Ketone bodies utilisation

Over-production Decreased ketone body utilisation at the peripheral level... 

Beis A., Zammit V. A. and Newsholme V. A. (1980) Activities of 3-hydroxybutyrate dehydrogenase, 3-oxoacid CoA-transferase and acetoacetyl-CoA thiolase in relation to ketone body utilisation in muscles from vertebrates and invertebrates. Eur. J. Biochem. 104, 209-215. 

The red blood cells contain an abundance of oxygen that they transport around the body, but ironically they cannot use this oxygen themselves and are entirely dependent on glucose for fuel by anaerobic glycolysis to produce ATP (Fig. 18.1). This is because they lack mitochondria and consequently the enzymes for the Krebs cycle. Similarly, red blood cells also lack the enzymes for fatty add oxidation and ketone body utilisation. 

The plasma concentration of ketone bodies in fed, healthy humans is very low (about 0.1 mmol/L) so that the rate of utilisation is very low. However, it is elevated in several conditions, e.g. starvation, hypoglycaemia, affer physical activity. In starvation in normal adults, it increases to about 3 mmol/L after three days and to 5-6 mmol/L after several more days (Figure 7.24). Nevertheless, it can increase to 3 nunol/L or higher within a few hours of completing a prolonged period of physical activity if food, particularly carbohydrate, is not eaten (known as accelerated starvation ) (Table 7.3). Ketone bodies are particularly important in children, since starvation can quickly result in severe hypoglycaemia. This is due to the fact that the amount of glycogen stored in the liver of a child is... 

There are two tissues that cannot use long-chain fatty acids, the small intestine and the brain. Both can, however, oxidise ketone bodies and therefore can restrict glucose utilisation. It is not known why these tissues do not oxidise fatty acids possibly the activity of the enzymes in oxidation is very low. 

In the fed state, the only fuel used by the brain is glucose, derived from the blood. In prolonged starvation or chronic hypoglycaemia, ketone bodies are nsed which rednce the rate of utilisation of glucose by the brain bnt, even so, glucose still provides about 50% of the energy. Consequently, under all conditions, maintenance of the blood glucose concentration is essential for the function of the brain the mechanisms that are responsible for this are discnssed in Chapters 6, 12 and 16. 

After 60 hours of starvation in lean subjects, fat utilisation (i.e. ketone bodies plus fatty acids) accounts for three-quarters of the energy expenditure (Table 16.1) a value which will rise even higher as starvation continues. Much of this increase is accounted for by hydroxybutyrate oxidation (the major ketone body) since, by 60 hours of starvation, the plasma concentration of hydroxybutyrate has increased 26-fold compared with a threefold increase in the concentration of fatty acid (the glucose concentration falls by less than 30%). By eight days of starvation there has been a sixfold increase in fatty acid concentration, whereas the concentration of hydroxybutyrate has increased about 50-fold (Table 16.2). The changes in these three major fuels in obese subjects during starvation for 38 days are shown in Figure 16.10. 

Figure 16.11 Pattern of fuel utilisation during prolonged starvation. The major metabolic change during this period is that the rates of ketone body formation and their utilisation by the brain increases, indicated by the increased thickness of lines and arrows. Since less glucose is required by the brain, gluconeogenesis from amino acids is reduced so that protein degradation in muscle is decreased. Note thin line compared to that in Figure 16.9.

The amino acids that are made available as a result of protein degradation in starvation are nsed as precursors of glucose, which is required for the brain. The decline in starvation-induced protein degradation is a result of the decreased requirement for glucose by the brain due to the increase in utilisation of ketone bodies. The qnestion arises, therefore, as to the mechanism by which the protein breakdown in muscle is reduced. Two answers, which are interdependent, have been put forward (i) decreased metabolic activity in tissues, and (ii) a decrease in the plasma level of thyroxine and hence triiodothyronine. 

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

Because carbohydrate utilisation is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins. Large amounts of acetyl CoA are then produced by P oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. Recall that mammals can synthesize oxaloacetate from pyruvate, a product of glycolysis, but not from acetyl CoA instead, they generate ketone bodies. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney s capacity to maintain acid—base balance. The untreated diabetic can go into a coma because of a lowered blood-pH level and dehydration. 

Fig. 4.10. Ketone body formation in the liver and its transport and utilisation in peripheral tissues, particularly skeletal muscle. HMG, hydroxymethylglutaryl.

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