Fatty acid oxidation, inhibition

Figure 16.1 The glucose/fatty add cycle. The dotted Lines represent regulation. Glucose in adipose tissue produces glycerol 3-phosphate which enhances esterification of fatty acids, so that less are available for release. The effect is, therefore, tantamount to inhibition of lipolysis. Fatty acid oxidation inhibits pyruvate dehydrogenase, phosphofructokinase and glucose transport in muscle (Chapters 6 and 7) (Randle et al. 1963).

Decreases in plasma VLDL primarily result from the ability of these compounds to stimulate the activity of lipoprotein lipase, the enzyme responsible for removing triglycerides from plasma VLDL (Fig. 30.5). Additionally, fibrates can lower VLDL levels through PPARa-mediated stimulation of fatty acid oxidation, inhibition of triglyceride synthesis, and reduced expression of apoC-lll. This latter effect enhances the action of lipoprotein lipase, because apoC-lll normally serves as an inhibitor of this enzyme. Favorable effects on FIDL levels appear to be related to increased transcription of apoA-l and apoA-ll as well as a decreased activity of cholesteryl ester transfer protein. 

In conclusion, fatty acid oxidation inhibits glucose oxidation and provides acetyl-CoA to the Krebs cycle it also ensures that any glucose that enters skeletal myocytes is not rapidly oxidized, but is converted into lactate that leaves the cells and is transported in the hlood to hepatocytes and cardiac myocytes. Although this conservation of glucose occurs in skeletal myocytes and other tissues, it does not occur in the brain because fatty acids do not cross the blood-brain barrier. Thus even after 2 days of starvation, the brain continues to use -120 g of glucose per day. 

Green PR, Kemper J, Lee S, Guo L, Satkowski M, Fiedler S, Stembiichel A, Rehm BHA (2002) Formation of short chain length/medium chain length polyhydroxyalkanoate copolymers by fatty acid oxidation inhibited Ralstonia eutropha. Biomacromolecules 3 208—213 Gross RA, DeMeUo C, Lenz RW, Brandi H, Fuller RC (1989) Biosynthesis and characterization of poly(P-hydroxyalkanoates) produced by Pseudomonas oleovorans. Macromolecules 22 1106-1115... 

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

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. 

Long-chain fatty acids can slowly cross the mitochondrial membrane by themselves, but this is too slow to keep up with their metabolism. The carnitine shuttle provides a transport mechanism and allows control of (3 oxidation. Malonyl-CoA, a precursor for fatty acid synthesis, inhibits the carnitine shuttle and slows down (3 oxidation (Fig. 13-5). 

Figure 7.15 Inhibition of acetyl-CoA carboxylase by cyclic AMP dependent protein kinase and AMP dependent protein kinase the dual effect of glucagon. Phosphorylation of acetyl-CoA carboxylase by either or both enzymes inactivates the enzyme which leads to a decrease in concentration of malonyl-CoA, and hence an increase in activity of carnitine palmitoyltransferase-I and hence an increase in fatty acid oxidation. Insulin decreases the cyclic AMP concentration maintaining an active carboxylase and a high level of malonyl-CoA to inhibit fatty acid oxidation.

Malonyl-CoA is also involved in the regulation of fatty acid oxidation, via inhibition of carnitine palmitoyltransferase. In non-lipogenic tissues, the only role of the carboxylase is provision of malonyl-CoA for regulation of the rate of fatty acid oxidation. 

Malonyl-CoA inhibits fatty acid oxidation in muscle. Insulin increases the concentration of malonyl-CoA in muscle and so inhibits fatty acid oxidation. A fall in... 

Figure 16.2 Redprocal relationship between the changes in the concentrations of glucose and fatty adds in blood during starvation in adult humans. As the glucose concentration decreases, fatty acids are released from adipose tissue (for mechanisms see Figure 16.4). The dotted line is an estimate of what would occur if fatty acid oxidation did not inhibit glucose utilisation. Such a decrease occurs if fatty acid oxidation in muscle is decreased by specific inhibitors.

Insulin inhibits glycogenolysis and gluconeogenesis. Glucagon opposes the effects of insulin and therefore helps to maintain the blood glucose level so that it has the same end result as that of fatty acid oxidation (See Figure 12.14). 

Fatty acid oxidation. Seeds, administered orally to rats at a dose of 200 g/kg, increased hepatic mitochondrial and the peroxisomal fatty acid oxidation rate " . Glucosidase inhibition. Ethyl acetate and water soluble fractions of the seed were inactive on the intestine " ... 

It is pentavalent antimonial. It inhibits -SH dependent enzymes and block glycolytic fatty acid oxidation pathways. It is rapidly absorbed after IM injection and excreted unchanged in urine. Used in cutaneous and visceral leishmaniasis. It is given parenterally (20 mg/kg/day IM/IV) for three weeks in cutaneous leishmaniasis and for four weeks in visceral and mucocutaneous disease. 

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