal level of glycaemia. The control of the level of glycaemia by the liver involves the storage of glucose as glycogen and the formation of glucose from endogenous source by gluconeogenesis.
The control of glycogen metabolism in the liver
As explained in detail in a recent review (Hers, Ann. Rev. Biochem. , 45, 167-189, 1976) the rate limiting steps of glycogen synthesis and breakdown in the liver are catalyzed by glycogen synthase and glycogen phosphorylase. Each of these enzymes exist in two forms: one active (a),and the other one inactive (b). The a and b forms are interconvertible through phosphorylation by kinases and dephosphorylation by phosphatases. Glucose is readily diffusable inside of the liver cell. It binds to phosphorylase a which can be considered as the glucose receptor of the liver. The glucose bound phosphorylase a is rapidly converted to phosphorylase b by phosphorylase phosphatase. A first effect of glucose is to decrease and eventually to arrest glycogen degradation in the liver. Furthermore, phosphorylase a is a strong inhibitor of synthase phosphatase, the enzyme that activates glycogen synthase. Therefore, the disappearance of phosphorylase a as a result of glucose binding allows the activation of glycogen synthase and the initiation of glycogen synthesis. Various ionic and hormonal effects including those of insulin appear to be explained by a primary action on the inactivation of phosphorylase. Glucagon causes glycogenolysis by the intermediary of cyclic AMP, activation of protein kinase, phosphorylase kinase and phosphorylase. Each step of this glycogenolytic pathway has been observed in hepatocytes incubated in the presence of the hormones. In contrast, catecholamines and other agonists including vasopressin and angiotensin stimulate glycogenolysis by another mechanism, possibly involving a change in calcium concentration. Insulin counteracts the effect of these glycogenolytic agents by acting at various steps of the glycogenolytic cascade.
The control of gluconeogenesis and the futile cycles
Futile cycle is a metabolic interconversion of which the net balance is the consumption of ATP. Three such cycles exist on the pathway of glycolysis and gluconeogenesis (1) at the level of glucose/ glucose 6-phosphate interconversion (2) at the level of fructose 6-phosphate/fructose diphosphate interconversion (3) at the level of pyruvate/phosphoenolpyruvate interconversion. The bestknown mechanism by which glucagon stimulates gluconeogenesis is the inactivation, by phosphorylation, of pyruvate kinase, preventing futile recycling between phosphoenolpyruvate and pyruvate. The control of the recycling between fructose 6-phosphate and fructose diphosphate is still badly understood but appears to be controlled by glucagon also. Recycling between glucose and glucose 6-phosphate occurs continuously and is controlled only by the concentration of substrate: it plays a major role in the control of glucose uptake and glucose output by the liver.
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Hers, H. THE CONTROL OF CARBOHYDRATE METABOLISM IN THE LIVER. Pediatr Res 14, 164 (1980). https://doi.org/10.1203/00006450-198002000-00021
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DOI: https://doi.org/10.1203/00006450-198002000-00021