The immediate and long term effects of clofibrate on the metabolism of the perfused rat liver

Abstract

A study was made of the immediate effects of CPIB (chlorophenoxy-isobutyrate) and of the effects of clofibrate (ethyl-CPIB) pretreatment on the metabolism of the perfused liver. Both treatments caused an increased hepatic uptake of lactate and free fatty acids. Pretreatment with clofibrate resulted in a decrease in perfusate glucose, an increase in ketogenesis and a decreased output of very low density lipoprotein triacylglycerol. A more oxidized redox state of both the cytosol and the mitochondria was indicated by decreased ratios of perfusate [lactate]/[pyruvate] and [3-hydroxybutyrate]/[acetoacetate] respectively. Increased hepatic O 2 consumption was associated with the increased liver weight of rats treated with the drug for 1 week. The fate of free fatty acids was followed by infusing [1— 14Cloleate. The increased oxidation of oleate to both CO 2 and ketone bodies in livers from animals pretreated with clofibrate was accompanied by a corresponding decreased incorporation of 14C into very low density lipoprotein triacylglycerol. Lipogenesis was depressed upon addition of CPIB to the perfusate, but was increased after pretreatment with clofibrate. No changes in cholesterol synthesis were detected. A hypothesis to account for the hypolipidaemic and other effects of clofibrate pretreatment is advanced. This is based on a primary enhancement of fatty acid oxidation accompanied by a reciprocal decrease in hepatic triacylglycerol secretion. It is suggested that increased peroxisomal oxidation of fatty acids may be a cause of the decreased redox potential. A consequent activation of pyruvate dehydrogenase would explain both the changes in carbohydrate metabolism and the increase in lipogenesis.