Effect of clofibrate treatment on acylcarnitine oxidation in isolated rat liver mitochondria.
The oxidation of palmitoyl- and octanoylcarnitine in liver mitochondria from normal and clofibrate-treated male rats was studied by measuring the ADP-stimulated oxygen consumption and acetyl group production (the sum of formed ketone bodies, acetylcarnitine and citrate). In the absence of malate the treatment approximately doubled the rate of acylcarnitine oxidation. In normal mitochondria the acetyl groups consisted almost totally of ketone bodies. The clofibrate-induced increase in acetyl group production was attributable to enhanced rates of ketone body and acetylcarnitine formation. The observed increase in acylcarnitine oxidation was associated with an elevated beta-hydroxybutyrate: acetoacetate ratio, reflecting an increased mitochondrial NADH:NAD+ ratio. In normal mitochondria the addition of malate in the presence of fluorocitrate doubled the rate of beta oxidation by forming citrate. The beta oxidation in mitochondria from clofibrate-treated rats was virtually unresponsive to added malate. The clofibrate-induced increase in ketogenesis was confirmed in disintegrated mitochondria. The treatment approximately doubled the rate of ketone body production from acetyl-CoA in disrupted organelles. The enhanced capacity of ketogenesis was accompanied by increased activity of the specific acetoacetyl-CoA thiolase (EC 2.3.1.8), which is the first step enzyme of the pathway. Clofibrate administration also increased the activities of general oxoacyl-CoA thiolase (EC 2.3.1.16), palmitoyl-CoA dehydrogenase (EC 1.3.99.3), and butyryl-CoA dehydrogenase (EC 1.3.99.2), which all take part in the beta oxidation of fatty acids.
D000090:Acetoacetates / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D000108:Acetylcarnitine / Q000378:metabolism; D000818:Animals; D002210:Caprylates / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives*; D002951:Citrates / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology*; D006885:Hydroxybutyrates / Q000378:metabolism; D007657:Ketone Bodies / Q000096:biosynthesis; D008293:Malates / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010172:Palmitoylcarnitine / Q000378:metabolism*; D051381:Rats
D000090:Acetoacetates; D002210:Caprylates; D002951:Citrates; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D008293:Malates; D010172:Palmitoylcarnitine; D000108:Acetylcarnitine; D010088:Oxidoreductases; D000102:Acetyl-CoA C-Acyltransferase; D000101:Acetyl-CoA C-Acetyltransferase; D002994:Clofibrate; D002331:Carnitine