Effect of sulfonylureas on hepatic fatty acid oxidation

In isolated rat livers perfused with oleic acid (0.1 mM), infusion of tolbutamide or glyburide decreased the rate of ketogenesis in a dose-dependent manner. The inhibition of fatty acid oxidation was maximal at 2.0 mM and 10 microM concentrations of tolbutamide and glyburide, respectively. Neither tolbutamide nor glyburide inhibited ketogenesis in livers perfused with octanoate. The inhibition of hepatic ketogenesis by sulfonylureas was independent of perfusate oleic acid concentration. Additionally, in rat livers perfused with oleic acid in the presence of L-(-)-carnitine (10 mM), submaximal concentrations of tolbutamide and glyburide did not inhibit hepatic ketogenesis. Finally, glyburide infusion into livers perfused with [U-14C]oleic acid (0.1 mM) increased the rate of 14C label incorporation into hepatic triglycerides by 2.5-fold. These data suggest that both tolbutamide and glyburide inhibit long-chain fatty acid oxidation by inhibiting the key regulatory enzyme, carnitine palmitoyltransferase I, most probably by competing with L-(-)-carnitine.