Gluconeogenic dependence on ketogenesis in isolated sheep hepatocytes

Dependence of gluconeogenesis on beta-oxidation and ketogenesis from long-chain fatty acids was examined in isolated sheep hepatocytes. Hepatocytes were incubated with a combination of gluconeogenic precursors (2 mM pyruvate, 20 mM lactate, and 5 mM propionate) plus other fatty acids, in the presence and absence of tetradecylglycidic acid, an inhibitor of the carnitine palmitoyltransferase reaction. Palmitate oxidation to total acid-soluble metabolites or beta-hydroxybutyrate was markedly inhibited by the addition of tetradecylglycidic acid. In general, oxidation of palmitate to carbon dioxide was not altered by tetradecylglycidic acid. Glucose production was inhibited 28 to 50% in the presence of tetradecylglycidic acid. Addition of acetate and butyrate inhibited gluconeogenesis, but octanoate addition had a slight stimulatory effect. In the presence of tetradecylglycidic acid, butyrate, but not acetate, addition further reduced gluconeogenesis. In contrast, addition of octanoate in the presence of tetradecylglycidic acid restored gluconeogenic rates to control values. The results are consistent with observations in several nonruminant species and suggest that, as in those species, ruminant gluconeogenesis requires at least a basal rate of beta-oxidation and ketogenesis from long-chain fatty acids to support maximum gluconeogenic rates.