Carbohydrate and fat metabolism

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Lipogenesis means the synthesis of lipid. More strictly, the term de novo lipogenesis means the synthesis of fatty acids and triacylglycerol from substrates other than lipids - particularly glucose, although amino acids which can be converted to acetyl-CoA can in principle also be substrates. The pathway itself was outlined in Box 4.3. It provides a means by which excess carbohydrate can be laid down for storage as triacylglycerol (since, as we have seen, this is the most energy-dense storage compound). The pathway of de novo lipogenesis may occur in both liver and adipose tissue. We do not know the relative importance of these tissues in humans; both are thought to play some role, although liver is likely to be more important.

The regulation of lipogenesis illustrates some useful points about metabolic regulation and its coordination in the whole body that were first brought up in the 'metabolic regulation puzzle' in Fig. 2.3. Fatty acids are synthesised from acetyl-CoA, and the pathway is stimulated by insulin, mainly by activation of the rate-controlling enzyme acetyl-CoA carboxylase (see Box 4.3). Acetyl-CoA may be produced from the breakdown of glucose, amino acids or fatty acids. What, then, prevents simultaneous fat oxidation, producing acetyl-CoA, and lipogenesis, reconverting acetyl-CoA to fatty acids? That would represent a 'futile' and energy-wasting metabolic cycle.

The first and easiest answer is that some important tissues do not carry out both these processes. Skeletal muscle has a high capacity for fatty acid oxidation, but it does not express fatty acid synthase. Adipose tissue has the capacity for fatty acid synthesis, but it seems hardly to oxidise fatty acids. But what about the liver, where both processes can certainly take place ? The answer is mainly the supply of substrate, regulated by insulin in other tissues. Under conditions when insulin might stimulate lipogenesis, it will also suppress fat mobilisation from adipose tissue; thus, the supply of fatty acids for oxidation in the liver will be diminished. In addition, under these conditions an increased concentration of malonyl-CoA will divert those fatty acids reaching the liver into esterification rather than oxidation (via inhibition of CPT-1 - see Fig. 4.3). Thus, several different regulatory points act together to direct metabolism in appropriate ways.

The pathway of lipogenesis, although of interest from the point of view of metabolic regulation, is probably not of major importance as a route of fat deposition in humans on a Western type of diet. The evidence for this is reviewed in Box 6.3.

Box 6.3 The physiological importance of de novo lipogenesis in humans on a Western diet

The occurrence of net lipogenesis in the body - that is, a rate of lipogenesis which exceeds the rate of fat oxidation in the body as a whole - can be detected by measuring the consumption of O2 and production of CO2 by the body (indirect calorimetry). Net lipogenesis results in a ratio (mole for mole) of CO2 production to O2 consumption which is greater than 1.00; this is mainly because pyruvate (3-carbon) has to be converted to acetyl-CoA (2-carbon), and for each mole of pyruvate used, one mole of CO2 is thus liberated. In contrast, the ratio of CO2 production to O2 consumption - called the respiratory quotient - for oxidation of glucose is 1.00, and that for fat is around 0.71 (discussed further in a later chapter, Box 11.2.)

If normal volunteers are fed a large carbohydrate breakfast (600 g carbohydrate, 9.6 MJ) then studied over the next 10 hours, they continue to oxidise rather than synthesise fat in a net sense (Acheson et al. 1982). If they are fed a very high carbohydrate diet for several days beforehand, then net lipogenesis will occur for a few hours after a high-carbohydrate meal; it is as though continuing high insulin concentrations have 'primed' the pathway (Acheson et al. 1984). Similarly, if volunteers are fed more than their normal daily energy requirements (overfeeding) then net lipogenesis will occur after a day or two, exactly as we might expect because this is the pathway for conversion of excess carbohydrate into fat for storage (Aarsland et al. 1997).

Another situation in which net lipogenesis is observed is in patients being fed intravenously to help them recover body mass lost during a severe illness. Sometimes these patients are given their energy almost entirely in the form of carbohydrate (glucose in solution), and then over a period of days they begin to show net lipogenesis; the carbohydrate taken in is being laid down as fat for storage (King et al. 1984).

Because these are extreme situations, it seems certain that in normal conditions lipogenesis is not a way in which we lay down fat in a net sense, although the metabolic pathways clearly exist and can be activated under some circumstances. The situation may well be different in people eating more traditional carbohydrate-based diets in developing countries.

In recent years novel techniques have been introduced using stable isotopic tracers to assess the contribution of de novo lipogenesis to hepatic triacylglyc-erol secretion (in VLDL particles). Note that this is not the same as net lipogenesis: the body as a whole might still be oxidising more fat than it is synthesising, but because of the capacity for lipogenesis in the liver, it might make a large contribution to hepatic triacylglycerol production. In fact, in almost all situations examined the absolute rate of hepatic de novo lipogenesis is small, and most hepatic triacylglycerol arises from hepatic uptake of fatty acids (as plasma NEFA and as triacylglycerol-fatty acids in lipoprotein particles). Metabolic interactions between fatty acids and glucose: the glucose-fatty acid cycle

The glucose-fatty acid cycle refers to important metabolic interactions between glucose and fat metabolism (Box 6.4). These interactions occur in adipose tissue and in muscle; the endocrine pancreas is involved via insulin secretion. They were first observed in rat heart muscle, but there is now considerable evidence that they occur in skeletal muscle in humans.

In adipose tissue, we have already seen these mechanisms at work. When the glucose concentration in plasma is high, the plasma insulin concentration responds. Insulin suppresses fat mobilisation (the release of fatty acids from adipose tissue). Thus, a high plasma glucose concentration leads to a low plasma non-esterified fatty acid concentration. In muscle, the rate at which fatty acids are utilised from plasma is dependent almost entirely on the plasma non-esteri-fied fatty acid concentration (and the blood flow) (see Section Thus, when additional glucose becomes available in the plasma - after a meal, for instance - the muscle will tend to switch to the use of glucose rather than fatty acids because, firstly, glucose uptake will be stimulated by insulin, and, secondly, the plasma non-esterified fatty acid concentration will fall and remove that substrate.

On the other hand, between meals (in the postabsorptive phase), the plasma glucose concentration falls a little, insulin secretion decreases, and the plasma non-esterified fatty acid concentration rises. In this situation the body's strategy is to 'spare' the use of carbohydrate for tissues such as the brain which

Box 6.4 The glucose-fatty acid cycle

The glucose-fatty acid cycle integrates the utilisation of fatty acids and glucose. These interactions between glucose and fatty acid metabolism were first described in 1963 by Philip Randle and colleagues (Randle et al. 1963). Central to this is a mechanism whereby the oxidation of fatty acids in muscle reduces the uptake and oxidation of glucose. The metabolic interactions involved are as follows. A high rate of fatty acid oxidation, and hence acetyl-CoA formation, leads to a high rate of citrate formation (via citrate synthase). In addition, the NADH/NAD+ and ATP/AD P ratios will be increased. The high acetyl-CoA/CoA and NADH/NAD+ ratios inhibit pyruvate dehydrogenase (via phosphoryla-tion, by pyruvate dehydrogenase kinase). Thus, the oxidation of pyruvate (derived from glycolysis) is suppressed. This is linked with coordinated inhibition of glucose uptake and glycolysis. Citrate (in the cytosol) is an inhibitor of the regulatory glycolytic enzyme phosphofructokinase (it potentiates the inhibition by ATP). (Box 4.3 shows how citrate can be exported from mitochondria to cytosol.) Fructose 6-phosphate and correspondingly glucose 6-phosphate build

up, and glucose 6-phosphate is an allosteric inhibitor of hexokinase. Hence, the pathway of glucose breakdown and oxidation is inhibited. Accumulation of free glucose is assumed to occur within the cell, thus inhibiting the uptake of further glucose. (There is some difficulty here, since free glucose concentrations in muscle are low and difficult to measure, and never seem to approach those in plasma as would be necessary for this story to hold completely. But the evidence for operation of the glucose-fatty acid cycle is so strong that it seems likely that our understanding of free glucose concentrations is at fault rather than the theory.) These interactions are illustrated in Fig. 6.4.1. There is also evidence for a direct inhibition of glucose transport into the cell, although the mechanism of that is not understood.

The glucose-fatty acid cycle may lead to adverse consequences in unusual situations when both non-esterified fatty acids and glucose are elevated. Some such situations will be discussed in later chapters: they include 'stress' and diabetes. This situation can also occur after a particularly large meal of both fat and carbohydrate. The muscle cannot oxidise non-esterified fatty acids and glucose at the rates expected from their concentrations in plasma; there is no mechanism for disposing of excess ATP, and it would clearly be wasteful of energy and of precious carbohydrate. Then the operation of the glucose-fatty acid cycle leads to an impairment of glucose uptake and metabolism, with the net effect that glucose uptake by muscle is reduced compared with that expected at given concentrations of insulin and glucose in the plasma. It appears that insulin does not stimulate glucose uptake as normal, and this is known as insulin resistance. Insulin resistance, perhaps better termed reduction in sensitivity to insulin, is a common alteration and will be covered in detail later (see Box 10.2 and Section 11.4.4).

cannot use fatty acids. This is achieved by the fact that oxidation of fatty acids in muscle suppresses the uptake and oxidation of glucose. The mechanism for this effect is described in Box 6.4, together with further consequences of the glucose-fatty acid cycle in situations of disturbed metabolism.

The glucose-fatty acid cycle is not a metabolic cycle in the normal sense - it does not involve the interconversion of glucose and fatty acids - but a series of metabolic regulatory events that coordinate glucose and fat metabolism under normal and some abnormal conditions.

The reverse of this interaction is also true and was examined in the previous section: when glucose and insulin levels are high, production of malonyl-CoA will inhibit fatty acid oxidation (this applies in both liver and skeletal muscle). This has recently been termed the 'reverse glucose-fatty acid cycle' (Sidossis & Wolfe 1996). We might see both mechanisms as providing fine tuning over the rate of utilisation of metabolic subtrates, particularly in skeletal muscle.

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