Inhibition 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. 

Starvation elicits mobilization of triglycerides from the adipose tissue and inhibits the endogenic cholesterol synthesis owing to the low activity of hydroxy-methylglutaryl-CoA reductase. The latter process provides the possibility for the active production of ketone bodies in the liver. 

In the brain, when ketones are metabolized to acetyl CoA, pyruvate dehydrogenase is inhibited. Glycolysis and subsequently glucose uptake in brain decreases. This important switch spares body protein (which otherwise would be catabolized to form glucose by gluconeogenesis in the liver) by allowing the brain to indirectly metabolize fetty acids as ketone bodies. 

Individuals with either type of diabetes are unable to take up glucose efficiently from the blood recall that insulin triggers the movement of GLUT4 glucose transporters to the plasma membrane of muscle and adipose tissue (see Fig. 12-8). Another characteristic metabolic change in diabetes is excessive but incomplete oxidation of fatty acids in the liver. The acetyl-CoA produced by JS oxidation cannot be completely oxidized by the citric acid cycle, because the high [NADH]/[NAD+] ratio produced by JS oxidation inhibits the cycle (recall that three steps convert NAD+ to NADH). Accumulation of acetyl-CoA leads to overproduction of the ketone bodies acetoacetate and /3-hydroxybutyrate, which cannot be used by extrahepatic tissues as fast as they are made in the liver. In addition to /3-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone, which results from the spontaneous decarboxylation of acetoacetate ... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

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. 

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. 

Glucagon exerts a ketogenic action on the liver which is more pronounced in insulin-deficient states. This action is thought to be due mainly to the inhibition of acetyl-CoA carboxylase with resulting decrease in malonyl-CoA. Malonyl-CoA is an inhibitor of carnitine acyltransferase I which is the rate-limiting step for mitochondrial fatty acid oxidation. A decrease in malonyl-CoA is thus postulated to lead to overproduction of acetyl-CoA which is then condensed to form ketone bodies. 

The cerebral requirement for oxidative substrate can be met by only two substrates glucose and ketone bodies. Unfortunately, the endocrine milieu of the infant of the diabetic mother inhibits both lipolysis (i.e., the mobilization of fatty acid stores) and hepatic ketogene-... 

Figure 32-5. P-oxidation and ketogenesis in the liver. The rate-limiting step in fatty acid oxidation and subsequent ketone body production is the activity of carnitine acyltrans-ferase I (CAT I).The activity of CAT I is inhibited by malonyl-CoA. Insulin deficiency results in inhibition of acetyl-CoA carboxylase, decreased levels of maloyl-CoA, and thus increased activity of CAT-I.Adapted from Foster and McGarry (1983).

Insulin whose release is promoted by ketone bodies, inhibits lipolysis to decrease the supply of fatty acids and thus curtail ketogenesis —> prevent ketoacidosis. 

Regulation of insulin secretion is affected by numerous factors, such as ftKxl, hormonal and neuronal stimuli, and innic mechanisms. In humans, the principal sub.slratc that stimulates the release of in.sulin from the islet /3-cells is glucose. In addition to glucose, other substrates (c.g., amino acids, free fatty acids, and ketone bodies) also can stimulate insulin. secretion directly. Secretin and ACTH can directly stimulate insulin secretion. Glucagon and other related peptides can increase the secretion of insulin, whereas somatostatin inhibits its secretion. 

C) inhibits the synthesis of ketone bodies from blood glucose... 

D. In the synthesis of cholesterol, but not of ketone bodies, HMG CoA is reduced by NADPH + H+ to mevalonic add. The enzyme, HMG CoA reductase, is highly regulated (it is inhibited by cholesterol and bile salts and induced by insulin). Mevalonic acid is converted to isopentenyl pyrophosphate, which provides isoprenoid units for the synthesis of cholesterol and its derivatives and for many other compounds. 

Dietary habits can influence the TK and toxicity of solvents in several ways. The mere bulk of food in the stomach and intestine can inhibit systemic absorption of VOCs. Solvents in the GI tract partition into dietary lipids, largely remaining there until the lipids are emulsified and digested. This substantially delays the absorption of VOCs such as CCI4 and its hepatotoxicity. Increased incidences of cancer have been observed in obese humans possibly due to increase in liver CYP2E1 by ketone body formation. Caloric restriction has clearly been shown to reduce the incidence of cancer. Fasting results in increased P450 activities and reduced GSH, which affect the TK and toxicity of VOCs. Food may contain certain natural constituents, pesticides, and other chemicals, which may enhance or reduce the solvent metabolism. 

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