Ketone body production and utilization

Glucose-sparing effect of fatty acid oxidation. Note the inhibition of glucose utilization by high levels of ATP and citrate. OA, Oxaloacetate  

6-hisP, fructose-1,6-bisphosphate 1,3-bisPG. 1,3-bisphosphoglyce-rate 3-PG, 3-phosphoglycerate PEP, phosphoenolpyruvate Pyr, pyruvate. 

Ketone body production and utilization. Ketone bodies are produced in the liver from fatty acids derived from adipocyte lipolysis. They are released and used as fuel in peripheral tissues. The initial step in acetoacetate metabolism is activation to acetoacetyl-CoA by succinyl-CoA. HMG-CoA, /S-hydroxy-y3-methylglutaryl-CoA HB, /i-hydroxybutyrate. 

Hepatic yd-oxidation, without oxidation of acetyl-CoA through the TCA cycle, produces a substantial amount of energy. At such a time, liver is actively engaged in gluconeogenesis so that mitochondrial oxaloacetate is depleted, TCA cycle activity is depressed, and acetyl-CoA levels rise. The last reaction in -oxidation is conversion of acetoacetyl-CoA to acetyl-CoA, with an equilibrium in favor of high levels of acetoacetyl-CoA. Thus, acetyl-CoA and acetoacetyl-CoA accumulate and form HMG-CoA cleavage of this last compound yields acetoacetate, which is reduced to jd-hydroxybutyrate. Acetone results from nonenzymatic decarboxylation of acetoacetate. Ketone body formation occurs exclusively in liver (see Chapter 18) and is prominent in starvation and diabetes owing to the 

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 

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In moderate ketonemia, the loss of ketone bodies via the urine is only a few percent of the total ketone body production and utilization. Since there are renal threshold-like effects (there is not a true threshold) that vary between species and individuals, measurement of the... 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Table 21.5 Ketone Body Production and Utilization in Fasting and Diabetes Mellitus (g/24 h) ...

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. 

There is some evidence that the adrenal hormones may exert a direct effect on fatty acid oxidation. The rate of ketone body production from octanoic acid by mouse liver slices was decreased by adrenalectomy and restored to normal by cortisone (Lipsett and Moore, 1951, 1952). Studies of the oxygen utilized per mole of octanoate disappearing led to the suggestion that the defect in fat metabolism in adrenalectomy precedes the condensation of acetyl-CoA to acetoacetate. This suggestion is consistent with the observation that adrenalectomy did not influence the rate of in vivo acetylation reactions by the rat (Dumm and Ralli, 1951). 

It is well established that many animal tissues can oxidize ketone bodies (Snapper and Grunbaum, 1927 Wick and Drury, 1941 Williamson and Krebs, 1961), and this has led to the concept that it is a physiological function of ketone bodies to serve as a fuel of respiration when carbohydrate is in short supply (Krebs, 1961). Experiments have shown that increased production of ketone bodies is closely matched by increased utilization (Bates et al., 1968). These authors suggest the sequence of events leading to "physiological ketosis" as a consequence of hormonal interrelationships a low blood sugar concentration causes an increase in adipose tissue lipolysis and a rise in the concentration of free fatty acids in the plasma. This in turn results in an increased rate of ketogenesis in the liver, which is followed by a rise in blood ketone-body concentrations, and an increased rate of peripheral utilization. 

In non-ruminant animals, including Man, the liver is the only organ that adds ketone bodies to the blood since its enzymes are active in ketone body production but inactive in ketone body utilization. This is exactly the reverse of the condition in muscle and other extrahepatic tissues which oxidize ketone bodies but do not produce them. 

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. 

Because carbohydrate utilization 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. 

Carbohydrates are more plentiful and constant in food supplies throughout the world when compared to other nutrients, such as proteins, vitamin A, folic acid, and iodine. A naturally occurring deficiency specifically in carbohydrates is im-known. However, deliberate omission of carbohydrates from the diet with continued consumption of fat as an energy source can lead to specific problems. Glucose is required as an energy source by the central nervous system. When there is a deficiency of glucose, the body adjusts its metabolism to provide ketone bodies, nutrients derived from fat, which can be utilized by the brain and other parts of the central nervous system. However, excessive production of the ketone bodies can result in acidosis, a lowering of the pH of the blood, which is potentially toxic. 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

The oxidation rate of fatty acids appears to be proportional to the concentration in plasma, and, as mentioned above, major products are ketone bodies, which can serve as respiratory fuel. In moderate forms of ketosis, glucagon secretion is antagonized by that of insulin consequently ketone bodies do not accumulate because g their utilization by peripheral tissues is accelerated and their genesis interrupted. In several forms of ketosis, homeostasis breaks down. In diabetics, the lipolytic effect of glucagon is not compensated for, and the increase in free fatty acids and ketone bodies in plasma is unchecked. Moreover, utilization of ketone bodies by peripheral tissue could be reduced. 

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