Effect of chronic clofibrate administration on mitochondrial fatty acid oxidation

The effect of chronic clofibrate administration on fatty acid oxidation by isolated liver and skeletal muscle mitochondria was studied to determine if the hypolipidemic action of clofibrate may be mediated by reducing levels of fatty acyl substrates via enhanced fatty acid oxidation. Oxygen consumption and CO₂ production associated with the oxidation of fatty acids were decreased 30 per cent in liver mitochondria from clofibrate-treated rats. By contrast, CO₂ production from acetate and citric acid cycle intermediates was not significantly affected. This indicates impairment of β-oxidation of fatty acids to the level of acetyl CoA, an interpretation supported by the findings of a decrease in ketone body production. In liver mitochondria, oxygen consumption associated with the oxidation of glutamate, succinate and ascorbate was depressed. The per cent decrease was comparable in the absence or presence of ADP or dinitrophenol, suggesting impairment of the respiratory chain. There was no effect on energy production or utilization, as evidence by unchanged respiratory control, ADP/O ratio, ATP-³²P exchange reaction, and substrate- or ATP-supported Ca²⁺ uptake. Unlike isolated liver mitochondria, there were no effects on oxygen uptake or fatty acid oxidation by muscle mitochondria. It is unlikely that the hypolipidemic effects of clofibrate are mediated by reducing fatty acyl substrate levels via enhanced fatty acid oxidation.