Relation of oxidation of long-chain fatty acids to gluconeogenesis in the perfused liver of the guinea pig: effect of 2-tetradecylglycidic acid (McN-3802).

1. The potent, specific inhibitor of long-chain fatty acid oxidation, 2-tetradecylglycidic acid (McN-3802), at 10 microM totally abolished ketogenesis from endogenous substrates in the isolated perfused guinea pig liver. This effect was accompanied by a marked inhibition of gluconeogenesis from lactate plus pyruvate and by a shift toward a more oxidized state of the mitochondrial (3-hydroxybutyrate/acetoacetate ratio) and cytoplasmic (lactate/pyruvate ratio) compartments. 2. The addition of octanoate (88-500 microM) almost completely reversed the inhibitory effect of 2-tetradecylglycidic acid on gluconeogenesis. Octanoate oxidation, measured by the rate of ketogenesis, was not inhibited. This protective effect of octanoate against inhibition of gluconeogenesis by 2-tetradecylglycidic acid was seen even though in some experiments the mitochondrial redox state remained two to three times the magnitude observed prior to octanoate addition. 3. Gluconeogenesis from 4 mM glycerol was not inhibited and gluconeogenesis from 4 mM propionate was only slightly inhibited by 2-tetradecylglycidic acid. 4. Thus, it would appear that fatty acid oxidation in guinea pig liver is essential for maintaining maximal rates of gluconeogenesis, especially from substrates dependent on pyruvate carboxylation for conversion to glucose. 5. A single dose of 2-tetradecylglycidic acid (orally, 10-25 mg/kg) given to guinea pigs previously fasted 72 h produced a highly significant decrease of total ketones, of the 3-hydroxybutyrate/acetoacetate ratio and of plasma glucose. A smaller hypoglycemic effect was seen when the drug was administered to animals fasted for only 24 h or 48 h. 6. It appears from evidence in vivo and in vitro that the guinea pig and rat respond similarly to inhibition of fatty acid oxidation. This may be important since it has been suggested that the role of fatty acid oxidation in glucose synthesis is markedly different in these two species.