Fatty acids Ketogenesis

THE FATE OF ACETYL-CoA FROM FATTY ACIDS KETOGENESIS... 

See also Oxidation of Saturated Fatty Acids, Unsaturated Fatty Acid Oxidation, Oxidation of Odd-Numbered Fatty Acids, Peroxisomal / -Oxidation, Fatty Acids, Ketogenesis... 

The central role of the mitochondrion is immediately apparent, since it acts as the focus of carbohydrate, hpid, and amino acid metabohsm. It contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and ketogenesis, as well as the respiratory chain and ATP synthase. 

KETOGENESIS OCCURS WHEN THERE IS A HIGH RATE OF FATTY ACID OXIDATION IN THE LIVER... 

Figure 22-7. Pathways of ketogenesis in the liver. (FFA, free fatty acids HMG, 3-hy-d roxy- 3-m et hy I g I uta ry I.)...

Theoretically, a fall in concentration of oxaloacetate, particularly within the mitochondria, could impair the ability of the citric acid cycle to metabolize acetyl-CoA and divert fatty acid oxidation toward ketogenesis. Such a fall may occur because of an increase in the [NADH]/[NAD+] ratio caused by increased P-oxida-tion affecting the equilibrium between oxaloacetate and malate and decreasing the concentration of oxaloacetate. However, pyruvate carboxylase, which catalyzes the conversion of pyruvate to oxaloacetate, is activated by acetyl-CoA. Consequently, when there are significant amounts of acetyl-CoA, there should be sufficient oxaloacetate to initiate the condensing reaction of the citric acid cycle. 

Inherited CPT-I deficiency affects only the fiver, resulting in reduced fatty acid oxidation and ketogenesis, witfi fiypoglycemia. CPT-II deficiency affects pri-... 

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. 

Ketogenesis is regulated at three cmcial steps (1) control of free fatty acid mobihzation from adipose tissue (2) the activity of carnitine palmitoyltransferase-1 in hver, which determines the proportion of the fatty acid flux that is oxidized rather than esteri-fied and (3) partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle. 

Three compounds acetoacetate, P-hydroxybutyrate, and acetone, are known as ketone bodies. They are suboxidized metabolic intermediates, chiefly those of fatty acids and of the carbon skeletons of the so-called ketogenic amino acids (leucine, isoleucine, lysine, phenylalanine, tyrosine, and tryptophan). The ketone body production, or ketogenesis, is effected in the hepatic mitochondria (in other tissues, ketogenesis is inoperative). Two pathways are possible for ketogenesis. The more active of the two is the hydroxymethyl glutarate cycle which is named after the key intermediate involved in this cycle. The other one is the deacylase cycle. In activity, this cycle is inferior to the former one. Acetyl-CoA is the starting compound for the biosynthesis of ketone bodies. 

Auestad, N., Korsak, R. A., Morrow, J. W. etal. Fatty acid oxidation and ketogenesis by astrocytes in primary culture. /. Neurochem. 56 1376-1386,1991. 

Ketogenesis (Figure 6.19) occurs in the liver at most times but is greatly accelerated when acetyl-CoA production from p-oxidation of fatty acids exceeds the capacity of the TCA cycle to form citrate, that is during periods of starvation or in diabetics who have... 

Answer C. Severe hypoglycemia lowers the insulin level and increases glucagon. This would favor fatty acid release from the adipose and ketogenesis in the liver. 

High rates of lipolysis and ketogenesis to provide the two fat fuels, fatty acids and ketone bodies (See Figures 7.6 and 7.7). 

It seems likely that the changes in the rates of fatty acid mobilisation, ketogenesis and glnconeogenesis are coordinated by increases in the plasma levels of glncagon and... 

In adipose tissue, glucagon triggers lipoly-sis, releasing fatty acids and glycerol. The fatty acids are used as energy suppliers by many types of tissue (with the exception of brain and erythrocytes). An important recipient of the fatty acids is the liver, which uses them for ketogenesis. 

T Fatty acid mobilization (adipose tissue) T Ketogenesis... 

Correct answer = C. Free fatty acids bound to albumin are increased as a result of an increased activity of hormone-sensitive lipase in adipose tissue. Hepatic ketogenesis is stimu lated by elevated levels of glucagon. The forma tion of acetyl CoA is inc reased. 

Badr MZ, Handler JA, Whittaker M, et al. 1990. Interactions between plasticizers and fatty acid metabolism in the perfused rat liver and in vivo Inhibition of ketogenesis by 2-ethylhexanol. Biochem Pharmacol 39 715-722. 

McGarry, J. D., Mannaerts, G. P., and Foster, D. W. 1977. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J. Clin. Invest. 60 265-270. 

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