The integration and control of metabolism
This chapter discusses the integration and control of metabolism. The main pathways of carbohydrate, fat, and protein metabolism, that is, of the major sources of energy, are described in terms of the enzymes responsible for them. However, the bodies of vertebrates contain about a hundred different types of cell each with a distinctive enzyme pattern. Some of the differences involve tissue-specific enzymes, but many are differences in the amounts and sensitivity of particular enzymes within the metabolic pathways. Not every tissue can burn all types of fuel. Tissues that depend on glucose as a major energy source include red- and white-blood corpuscles, brain, retina, renal medulla, intestinal mucosa, and skeletal muscle in severe exercise. Liver, kidney cortex, heart muscle, and skeletal muscle, except in severe exercise, obtain most of their energy from the oxidation of fatty acids, while the brain and renal cortex, as well as both heart and skeletal muscle, can utilize ketone bodies. The necessary control and integration of energy and other types of metabolism within and between the tissues is brought about by the action of hormones that, in conjunction with the nervous system, ensure that the cells of the body exist in a controlled environment of more or less constant composition.
The main pathways of carbohydrate, fat and protein metabolism, that is of the major sources of energy, were described earlier in terms of the enzymes responsible for them. However, the bodies of vertebrates contain about a hundred different types of cell each with a distinctive enzyme pattern. Some of the differences involve tissue-specific enzymes but many are differences in the amounts and sensitivity of particular enzymes within the metabolic pathways. Not every tissue can burn all types of fuel (glucose, fatty acids, ketone bodies, amino acids and lactate). Tissues which depend on glucose as a major energy source include red and white blood corpuscles, brain, retina, renal medulla, intestinal mucosa, and skeletal muscle in severe exercise. Liver, kidney cortex, heart muscle and skeletal muscle, except in severe exercise, can obtain most of their energy from the oxidation of fatty acids, while the brain and renal cortex, as well as both heart and skeletal muscle, can utilize ketone bodies. Not only are there fundamental differences of this sort in the metabolism of different tissues but, furthermore, the pathways which predominate in the various tissues can alter significantly in response to external factors such as dietary variation. The necessary control and integration of energy and other types of metabolism within and between the tissues is brought about by the action of hormones which, in conjunction with the nervous system, ensure that the cells of the body exist in a controlled environment of more or less constant composition.
The liver is generally recognized as the organ which serves the metabolic needs of the body as a whole, and specialized as well as general metabolic pathways are found within it. The liver derives most of its blood supply from the portal vein which drains the intestinal tract, and materials absorbed from the intestine must pass through the liver before entering the general circulation. Consequently the liver is exposed to widely varying concentrations of incoming metabolites as well as to certain potentially toxic substances so that it requires considerable metabolic versatility. The liver contains the enzymes necessary for the pathways of glycogen synthesis and breakdown and for glycolysis and gluconeogenesis. In particular, it contains the enzyme glucose 6-phosphatase which converts glucose 6-phosphate obtained from glycogenolysis or gluconeogenesis into glucose which can then be released into the plasma.
Liver hexokinase is similar to the hexokinases in other tissues and has a low Km for glucose (0·01−0.1 mM) but glucokinase which catalyses the same reaction has a much higher Km for glucose (). The concentration of glucose in the blood is normally of the order of 3−7 mM, and glucose equilibrates rapidly across the liver cell membrane. Hexokinase is therefore normally operating at its maximum rate which is relatively low in liver. The presence of glucokinase with its high Km allows the liver cell to respond to an increased concentration of blood glucose by increasing the rate of glucose phosphorylation (Figure 23.1) and hence of overall glucose metabolism.
The liver also contains pathways for both the synthesis and the oxidation of fatty acids as well as the urea cycle enzymes and many enzymes involved in amino acid catabolism and amino acid synthesis. Other important overall reactions catalysed by the liver are the formation of ketone bodies, cholesterol and bile acid synthesis, the synthesis and breakdown of triglycerides, phospholipid synthesis and the detoxification of foreign compounds such as drugs. It is clear that control mechanisms must exist to prevent the simultaneous operation of the many opposing pathways such as glycogen synthesis and glycogenolysis which would lead to the futile cycling of metabolites and net loss of cell ATP.
Adipose tissue is required to store fuel in the form of triglycerides in times of plenty and to release fatty acids and glycerol into the blood for use by other tissues when glucose is in short supply. Thus the major metabolic pathways in this tissue are those for lipogenesis and lipolysis. Adipose tissue takes up glucose readily and contains an active glycolytic pathway, which generates both acetyl units for fatty acid synthesis and dihydroxyacetone phosphate for production of the glycerophosphate needed for triglyceride synthesis. The enzymes pyruvate dehydrogenase, ATP citrate lyase, acetyl-CoA carboxylase and fatty acid synthase are present with relatively high activity, as are the enzymes of the pentose phosphate pathway which is responsible for the generation of some of the NADPH required for fatty acid synthesis. It also contains an adrenaline-sensitive lipase which releases fatty acids and glycerol into the blood when extra energy is required. Adipose tissue does not catalyse gluconeogenesis or the metabolism of glycogen to any extent and the pathways of amino acid metabolism and fatty acid oxidation are of little quantitative significance in this tissue. Since adipose tissue is capable of both the synthesis and the breakdown of triglycerides, the key enzymes in these pathways are subjected to coordinated metabolic control so that both pathways are not active simultaneously.
Skeletal muscles are specialized for the production of large quantities of ATP and the conversion of its chemical energy into mechanical energy for the contraction process. They are required to vary their activity, and hence their energy production, to a far greater degree than any other tissue. When resting they must prepare themselves for bursts of intense activity during which, in spite of a tremendous increase in blood supply, there may be a shortage of oxygen which necessitates anaerobic functioning for limited periods.
A particular feature of muscle is the presence of phosphocreatine which acts as a second source of readily available high-energy phosphate. Creatine is a substituted guanidine compound, methylguanidine acetic acid, which is synthesized in the body from glycine, arginine and methionine.
Creatine is readily phosphorylated by ATP in a reversible reaction catalysed by creatine kinase. The standard free energy of hydrolysis of phosphocreatine is −43 kJ (−10·3 kcal) so the equilibrium favours ATP formation.
In resting muscle phosphocreatine is present at at least five times the molar concentration of total adenine nucleotides and during contraction the creatine kinase reaction helps to maintain the intracellular concentration of ATP.
A further feature of muscles is the presence of appreciable amounts of myoglobin which acts as an auxiliary source of oxygen (page 373). The muscles of diving mammals such as seals, whales and dolphins and the flight muscles of birds owe their deep red colour to myoglobin, which in Man is present in significant amounts only in heart muscle.
Heart muscle, like skeletal muscle, is essentially an energy expender and is required to adapt itself to a tremendously varied work load. The oxygen supply of heart muscle, unlike that of skeletal muscle, is nearly always adequate since, when during contraction the blood supply is cut down, oxygen can be obtained from the store held by the myoglobin.
Skeletal muscle takes up glucose from the circulation and stores it in the form of glycogen. Under resting conditions, muscle uses fatty acids or ketone bodies rather than glucose as a energy source. During contraction, stored glycogen is broken down. Muscle cells do not contain glucose 6-phosphatase, and the glucose 6-phosphate formed is metabolized internally to pyruvate, and oxidized via the citrate cycle. If pyruvate is produced more rapidly than it can be oxidized it is converted to lactate which is released into the bloodstream.
Protein breakdown and amino acid metabolism are also of importance in muscle, and the major nitrogen-containing products are glutamine and alanine, which are released by the tissue. The pathways of gluconeogenesis and fatty acid synthesis do not exist in muscle. Heart muscle differs from skeletal muscle in that at high work loads it can use the lactate released by skeletal muscle as an energy source. Pyruvate produced by glycolysis in the heart is not converted to lactate. Heart lactate dehydrogenase is inhibited by high concentrations of pyruvate while lactate dehydrogenase from skeletal muscle is not (page 230).
The brain is very active and has a high rate of energy utilization at all times. Although it accounts for only about 1·4% of the total body weight it accounts for nearly 25% of the basal energy expenditure. Thus it uses about 120 g of glucose (= 2000 kJ) per day. It has not been found possible to demonstrate any significant increase in the overall energy consumption of subjects performing tasks requiring intense mental concentration.
Under normal conditions glucose is the only source of energy that is used by the brain which, as a result, is extremely sensitive to alterations in the blood glucose concentration. This is clearly demonstrated by the convulsions which occur in hypoglycaemia and the coma which results from prolonged hyperglycaemia. When the blood sugar is maintained within the normal range, the properties of hexokinase described earlier will ensure that the glucose 6-phosphate will be kept sufficiently high to provide the necessary energy. But when, as a result of prolonged starvation, glucose is in short supply and the only source is gluconeogenesis, the brain develops the ability to oxidize ketone bodies which circulate in appreciable amounts during starvation conditions. Studies on obese subjects undergoing 5−6 weeks of therapeutic starvation showed that the utilization of glucose by the brain was reduced to about 24 g day−1 and that nearly 40 g of ketone bodies were oxidized.
Another notable feature of brain metabolism is the high rate of turnover of its proteins. A steady supply of amino acids is therefore essential even if it has to be at the expense of other tissues. These amino acids cannot replace glucose as substrates for energy production even though glutamate and glutamine are present in high concentration and are actively metabolized. Glutamate serves not only as a precursor of γ-aminobutyrate (GABA), which plays a role in the regulation of neuronal activity, but also as a ‘scavenger’ for ammonia which is highly toxic and acts as a convulsive agent.
The main function of the kidney is to regulate the composition of the body fluids and a pathway of particular importance in this respect is the conversion of glutamine to ammonia and glucose. This conversion is involved in acid/base homeostasis (page 395), and is greatly stimulated in metabolic acidosis. The kidney uses fatty acids as a major energy source and much of the ATP produced from their oxidation is utilized in the active transport of metabolites. The kidney is the only tissue other than the liver which is capable of gluconeogenesis, and, under certain conditions, kidney gluconeogenesis can make a significant contribution to the overall glucose requirements.
From what has been said it is apparent that it is the different enzyme patterns which arise from the tissue-specific expression of genes that mainly account for the varying metabolic capabilities of different tissue. Thus, for example, the enzymes fructose 1,6-bisphosphatase and glucose 6-phosphatase occur only in liver and kidney and these are the only tissues capable of gluconeogenesis. Similarly, carbamoyl phosphate synthase, which is involved in the synthesis of urea and is ammonia dependent, occurs in the mitochondria of liver but not of other tissues. At the same time, the enzymic profile of tissues can vary to some extent in response to external factors such as diet.
The metabolic pathways which predominate in various tissues may vary according to the conditions prevailing at the time, notably with respect to (a) substrate availability, i.e. nutritional state and (b) substrate utilization, i.e. muscular activity and, in the longer term, with growth and ageing processes.
During the period immediately after eating a meal, synthetic and storage processes predominate. Under these conditions, the major pathways operating in the liver are the synthesis of glycogen and fatty acids from glucose and the conversion of the fatty acids into triglycerides (Figure 23.2). The amino acids which are not needed for protein and other synthetic processes cannot be stored and are catabolized. The nitrogen atoms derived from the amino groups are excreted as urea whereas the carbon skeletons are mostly oxidized.