Ketone body oxidation

Figure 7.17 The pathway of ketone body oxidation hydroxybutyrate to acetyl-CoA. Hydroxybutyrate is converted to acetoacetate catalysed by hydroxybutyrate dehydrogenase acetoacetate is converted to acetoacetyl-CoA catalysed by 3-oxoacid transferase and finally acetoacetyl-CoA is converted to acetyl-CoA catalysed by acetyl-CoA acetyltransferase, which is the same enzyme involved in synthesis of acetoacetyl-CoA.

Figure 7.19 The physiological pathway for ketone body oxidation from triacylglycerol in adipose tissue to their oxidation in a variety of tissues/organs. The pathway spans three tissues/ organs. The flux-generating step is the triacylglycerol lipase and ends with CO2 in one or more of the tissues/organs.

Ketone Body Oxidation Long-term starvation or ketoacidosis. 

Under normal conditions, the brain cannot use ketone bodies because it lacks the enzyme needed to activate acetoacetate. However, this enzyme is induced in brain after about 4 days of starvation, permitting the brain to obtain 40-70% of its energy from ketone body oxidation while... 

The liver maintains blood glucose levels during fasting, and its role is thus critical. Glucose is the major fuel for tissues such as the brain and neural tissue, and the sole fuel for red blood cells. Most neurons lack enzymes required for oxidation of fatty acids, but can use ketone bodies to a limited extent. Red blood cells lack mitochondria, which contain the enzymes of fatty acid and ketone body oxidation, and can use only glucose as a fuel. Therefore, it is imperative that blood glucose not decrease too rapidly nor fall too low. 

The liver lacks an enzyme required for ketone body oxidation. However, ketone bodies can be further oxidized by most other cells with mitochondria, such as muscle and kidney. In these tissues, acetoacetate and p-hydroxybutyrate are converted to acetyl CoA and then oxidized in the TCA cycle, with subsequent generation of ATP. 

Skeletal muscles use many fuels to generate ATP. The most abundant immediate source of ATP is creatine phosphate. ATP also can be generated from glycogen stores either anaerobically (generating lactate) or aerobically, in which case pyruvate is converted to acetyl CoA for oxidation via the TCA cycle. All human skeletal muscles have some mitochondria and thus are capable of fatty acid and ketone body oxidation. Skeletal muscles are also capable of completely oxidizing the carbon skeletons of alanine, aspartate, glutamate, valine, leucine, and isoleucine, but not other amino acids. Each of these fuel oxidation pathways plays a somewhat unique role in skeletal muscle metabolism. 

Ketone body oxidation also increases during exercise. Their utilization as a fuel is dependent on their rate of production by the liver. Ketone bodies are, however, never a major fuel for skeletal muscle (muscles prefer free fatty acids). 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

McGarry, J. D., and Foster, D. W., 1980. Regulation of hepatic fatty acid oxidation and ketone body production. Annual Review of Biochemistry 49 395-420. 

The citrate cycle is the final common pathway for the oxidation of acetyl-CoA derived from the metabolism of pyruvate, fatty acids, ketone bodies, and amino acids (Krebs, 1943 Greville, 1968). This is sometimes known as the Krebs or tricarboxylic acid cycle. Acetyl-CoA combines with oxaloacetate to form citrate which then undergoes a series of reactions involving the loss of two molecules of CO2 and four dehydrogenation steps. These reactions complete the cycle by regenerating oxaloacetate which can react with another molecule of acetyl-CoA (Figure 4). 

The amino acids are required for protein synthesis. Some must be supplied in the diet (the essential amino acids) since they cannot be synthesized in the body. The remainder are nonessential amino acids that are supplied in the diet but can be formed from metabolic intermediates by transamination, using the amino nitrogen from other amino acids. After deamination, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination (1) are oxidized to CO2 via the citric acid cycle, (2) form glucose (gluconeogenesis), or (3) form ketone bodies. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and d(—)-3-liydroxyl)utyrate (P-hydroxybutyrate). Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone. These three substances are collectively known as the ketone bodies (also called acetone bodies or [incorrectly ] ketones ) (Figure 22-5). Acetoacetate and 3-hydroxybu-... 

Enzymes responsible for ketone body formation are associated mainly with the mitochondria. Two acetyl-CoA molecules formed in P-oxidation condense with one another to form acetoacetyl-CoA by a reversal of the thiolase reaction. Acetoacetyl-CoA, which is the... 

In extrahepatic tissues, acetoacetate is activated to acetoacetyl-CoA by succinyl-CoA-acetoacetate CoA transferase. CoA is transferred from succinyl-CoA to form acetoacetyl-CoA (Figure 22-8). The acetoacetyl-CoA is split to acetyl-CoA by thiolase and oxidized in the citric acid cycle. If the blood level is raised, oxidation of ketone bodies increases until, at a concentration of approximately 12 mmol/L, they saturate the oxidative machinery. When this occurs, a large proportion of the oxygen consumption may be accounted for by the oxidation of ketone bodies. 

In most cases, ketonemia is due to increased production of ketone bodies by the liver rather than to a deficiency in their utilization by extrahepatic tissues. While acetoacetate and d(—)-3-hydroxybutyrate are readily oxidized by extrahepatic tissues, acetone is difficult to oxidize in vivo and to a large extent is volatilized in the lungs. 

After uptake by the liver, free fatty acids are either P Oxidized to COj or ketone bodies or esterified to triacylglycerol and phospholipid. There is regulation of entry of fatty acids into the oxidative pathway by carnitine palmitojdtransferase-I (CPT-I), and the remainder of the fatty acid uptake is esterified. CPT-I activity is... 

Figure 22-8. Transport of ketone bodies from the liver and pathways of utilization and oxidation in extrahepatic tissues.

The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-GoA lyase. 

Figure 27-1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of preference (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase FFA, free fatty acids VLDL, very low density lipoproteins.)...

Heart Pumping of blood Aerobic pathways, eg, P-oxidation and citric acid cycle Free fatty acids, lactate, ketone bodies, VLDL and chylomicron triacylglycerol, some glucose Lipoprotein lipase. Respiratory chain well developed. 

In starvation, glucose must be ptovided for the brain and erythrocytes initially, this is supphed from hver glycogen reserves. To spare glucose, muscle and other tissues reduce glucose uptake in response to lowered insuhn secretion they also oxidize fatty acids and ketone bodies preferentially to glucose. 

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... 

In addition to these interconversions, the metabolism of fat and the metabolism of carbohydrate are inseparably related. This fact is most clearly demonstrated by the appearance of such abnormal products of fat oxidation as the so-called ketone bodies in the blood and urine whenever the supply of carbohydrate is deficient or in cases where the organism is unable to metabolize this foodstuff. Whether ketonuria results because the metabolism of fat must occur concomitantly with that of D-glucose (ketolysis), or whether the presence of D-glucose prevents any fat breakdown because it is preferentially oxidized (antiketogenesis) is still a moot question. 

Allen and DuBois136 have calculated that the R. Q. of 0.707, obtainable when fat is completely oxidized, would be lowered to 0.669 if the /3-hydroxybutyric acid were not metabolized. If more than one molecule of the ketone bodies is produced from one molecule of the fatty acid, as has been suggested,83 the R. Q. would be further lowered. This may be further complicated by a resulting upset in acid-base balance. 

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