Ketone body formation

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... 

One suggestion to explain this discrepancy is that two pathways of fat catabolism are available and that ketone body formation is the resultant of only one type of breakdown.177 This latter type, also called the indirect fat utilization, 182 occurs in the liver the catabolism of fat in the muscle, called the -direct method, either involves no ketogenesis or the ketone bodies are immediately utilized and no accumulation occurs. 

Obviously, more direct experimental work is required on this difficult problem before we can arrive at a satisfactory conclusion on whether fat is directly metabolized in the muscle without ketone body formation. 

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

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

Two conditions in which the rate of ketone body formation is increased are hypoglycaemia and prolonged starvation in adults or short-term starvation in children. What is the mechanism for increasing the rate Although there are several fates for fatty acids in the liver, triacylglycerol, phospholipid and cholesterol formation and oxidation via the Krebs cycle, the dominant pathway is ketone body formation (Figure 7.20). Three factor regulate the rate of ketone body formation (i) hormone sensitive lipase activ-... 

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.

Figure 16.6 Extension of the glucose/fatty acid cycle by inclusion of ketone body formation and gluconeogenesis. The liver has three indirect effects on the glucose/fatty acid cycle which help to conserve the blood glucose and maintain its normal level.

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.

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). 

Healthy, well-nourished individuals produce ketone bodies at a relatively low rate. When acetyl-CoA accumulates (as in starvation or untreated diabetes, for example), thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA, the parent compound of the three ketone bodies The reactions of ketone body formation occur in the matrix of liver mitochondria. The six-carbon compound /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) is also an intermediate of sterol biosynthesis, but the enzyme that forms HMG-CoA in that pathway is cytosolic. HMG-CoA lyase is present only in the mitochondrial matrix. 

FIGURE 17-20 Ketone body formation and export from the liver. 

Stage Synthesis of Mevalonate from Acetate The first stage in cholesterol biosynthesis leads to the intermediate mevalonate (Fig. 21-34). Two molecules of acetyl-CoA condense to form acetoacetyl-CoA, which condenses with a third molecule of acetyl-CoA to yield the six-carbon compound /3-hydroxy-/3-methylglu-taryl-CoA (HMG-CoA). These first two reactions are catalyzed by thiolase and HMG-CoA synthase, respectively. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isozyme that catalyzes HMG-CoA synthesis in ketone body formation (see Fig. 17-18). 

Ketone body formation acetyl-CoA------> acetoacetate, /3-hydroxybutyrate... 

Formation of mevalonate. The first two enzymes, thiolase and synthase, are found in both cytosol and mitochondria. The lyase that catalyzes ketone body formation is found only in the mitochondria. The reductase that catalyzes mevalonate formation is found in the endoplasmic reticulum. 3-Ketobutyryl-CoA is also known as acetoacetyl-CoA. 

The term ketone bodies refers primarily to two compounds acetoacetate and P-hydroxy-butyrate, which are formed from acetyl-CoA when the supply of TCA-cycle intermediates is low, such as in periods of prolonged fasting. They can substitute for glucose in skeletal muscle, and, to some extent, in the brain. The first step in ketone body formation is the condensation of two molecules of acetyl-CoA in a reverse of the thiolase reaction. 

The key enzyme in this pathway is HMG-CoA reductase in connection with ketone body formation. The reactions leading to HMG-CoA are shared with that pathway. 

To minimize ketosis, a slow but steady degradation of nonessential proteins would provide three-, four-, and five-carbon products essential to the formation of glucose by gluconeogene-sis. This would avoid the inhibition of the citric acid cycle that occurs when oxaloacetate is withdrawn from the cycle to be used for gluconeogenesis. The citric acid cycle could continue to degrade acetyl-CoA, rather than shunting it into ketone body formation. 

The first two steps in cholesterol biosynthesis from acetyl-CoA are identical to those of ketone body formation (Figure 19.10). The difference is that ketone bodies are formed in the mitochondria, whereas cholesterol synthesis initially takes place in the ER. A thiolase catalyzes the condensation of two acetyl-CoA molecules to acetoacetyl-CoA, and the combination of a third acetyl-CoA with acetoacetyl-CoA to form /8-hydroxymethylglutaryl-CoA (HMG-CoA) is catalyzed by HMG-CoA synthase. Although HMG-CoA is split into acetoacetate and acetyl-CoA in the mitochondria, in cholesterol biosynthesis, HMG-CoA is reduced by a microsomal enzyme, HMG-CoA reductase, to mevalonate (see Figure 19.17). The reducing agent is NADPH. 

Mitachordriol matrix Citric acid cycie Oxidative phosphorylation / Oxidation of fatty acids Ketone-body formation... 

Diabetes mellitus, the most common serious metabolic disease, is due to metabolic derangements resulting in an insufficiency of insulin and an excess of glucagon relative to the needs of the individual. The result is an elevated blood-glucose level, the mobilization of triacylglycerols, and excessive ketone-body formation. Accelerated ketone-body formation can lead to acidosis, coma, and death in untreated insulin-dependent diabetics. 

A major factor in stinoulating ketone body production is increased availability of FTAs. An increased rate of FFA mobilisation from the adipose tissue, with the consequent increase in FFA levels in the liver, may be sufficient to enhance ketone body formation. Increased release of FFAs occurs when the glucagon/insulin ratio... 

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