AJP - Endocrinology and Metabolism, Vol 272, Issue 3 E359-E366, Copyright © 1997 by American Physiological Society

ARTICLES

Carnitine effects on coenzyme A profiles in rat liver with hypoglycin inhibition of multiple dehydrogenases

Y. K. Lieu, B. Y. Hsu, W. A. Price, B. E. Corkey and C. A. Stanley
Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 19104, USA.

To examine the changes in coenzyme A profile and the possible corrective effects of carnitine supplementation in the genetic disorders of mitochondrial beta-oxidation, we carried out experiments using an inhibitor of multiple acyl-CoA dehydrogenase enzymes, methylenecyclopropaneacetic acid (MCPA), in rat hepatocytes. MCPA irreversibly inhibited ketone synthesis from straight-chain fatty acids (butyrate, octanoate, palmitate) and branched-chain fatty acids (alpha-ketoisocaproate) with a parallel 70-90% reduction of hepatocyte acetyl-CoA levels. Alone, MCPA or substrates halved free CoA levels to 15% of total CoA and doubled short- and medium-chain acyl-CoA levels to 30% of total CoA. With MCPA plus substrates combined, free CoA levels were 10% of total CoA, and short- and medium-chain acyl-CoA levels were 45% of total CoA. Comparable changes in CoA profiles were found in a patient with a severe genetic defect in beta-oxidation. Neither the suppression of ketogenesis nor the alterations in CoA profiles induced by MCPA inhibition could be corrected by carnitine supplementation.

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