Liver metabolism

By understanding how the liver is placed within the circulatory system, we can understand the rationale behind many of its metabolic functions. It is the first organ to 'get its pick' of the nutrients which enter the body from the intestine after a meal, and we might therefore predict that it would have a major role in energy storage after a meal. This is indeed so, at least for carbohydrate; storage and later release of glucose are major functions of the liver. It also has an important role in amino acid metabolism. Although most dietary fat bypasses the liver as it enters the circulation (see Section 3.3.3), the liver does have important roles in fat metabolism. Also, short- and medium-chain fatty acids from the diet reach the liver directly in the portal vein.

4.1.2.1 Carbohydrate metabolism in the liver

The major pathways of glucose metabolism in the liver, and their hormonal regulation, are summarised in Fig. 4.2.

Fed conditions

Glucose is absorbed from the intestine into the portal vein, where its concentration may reach almost 10 mmol/l after a meal. (Arterial blood glucose concentration is normally around 5 mmol/l.) The hepatocytes, especially the periportal cells, are therefore exposed to high concentrations of glucose during the absorptive phase. Liver cells have predominantly the GLUT-2 type of

Fig. 4.2 Outline of glucose metabolism and its hormonal regulation in the liver.

Dashed arrows in pathways indicate multiple enzymatic steps. The dotted shape is the mitochondrial membrane. GLUT2, hepatic glucose transporter (see Box 2.2); G 6-P, glucose 6-phosphate; GK, glucokinase; G-6-Pase, glucose-6-phosphatase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; Ribose 5-P, ribose 5-phosphate; TCA cycle, tricarboxylic acid (Krebs) cycle. A 'plus' sign indicates stimulation, a 'minus' sign inhibition. Note that the pathway for gluconeogenesis is over-simplifed (see Box 4.2), and no detail of the pathways of fatty acid and cholesterol synthesis is shown (see Box 4.3).

Glucose

Lactate

Glucose

Lactate

Fig. 4.2 Outline of glucose metabolism and its hormonal regulation in the liver.

Dashed arrows in pathways indicate multiple enzymatic steps. The dotted shape is the mitochondrial membrane. GLUT2, hepatic glucose transporter (see Box 2.2); G 6-P, glucose 6-phosphate; GK, glucokinase; G-6-Pase, glucose-6-phosphatase; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; Ribose 5-P, ribose 5-phosphate; TCA cycle, tricarboxylic acid (Krebs) cycle. A 'plus' sign indicates stimulation, a 'minus' sign inhibition. Note that the pathway for gluconeogenesis is over-simplifed (see Box 4.2), and no detail of the pathways of fatty acid and cholesterol synthesis is shown (see Box 4.3).

glucose transporter (Box 2.2), which is not responsive to insulin, and has a relatively high Km for glucose so that it normally operates well below saturation. In addition, because there are many transporters, there is a high maximal activity (Vmax) for glucose transport. This means that the rate and direction of movement of glucose across the hepatocyte membrane are determined by the relative glucose concentrations inside and outside the cell.

Within the hepatocyte, glucose is phosphorylated to form glucose 6-phos-phate - the initial step in its metabolism by any pathway - by the enzyme glu-cokinase. This enzyme belongs to the family of hexokinases (hexokinase Type IV), but differs from the other hexokinases found in muscle and other tissues in that it has a high Km for glucose (12 mmol/l) and is not inhibited by its product, glucose 6-phosphate, at physiological concentrations.1 Like the GLUT2 transporter it has a high capacity (high Vmax) and is unaffected, in the short term, by insulin.

The overall result is that when the glucose concentration outside the hepatocyte rises, glucose will be rapidly taken into cells and phosphorylated; the liver is often described as acting like a 'sink' for glucose. Another way of expressing this is to say that it acts like a buffer, taking up glucose when the concentration outside is high (e.g. after ingestion of a carbohydrate-containing meal) and releasing it, by specific mechanisms discussed below, when it is required elsewhere in the body.

The presence of the high-Km glucose transporter and the high-Km glucoki-nase would not, alone, enable the hepatocyte to take up unlimited quantities of glucose, as glucose 6-phosphate would simply accumulate within the cell until glucose phosphorylation ceased. Instead, there are specific mechanisms for stimulating the disposal of glucose 6-phosphate.

Glucose 6-phosphate may enter the pathways of glycogen synthesis or glycolysis. Insulin and glucose both activate the storage of glucose as glycogen. They activate the main regulatory enzyme of glycogen synthesis (glycogen synthase) and inhibit glycogen breakdown (by glycogen phosphorylase). This control is brought about in both cases by changes in the phosphorylation of the enzyme (Box 4.1). The result is a rapid stimulation of glycogen synthesis and suppression of glycogen breakdown, so that net storage of glycogen occurs. Because insulin is secreted from the pancreas and reaches the liver directly, and because glucose from the small intestine also arrives in the hepatic portal vein, they can bring about precise coordination of this system.

Glucose 6-phosphate can also be metabolised via glycolysis to pyruvate in hepatocytes. This pathway is also activated in fed conditions. Details are given in Box 4.2. Some of the resulting pyruvate may be oxidised directly in the tricarboxylic acid cycle, some released after conversion to lactate. Most of the energy required by the liver for its multiple metabolic purposes is, however, derived from the oxidation of amino acids and fatty acids rather than glucose.

Note that expression of several of the enzymes of glycolysis is induced by insulin and glucose (Tables 2.5, 2.6). In a situation of prolonged high carbo hydrate intake, this would reinforce the shorter-term mechanisms that have mainly been discussed above.

Overnight fasted conditions

Glycogen breakdown, controlled by reciprocal activation of glycogen phos-phorylase and inhibition of glycogen synthase, is brought about by a change in the balance of hormones. The activation (by phosphorylation) of glycogen phosphorylase is regulated by a number of hormones including glucagon, and by the catecholamines, adrenaline and noradrenaline (Box 4.1). (The role of the catecholamines in metabolic regulation during normal daily life is probably small, although it becomes important in 'stress situations', considered in Chapters 7 and 8.) Activation of glycogen phosphorylase is opposed by insulin and glucose, as we have seen. As the absorption of a meal is completed, tissues such as brain and muscle are still using glucose, and its concentration in the blood will begin to fall, albeit slightly; the balance of the hormones insulin and glucagon secreted by the pancreas will then change in favour of glucagon. Again, the anatomical relationship of the liver to the endocrine pancreas means that hepatic metabolism is very directly regulated by this balance.

Glycogen will therefore be broken down when the concentration of glucose in the blood falls. The 'purpose' of this is to liberate the carbohydrate, stored in the liver after meals, into the bloodstream. The breakdown of glycogen leads to the production of glucose 1-phosphate, which is in equilibrium with glucose 6-phosphate (catalysed by the enzyme phosphoglucomutase). Glucose 6-phosphate cannot be converted to glucose by the enzyme glucokinase, which catalyses an essentially irreversible reaction, and the formation of glucose from glucose 6-phosphate is instead brought about by glucose-6-phosphatase (Fig. 4.2). Like glucokinase, the Km of glucose-6-phosphatase is high relative to normal concentrations of its substrate, glucose 6-phosphate. Glucose-6-phos-phatase is not free in the cytoplasm: it is a membrane-bound enzyme present in the membranes of the endoplasmic reticulum (a complex of membranes enclosing a compartment separate from the cell cytoplasm). Its catalytic site faces into the lumen of the endoplasmic reticulum and the enzyme is associated with subunits that act as specific transporters for the facilitated diffusion of glucose 6-phosphate (from the cytosol into the lumen), and glucose (from lumen to cytosol); the latter is a member of the GLUT family, possibly GLUT9.

Neither glucokinase nor glucose-6-phosphatase is directly regulated in the short term by hormonal signals (they are over a matter of some hours, by changes in the amount of enzyme protein present), and the net flux between glucose and glucose 6-phosphate is therefore determined by their relative concentrations. During glycogen breakdown, brought about because the plasma glucose concentration is falling, the net flux will be towards the formation and export from the cell of glucose.

The other important function of the liver in glucose metabolism is the synthesis of glucose from other precursors, gluconeogenesis. In terms of function,

Box 4.1 Hormonal regulation of glycogen breakdown (glycogenolysis) and synthesis (glycogenosis) in the liver

Glycogen breakdown

Adrenaline or noradrenaline, acting via P-adrenergic receptors, and glucagon act through the pathway shown in Fig. 2.4.2, Box 2.4, to activate protein kinase-A (PKA), which phosphorylates phosphorylase kinase (phosph kinase in Fig. 4.1.1), converting it from its dephosphorylated, inactive form (b) to its phosphorylated, active form (a). Phosphorylase kinase then phosphorylates and activates glycogen phosphorylase (gly phosphorylase in Fig. 4.1.1), converting it from its dephosphorylated, inactive form (b) to its phosphorylated, active form (a). Glycogen phosphorylase acts on glycogen, releasing (by phos-phorolysis, which is similar to hydrolysis) one molecule at a time of glucose 1 -phosphate; this may be converted to glucose and released into the circulation. Glycogenolysis is inhibited by insulin, which activates a protein phosphatase (protein phosphatase-1 G, a form specifically found associated with glycogen); this dephosphorylates (and thus inactivates) phosphorylase kinase. [The regulation of protein phosphatase-1G by insulin is complex. It may involve reduction of cAMP by insulin and lowered activation of glycogen phosphorylase: phosphorylase a is an allosteric inhibitor of protein phosphatase-1G.]

cAMP

Insulin cAMP

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