Ketone bodies during starvation

Skeletal muscle can utilize ketone bodies during starvation. 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Gjedde, A. and Crone. C. (1975) Induction processes in blood-brain bansfer of ketone bodies during starvation. 

The Plasma Levels of Fatty Acids, Glucose, and Ketone Bodies During the Early Days of Starvation. 

Two acetyl CoAs can combine to form acetoacetyl CoA by the reverse of b-ketothiolase. The acetoacetyl CoA then combines with another acetyl CoA to make hydroxymethyl glutaryl CoA (HMG CoA) by the enzyme hydroxymethyl glutaryl CoA synthase. The HMG CoA in the mitochondrion can be cleaved by HMG CoA lyase in the mitochondrion to form acetoacetate and acetyl CoA. In this conversion, the formation of acetoacetyl CoA from two acetyl CoAs releases a free CoA and formation of HMG CoA from acetyl CoA and acetoacetyl CoA also releases a free coenzyme A. Thus, the release of free coenzyme A allows beta oxidation to continue with the production of acetoacetate. During diabetes and starvation, almost 90% of carbon from a fatty acid such as oleate can be accounted for in the form of ketone bodies during experiments with perfused livers. At this time, it would be worth noting that this process occurs in the mitochondrion later it will be seen that HMG CoA in the cytosol is a major precursor for cholesterol synthesis. 

Inherited aldolase A deficiency and pyruvate kinase deficiency in erythrocytes cause hemolytic anemia. The exercise capacity of patients with muscle phos-phofiaictokinase deficiency is low, particularly on high-carbohydrate diets. By providing an alternative lipid fuel, eg, during starvation, when blood free fatty acids and ketone bodies are increased, work capacity is improved. 

Many tissues (muscle, liver, renal cortex) prefer fat for an energy supply, at least in the resting state. The exception is red blood cells and brain. These tissues depend heavily on glycolysis for energy. Red cells cannot survive without glucose (no mitochondria), but during prolonged starvation, brain can adapt to utilize fat metabolites produced by the liver (ketone bodies). 

KETONE BODIES are generated by the liver and used by muscle and brain (after adaptation during starvation). 

During starvation or hypoglycaemia, the liver partially oxidises fatty acids to form ketone bodies, which are released and oxidised by the brain, intestine and the essential muscles (see below) (Figure 7.7). 

Figure 7.21 Provision of the fat fueb for the brain during hypo-glycaemia. During hypoglycaemia it is essential that ketone bodies are available for the brain to provide a fat fuel for ATP generation to maintain mental functions. This sequence of processes from adipose tissue to the brain is therefore, a survival pathway especially for children during short-term starvation or hypoglycaemia. (Box 7.2) (Chapter 16).

In the 1970s the physiological importance of ketone bodies was revived, quite dramatically, when George Cahill and his colleagues demonstrated that ketone bodies could be used by the human brain during prolonged starvation and, furthermore, contributed significantly to ATP... 

Figure 7.24 The increase in the plasma ketone body concentration during starvation in adults and children. The ketone body comprises both acetoacetate and hydroxybutyrate.

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. 

The rise in blood ketone bodies continues during intermediate and prolonged starvation. After about 20 days the concentration reaches a plateau at about 8 mmol/L, mostly hydroxybutyrate (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.

During anaerobic glycolysis in the muscles and erythrocytes, glucose is converted into lactate, releasing protons in the process (see p. 338). The synthesis of the ketone bodies acetoacetic acid and 3-hydroxybutyric acid in the liver (see p. 312) also releases protons. Normally, the amounts formed are small and of little influence on the proton balance. If acids are formed in large amounts, however (e. g., during starvation or in diabetes mellitus see p. 160), they strain the buffer systems and can lead to a reduction in pH (metabolic acidoses lactacidosis or ketoacidosis). 

During periods of hunger, muscle proteins serve as an energy reserve for the body. They are broken down into amino acids, which are transported to the liver. In the liver, the carbon skeletons of the amino acids are converted into intermediates in the tricarboxylic acid cycle or into acetoacetyl-CoA (see p. 175). These amphibolic metabolites are then available to the energy metabolism and for gluconeogenesis. After prolonged starvation, the brain switches to using ketone bodies in order to save muscle protein (see p. 356). 

During periods of starvation, the brain after a certain time acquires the ability to use ketone bodies (see p. 312) in addition to glucose to form ATP. In the first weeks of a starvation period, there is a strong increase in the activities of the enzymes required for this in the brain. The degradation of ketone bodies in the CNS saves glucose and thereby reduces the breakdown of muscle protein that maintains gluconeogenesis in the liver during starvation. After a few weeks, the extent of muscle breakdown therefore declines to one-third of the initial value. 

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