Prevention of inhibitory effect of free fatty acids on insulin binding and action in isolated rat hepatocytes by etomoxir.

We recently demonstrated a marked inhibitory effect of high physiological concentrations of free fatty acids (FFAs) on insulin binding, degradation, and action in isolated rat hepatocytes. To elucidate the mechanism, male rats were treated for 3 days with saline (control) or etomoxir (ethyl 2-[6-(p-chlorophenoxy)hexyl]-glycidate), a prodrug, which in vivo is converted to a specific competitive inhibitor of carnitine palmitoyltransferase, and thus, lipid oxidation. Oleic acid (0.4 mM) reduced both 125-I-labeled insulin binding and insulin-stimulated [14C]aminoisobutyric acid transport approximately 40% in cells from control animals. However, this FFA concentration was without effect in cells from etomoxir-treated animals. Etomoxir increased EC50 for the inhibitory effect of oleic acid on insulin binding approximately threefold. The data indicate that the mitochondrial oxidation of fatty acids may be important for their inhibitory effect on insulin binding and action in isolated rat hepatocytes.