2-bromooctanoic-acid and 2-tetradecylglycidic-acid

1. The induction of peroxisomal beta-oxidation activities by bezafibrate in cultured rat hepatocytes and in the rat in vivo was prevented by inhibitors of carnitine acyltransferase, e.g. 2-bromopalmitate, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate or 2-tetradecylglycidic acid. 2. The prevention of peroxisomal proliferation by carnitine palmitoyltransferase inhibitors could not be accounted for by inhibition of mitochondrial beta-oxidation, since 2-bromo-octanoate, acting as an inhibitor of beta-oxidation, did not prevent the induction of peroxisomal activities in cultured rat hepatocytes. 3. The putative role of the acylcarnitine derivative of bezafibrate was analysed by studying the formation of bezafibroylcarnitine with bezafibroyl-CoA as substrate. However, no bezafibroylcarnitine formation was demonstrated in the presence of rat liver preparations capable of catalysing transfer to carnitine of medium- or long-chain fatty acids. 4. The prevention of peroxisomal proliferation by carnitine acyltransferase inhibitors may help in dissecting the causal relationship between the multiple effects mediated by peroxisomal proliferators.

Topics: Acyltransferases; Animals; Bezafibrate; Caprylates; Carnitine O-Palmitoyltransferase; Cells, Cultured; Epoxy Compounds; Fatty Acids; Glycerol; Liver; Microbodies; Palmitates; Palmitic Acid; Palmitic Acids; Rats

A method has been devised to quantitate rates of ketogenesis (acetoacetate + beta-hydroxybutyrate production) in discrete regions of the liver lobule based on changes in NADH fluorescence. In perfused livers from fasted rats, ketogenesis was inhibited nearly completely with either 2-bromoctanoate (600 microM) or 2-tetradecylglycidic acid (25 microM). During inhibition of ketogenesis, a linear relationship (r = 0.90) was observed between decreases in NADH fluorescence detected from the liver surface and decreases in ketone body production. NADH fluorescence was monitored subsequently from individual regions of the liver lobule by placing microlight guides on periportal and pericentral regions of the liver lobule visible on the liver surface. Rates of ketogenesis in sublobular regions were calculated from regional decreases in NADH fluorescence and changes in the rate of ketone body formation by the whole liver during infusion of inhibitors. In the presence of bromoctanoate, ketogenesis was reduced 80% and local rates of ketogenesis were decreased 31 +/- 4 mumol/g/h in periportal areas and 28 +/- 3 mumol/g/h in pericentral regions. Similar results were observed with tetradecylglycidic acid. Therefore, it was concluded that submaximal rates of ketogenesis from endogenous, mainly long-chain fatty acids are nearly equal in periportal and pericentral regions of the liver lobule in liver from fasted rats. Rates of ketogenesis and NADH fluorescence were strongly correlated during fatty acid infusion. Infusion of 250 microM oleate increased NADH fluorescence maximally by 8 +/- 1% over basal values in periportal regions and 17 +/- 4% in pericentral areas. Local rates of ketogenesis, calculated from these changes in fluorescence, increased 35 +/- 6 mumol/g/h in periportal areas and 55 +/- 5 mumol/g/h in pericentral regions. Thus, oleate stimulated ketogenesis nearly 60% more in pericentral than in periportal regions of the liver lobule.

Topics: Animals; Caprylates; Epoxy Compounds; Fatty Acids; Female; Fluorescence; Ketone Bodies; Liver; NAD; Oleic Acid; Oleic Acids; Rats