The liver is extremely important in maintaining an adequate supply of nutrients for cell metabolism and regulating blood glucose concentration (Fig. 28.3). After the ingestion of a meal, the blood glucose increases to a concentration of 120 to 150 mg/dL, usually in 1 to 2 hours. Glucose is taken up by hepatocytes by a facilitated carrier-mediated process and is converted to glucose 6-phosphate and then UDP-glucose. UDP-glucose can be used for glycogen synthesis, or glycogenesis. It is generally believed that blood glucose is the major precursor of glycogen. However, recent evidence seems to indicate that the lactate in blood (from the peripheral metabolism of glucose) is also a major precursor of glycogen. Amino acids (e.g., alanine) can supply pyru-vate to synthesize glycogen.
Glycogen is the main carbohydrate store in the liver, and may amount to as much as 7 to 10% of the weight of a normal, healthy liver. The glycogen molecule resembles a tree with many branches (see Fig. 27.19). Glucose units are linked via a-1,4- (to form a straight chain) or a-1,6 (to form a branched chain) glycosidic bonds. The advantage of such a configuration is that the glycogen chain can be broken down at multiple sites, making the release of glucose much more efficient than would be the case with a straight-chain polymer.
During fasting, glycogen is broken down by glyco-genolysis. The enzyme glycogen phosphorylase catalyzes the cleavage of glycogen into glucose 1-phosphate. Glycogen phosphorylase acts only on the a-1,4-glycosidic bond,
Glucose (present in high
Glucose (present in high
and the enzyme a-1,6-glucosidase is used to break the a-1,6-glycosidic bonds.
Glucose 1-phosphate is converted to glucose 6-phos-phate by the enzyme phosphoglucomutase. The enzyme glucose-6-phosphatase, which is present in the liver but not in muscle or brain, converts glucose 6-phosphate to glucose. This last reaction enables the liver to release glucose into the circulation. Glucose 6-phosphate is an important intermediate in carbohydrate metabolism because it can be channeled either to provide blood glucose or for glycogen formation.
Both glycogenolysis and glycogenesis are hormonally regulated. The pancreas secretes insulin into the portal blood. Therefore, the liver is the first organ to respond to changes in plasma insulin levels, to which it is extremely sensitive. For instance, a doubling of portal insulin concentration completely shuts down hepatic glucose production. About half the insulin in portal blood is removed in its first pass through the liver. Insulin tends to lower blood glucose by stimulating glycogenesis and suppressing glycogenolysis and gluconeogenesis. Glucagon, in contrast, stimulates glycogenolysis and gluconeogenesis, raising blood sugar levels. Epinephrine stimulates glycogenolysis.
The liver regulates the blood glucose concentrations within a narrow limit, 70 to 100 mg/dL. Although one might expect patients with liver disease to have difficulty regulating blood glucose, this is usually not the case because of the relatively large reserve of hepatic function. However, those with chronic liver disease occasionally have reduced glycogen synthesis and reduced gluconeoge-nesis. Some patients with advanced liver disease develop portal hypertension, which induces the formation of por-tosystemic shunting, resulting in elevated arterial blood levels of insulin and glucagon.
acids, and lactate. The process is energy-dependent, and the starting substrate is pyruvate. The energy required seems to be derived predominantly from the ^-oxidation of fatty acids. Pyruvate can be derived from lactate and the metabolism of glucogenic amino acids—those that can contribute to the formation of glucose. The two major organs involved in the production of glucose from noncarbo-hydrate sources are the liver and the kidneys. However, because of its size, the liver plays a far more important role than the kidney in the production of sugar from noncarbo-hydrate sources.
Gluconeogenesis is important in maintaining blood glucose concentrations especially during fasting. The red blood cells and renal medulla are totally dependent on blood glucose for energy, and glucose is the preferred substrate for the brain. Most amino acids can contribute to the carbon atoms of the glucose molecule, and alanine from muscle is the most important. The rate-limiting factor in gluconeogenesis is not the liver enzymes but the availability of substrates. Gluconeogenesis is stimulated by epi-nephrine and glucagon but greatly suppressed by insulin. Thus, in type 1 diabetics, gluconeogenesis is greatly stimulated, contributing to the hyperglycemia observed in these patients (see Chapter 35).
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