Inhibition of mitochondrial fatty acid oxidation in pentenoic acid-induced fatty liver: A possible model for Reye's syndrome

Rats treated with six to eight doses (80 mg/kg, i.p.) of 4-pentenoic acid, an inhibitor of mitochondrial fatty arid oxidation in vitro, during a 48-hr starvation period developed microvesicular fatty infiltration of the liver similar to that observed in Reye's Syndrome. Hepatic triglycorides were elevated an average of 5-fold, although considerable variability was found between individual rats. Fed rats did not develop fatty liver upon similar treatment with pentenoic acid. Liver mitochondria isolated from rats with pentenoic acid-induced fatty liver showed a persistent inhibition of fatty acid oxidation. Rates of oxidation of pahnitoylcamitine and decanoylcamitine were decreased about 70%, while that of octanoylcamitine was decreased 50%. Camitine-independent oxidation of octanoate was also inhibited. Oxidation rates for substrates other than fatty acids, including glutamate, succinate, pyruvate, and α-ketoglutarate, were unaffected. Measurements of flavoprotein reduction in intact mitochondria indicated that neither palmitoylcamitine nor palmitoyl CoA plus l-carnitine could elicit reduction of acyl-CoA dehydrogenase and electron transferring flavoprotein in mitochondria from rats with pentenoic acid-induced fatty liver. These results support a site of inhibition of mitochondrial β-oxidation at the level of acyl-CoA dehydrogenase for pentenoic add treatment in vivo, and they suggest a role for nutritional or hormonal factors in the metabolic disposition of pentenoic add vivo and in the development of fatty liver.