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

Abstract

Rats treated with six to eight doses (80 mg/kg, i.p.) of 4-pentenoic acid, an inhibitor of mitochondrial fatty acid 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 triglycerides 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 palmitoylcarnitine and decanoylcarnitine were decreased about 70%, while that of octanoylcarnitine was decreased 50%. Carnitine-independent oxidation of octanoate was also inhibited. Oxidation rates for substrates other than fatty acids, including glutamate, succinate, pyruvate, and alpha-ketoglutarate, were unaffected. Measurements of flavoprotein reduction in intact mitochondria indicated that neither palmitoylcarnitine 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 beta-oxidation at the level of acyl-CoA dehydrogenase for pentenoic acid treatment in vivo, and they suggest a role for nutritional or hormonal factors in the metabolic disposition of pentenoic acid in vivo and in the development of fatty liver.

• Authors: W S Thayer
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 33 Issue 8 Pg. 1187-94 (Apr 15 1984) ISSN: 0006-2952 [Print] England
• PMID: 6712730 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fatty Acids
• Fatty Acids, Monounsaturated
• Fatty Acids, Unsaturated
• 4-pentenoic acid

Topics

• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fatty Acids (metabolism)
• Fatty Acids, Monounsaturated
• Fatty Acids, Unsaturated (pharmacology)
• Fatty Liver (chemically induced, metabolism, pathology)
• Male
• Mitochondria, Liver (drug effects, metabolism, ultrastructure)
• Oxidation-Reduction (drug effects)
• Rats
• Rats, Inbred Strains
• Reye Syndrome (metabolism)
• Starvation (metabolism, physiopathology)