Ketone bodies degradation

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 ... 

Synthesis and storage pathways are on degradative pathways are off. AA = amino acids KB = ketone bodies ALA = alanine LAC = lactate. 

GLUCONEOGENESIS FATTY ACID OXIDATION PROTEIN DEGRADATION KETONE BODY FORMATION... 

GLYCOLYSIS FATTY ACID OXIDATION KETONE BODY USE PROTEIN DEGRADATION... 

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

Degrades glycogen and burns fat Bums fat and ketone bodies and degrades proteins Bums fat and ketone bodies and degrades proteins... 

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 plasma ketone body level increases twice as fast over live days starvation in lean snbjects compared with obese this may be an attempt by the body to restrict protein degradation in the lean by providing an alternative fnel to glucose for the brain as qnickly as possible. 

In normal young children, the contribution of amino acid oxidation to energy requirement in starvation is about 1%, similar to that in the obese. In malnourished children, who have a protein-energy deficiency, it is even lower (4%). This suggests that a mechanism exists to protect muscle protein from degradation in children. Such a mechanism may involve a faster and greater increase in ketone body formation in children compared with adults (Chapter 7). 

Figure 16.12 Role of ketone bodies leading to a reduction in the high rate of protein degradation in prolonged starvation.

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). 

Several cycles are required for complete degradation of long-chain fatty acids—eight cycles in the case of stearyl-CoA (C18 0), for example. The acetyl CoA formed can then undergo further metabolism in the tricarboxylic acid cycle (see p. 136), or can be used for biosynthesis. When there is an excess of acetyl CoA, the liver can also form ketone bodies (see p. 312). 

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. 

In the absence of insulin and in response to glucagon stimulation, triacylglycerol degradation in adipose tissue runs unabated and the flood of fatty acids reaching the liver leads to ketone body synthesis and packaging of some triacylglycerols into VLDLs. 

The seven amino acids that are degraded entirely or in part to acetoacetyl-CoA and/or acetyl-CoA—phenylalanine, tyrosine, isoleucine, leucine, tryptophan, threonine, and lysine—can yield ketone bodies in the liver,... 

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