On the mechanism of sodium 2-5-4 chlorophenylpentyloxirane-2-carboxylate (POCA) inhibition of hepatic gluconeogenesis

Abstract

Inhibition of hepatic long chain fatty acid oxidation by 2-5-4 chlorophenylpentyloxirane-2-carboxylate (POCA) leads to decreased gluconeogenic rates from lactate or from low concentrations of pyruvate. The inhibitory effect is fully overcome by concentrations of pyruvate above 0.8 mM or by the simultaneous administration of a medium chain fatty acid. At low pyruvate availability the energy cost of gluconeogenesis is mainly supported by fatty acid oxidation and POCA-induced inhibition of glucose production is secondary to a decreased energy availability. This is supported by the following observations: (i) POCA decreases hepatic respiration and phosphorylation potential; (ii) the rate of pyruvate-induced respiration was the same regardless of whether gluconeogenesis was inhibited or not by POCA; and (iii) concentrations of pyruvate above 0.8 mM, at which gluconeogenesis is not inhibited, prevented the POCA-induced decrease in the phosphorylation potential. It is concluded that inhibition of long chain fatty acid oxidation by POCA leads to a switch of energy fuel, and results in the oxidation of more pyruvate to meet the cellular energy demands. When pyruvate availability is low and thus, presumably, its mitochondrial transport restricted, pyruvate carboxylation most probably becomes limiting as a result of the increased flux through pyruvate dehydrogenase, in the presence of POCA.