Regulation of fatty acid oxidation in heart muscle. Effects of pyruvate and dichloroacetate.
The possibility of a mutual regulation between carbohydrate and fatty acid oxidation was studied in isolated perfused rat hearts. Infusions of pyruvate and/or dichloroacetate were employed to convert fully the pyruvate dehydrogenase complex into its active form during [1-14C]octanoate oxidation, the rate of which was measured by the production of 14CO2. It was found that 5 mM dichloroacetate suppressed the oxidation of 0.1 mM octanoate by 58%, but 10 mM external pyruvate was without effect. Dichloroacetate reduced the tissue malate concentration by 41% and the citrate concentration by 76% at a 0.1 mM octanoate concentration, but had no effect on the metabolite concentrations or fatty acid oxidation rate in perfusions with 1 mM octanoate. Metabolite depletion was probably partly due to inhibition of the carboxylation of pyruvate, as verified by determination of the metabolite labelling kinetics from [1-14C]pyruvate. It is, therefore, possible that the dichloroacetate-induced inhibition of octanoate oxidation could also be partly due to inhibition of tricarboxylic acid cycle secondary to metabolite depletion. Since both dichloroacetate and pyruvate converted pyruvate dehydrogenase to its active form, but only dichloroacetate inhibited fatty acid oxidation, the latter effect could not be due to oxidation of a competing substrate, but instead may result from an inhibition of fatty acid uptake, activation or transport, as also indicated by the observed decrease in the acid-soluble acyl-CoA concentration. This interpretation is also supported by the mitochondrial redox effects of dichloroacetate observed during octanoate oxidation in the perfused heart.