Oxidation of fatty acids, inhibition

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. 

Gamble, J. Lopaschuk, G.D. Insulin inhibition of 5 -adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism, 46, 1270-1274 (1997)... 

Caspary F, Elliott G, Nave BT, Verzaal P, Rohrbach M, Das PK, Nagelkerken L, Nieland JD. A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by Etomoxir. Brit J Dermatol 2005 153 937-44. 

The clinical efficacy of fatty acid oxidation inhibitors has not yet been proven. Some beneficial effects have been noted in insulin-dependent diabetics, but no controlled clinical trials in non-insulin-dependent diabetics have been reported. Although the inhibition of fatty acid oxidation causes hypoglycaemia in the fasted state, it is unclear whether these compounds will be effective in an individual with normal eating habits. The safety and efficacy of this class of compounds can be determined only by further studies. 

While hydrazonopropionic acids exert their primary hypoglycaemic action through an inhibition of fatty acid oxidation, other apparently unrelated effects are also evident (i.e., inhibition of monoamine oxidase and jejunal glucose uptake). The use of either TDGA or POCA as a hypoglycaemic agent would seem to offer a more directed and defined approach, with less risk of side-effects unrelated to the primary mechanism of action of the drug. 

Mitochondrial dysfunction has long been considered to play a central role in the development of cell injury during ischemia-reperfusion and hypoxia-reoxygenation [19]. Besides the inhibition of fatty acid oxidation, mitochondrial energy generation is diminished because of defects in respiratory chain function. Inhi-hition of the FO-Fl-ATPase leading to impaired function of respiratory complex I has been observed in I/R injury. Similar to ischemia, dsplatin has been shown to affed mitochondrial respiratory complexes and func-... 

However, ethanol ingestion also has acute effects on liver metabolism, including inhibition of fatty acid oxidation and stimulation of triacylglycerol synthesis, leading to a fatty liver. It also can result in ketoacidosis or lactic acidosis and cause hypoglycemia or hyperglycemia, depending on the dietary state. These effects are considered reversible. 

McGarry, J.D., Leatherman, G.F. Foster, D.W. (1978)/. Biol. Chem. 253, 4128 136. CPTase I The site of inhibition of fatty acid oxidation by malonyl-CoA. 

Metabolic disturbances caused by the therapeutie range of VPA are partial and are normally well compensated by the mechanism described above. They could nevertheless significantly impair the whole aetivity of fatty aeid oxidation when there is an additional insult, such as may occiu with concomitant use of other epileptic drugs, viral infection or underlying inborn errors of metabolism. In these conditions, if the biosynthesis of ACDs is not be regulated normally, the inhibition of fatty acid oxidation may result in serious clinical problems. 

In rats, a diet containing biotin reduced acetyl-CoA carboxylase 2, which plays an essential role in the inhibition of fatty acid oxidation (Munday and Hemingway 1999). Therefore, pharmacological doses of biotin may increase fatty acid oxidation by decreasing the acetyl-CoA carboxylase 2 activity. 

Pearce FJ, Deleeuw G, Forster J, Williamson JR, Tutwiler GF (1979) Inhibition of fatty acid oxidation in normal and hypoxic perfused rat hearts by 2-Tetradecylglycidic acid. J Mol Cell Cardiol 11 893-915... 

Stephens, T.W., Higgins, A.J., Cook, G.A. Harris, R.A. (1985) Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem. J. 227, 651-660. 

Sherratt, H.S.A., Holland, P.C., Osmundsen, H. and Senior, A.E. (1975), On the mechanism of inhibition of fatty acid oxidation by hypoglycin and by pent-4-enoic acid. In Hypoglycin (ed. E. A. Kean), Academic Press, New York, pp. 127-143. 

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