Regulation of fatty acid oxidation in heart

The control of fatty acid oxidation in heart is reviewed with special emphasis on the energy-linked regulation of this process. Studies with perfused working hearts and isolated mitochondria have revealed an inverse relationship between the energy-dependent rate of fatty acid oxidation and the intramitochondrial ratio of [acetyl-CoA]:[free CoA] at sufficiently high concentrations of fatty acids. Studies with isolated enzymes demonstrated a strong inhibition of 3-ketoacyl-CoA thiolase by acetyl-CoA at low concentrations of free CoA. Together these observations prompted the proposal that the rate of fatty acid oxidation is tuned to the energy demand of heart via the regulation of 3-ketoacyl-CoA thiolase by the [acetyl-CoA]:[free CoA] ratio. Evidence in support of this regulatory model has been obtained with isolated rat heart mitochondria in which either the activity of 3-ketoacyl-CoA thiolase was decreased by use of mechanism-based inhibitors or the intramitochondrial ratio of [acetyl-CoA]:[free CoA] was adjusted with L-carnitine. Because intermediates of beta-oxidation normally do not accumulate in mitochondria, it remains unclear how the entry of fatty acyl-CoA into the beta-oxidation spiral is tuned to the activity of 3-ketoacyl-CoA thiolase. A control of fatty acid oxidation in heart via the regulation of carnitine palmitoyltransferase I by malonyl-CoA has not been established even though malonyl-CoA is present in this tissue and strongly inhibits myocardial carnitine palmitoyltransferase I.