Metabolism of Ketone Bodies

Ketone bodies consist of acetoacetate, D-jS-hydroxy-butyrate (D-3-hydroxybutyrate), and acetone. They are 

Ketone bodies are oxidized primarily in extrahepatic tissues (e.g., skeletal muscle, heart, kidney, intestines, brain) within mitochondria. 8-Hydroxybutyrate is oxidized 

Activation of acetoacetate requires transfer of coenzyme A from succinyl-CoA, derived from the TCA cycle, by succinyl-CoA-acetoacetate-CoA transferase (thiophorase)  

Physiological and Pathological Aspects of Metabolism of Ketone Bodies 

Acetoacetate and 6-hydroxybutyrate are products of normal metabolism of fatty acid oxidation and serve as metabolic fuels in extrahepatic tissues. Their level in blood depends on the rates of production and utilization. Oxidation increases as their plasma level increases. Some extra-hepatic tissues (e.g., muscle) oxidize them in preference to glucose and fatty acid. Normally, the serum concentration of ketone bodies is less than 0.3 mM/L. 

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Nehhg, A. Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot. Essent. Fatty Acids 70 265-275, 2004. 

Patel, M. S., Johnson, C. A., Rajan, R. etal. The metabolism of ketone bodies in developing human brain development of ketone-body-utilizing enzymes and ketone bodies as precursors for lipid synthesis. /. Neurochem. 25 905-908, 1975. 

During periods of fasting, muscles may also derive energy from the metabolism of ketone bodies (3-hydroxybutyrate and acetoacetate). These intermediates are... 

FIGURE 24.29 Reconversion of ketone bodies to acetyl-CoA in the mitochondria of many tissues (other than liver) provides significant metabolic energy. 

The primary fate of acetyl CoA under normal metabolic conditions is degradation in the citric acid cycle to yield C02. When the body is stressed by prolonged starvation, however, acetyl CoA is converted into compounds called ketone bodies, which can be used by the brain as a temporary fuel. Fill in the missing information indicated by the four question marks in the following biochemical pathway for the synthesis of ketone bodies from acetyl CoA ... 

Ketosis An abnormal increase of ketone bodies present in conditions of reduced or disturbed carbohydrate metabolism. 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

Ketosis is a pathologic state produced by an excess of ketone bodies in the organism. However, ketosis may be regarded as a lipid metabolism pathology with a certain reserve, since excessive biosynthesis of ketone bodies in the liver is sequent upon an intensive hepatic oxidation not only of fatty acids, but also of keto-genic amino acids. The breakdown of the carbon frameworks of these amino acids leads to the formation of acetyl-CoA and acetoacetyl-CoA, which are used in... 

The formation of ketone bodies is a consequence of prolonged metabolism of fat (Fig. 17-12). Their formation in the liver actually enables liver to metabolize even more fat by freeing up CoA that would otherwise be tied up as acetyl-CoA waiting to get into the TCA cycle. The liver exports the ketone bodies and other tissues, particularly the brain, can adapt to use them. 

With increasing metabolism of fat through p oxidation, much of the mitochondrial CoA pool may become tied up as acyl- or acetyl-CoA. In such cases, the supply of free CoA can be diminished, and this may limit the rate of p oxidation. Upon prolonged fasting and heavy reliance on fat for energy, the liver induces the enzymes required for the formation of ketone bodies and brain induces enzymes required for their metabolism. 

Finally, we may add that fluorocitrate interferes with fat metabolism in vivo, because it leads to rapid and marked urinary appearance of ketone bodies.1 Unlike fluoroacetate, intraperi-toneal fluorocitrate (20 mg./kg.) (synthetic), though increasing the citrate in the brain, produces no convulsions in 2 hr. 

Fatty acid metabolism Synthesis and degradation of ketone bodies... 

Figure 7.20 The major quantitative pathway for fatty acid metabolism in the liver is ketone body formation. This is another indication of the importance of ketone bodies as a fuel.

The three fat fuels and their metabolism are involved directly or indirectly in diseases such as diabetes mellitus, syndrome X, obesity, atherosclerosis and coronary heart disease, which are discussed in other chapters in this book. This section considers the problems associated with high blood levels of ketone bodies and long-chain fatty acids. 

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 degradation of fat that occurs in insulin deficiency also has serious effects. Some of the fatty acids that accumulate in large quantities are taken up by the liver and used for lipoprotein synthesis (hyperlipidemia), and the rest are broken down into acetyl CoA. As the tricarboxylic acid cycle is not capable of taking up such large quantities of acetyl CoA, the excess is used to form ketone bodies (acetoacetate and p-hydroxy-butyrate see p. 312). As H"" ions are released in this process, diabetics not receiving adequate treatment can suffer severe metabolic acidosis (diabetic coma). The acetone that is also formed gives these patients breath a characteristic odor. In addition, large amounts of ketone body anions appear in the urine (ketonuria). 

The ketone bodies are released by the liver into the blood, in which they are easily soluble. Blood levels of ketone bodies therefore rise during periods of hunger. Together with free fatty acids, 3-hydroxybutyrate and acetoacetate are then the most important energy suppliers in many tissues (including heart muscle). Acetone cannot be metabolized and is exhaled via the lungs or excreted with urine. 

Mitchell GA, Kassovska-Bratinova S, Boukaftane Y, Robert MF, Wang SP, Ashmarina L, Lambert M, Lapierre P, Potier E (1995) Medical aspects of ketone body metabolism. Clin Invest Med 18 193-216... 

In diabetes, it appears that stabilization of mRNA occurs, leading to an increased amount rather than an increase in synthesis. The induction caused by this disease may reflect the necessity to metabolize the ketone bodies produced. 

Effects on lipid metabolism Glucagon favors hepatic oxidation of fatty acids and the subsequent formation of ketone bodies fan acetyl CoA. The lipolytic effect of glucagon in adipose tissue is minimal in humans. 

The three compounds, acetoacetate, acetone, and 3-hydroxybutyrate, are known as ketone bodies.60b The inability of the animal body to form the glucose precursors, pyruvate or oxaloacetate, from acetyl units sometimes causes severe metabolic problems. The condition known as ketosis, in which excessive amounts of ketone bodies are present in the blood, develops when too much acetyl-CoA is produced and its combustion in the critic acid cycle is slow. Ketosis often develops in patients with Type I diabetes mellitus (Box 17-G), in anyone with high fevers, and during starvation. Ketosis is dangerous, if severe, because formation of ketone bodies produces hydrogen ions (Eq. 17-5) and acidifies the blood. Thousands of young persons with insulin-dependent diabetes die annually from ketoacidosis. 

Most often the metabolic state of an organism is reflected by the small molecules present in plasma. Figure 24.4 illustrates the plasma levels of glucose, ketone bodies, and fatty acids as a function of the number of days of starvation. As you can see, the glucose level drops about 30% as the period of starvation becomes prolonged the fatty acid level rises about twofold, while the level of ketone bodies rises severalfold. 

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