The Stimulation of the Mitochondrial Uncoupler-Dependent ATPase in Isolated Hepatocytes by Catecholamines and Glucagon and Its Relationship to Gluconeogenesis

Abstract

Mitochondria prepared from isolated hepatocytes incubated with glucagon, epinephrine and norepinephrine, exhibited stimulated rates of uncoupler-dependent ATPase activity, although no effect of the hormones was apparent on the basal ATPase activity in the absence of 2,4-dinitrophenol. The hormonal stimulation of the ATPase activity behaved in a dose-dependent manner with increasing concentrations of the effectors. Glucagon exhibited an effect on the ATPase only after an initial lag period during which time there was an elevation in the intracellular level of adenosine 3′,5′-monophosphate (cyclic AMP), and incubation of the cells with cyclic AMP itself resulted in a stimulation of the ATPase. The effect of the catecholamines was not mediated through cyclic AMP, but through an α-receptor mechanism. Norepinephrine stimulation of the mitochondrial ATPase exhibited a shorter lag period than that demonstrated for glucagon, strengthening the postulate that the glucagon and catecholamine effects are mediated by independent mechanisms. The hormonal stimulation of the uncoupler-dependent ATPase activity is correlated with the stimulation of gluconeogenesis produced by glucagon and catecholamines both in terms of dose of hormone required and time of onset of effect. It is proposed that the stimulation of the ATPase leads, in the intact cell, to an increased rate of formation of ATP. This contributes to the control of gluconeogenesis from three-carbon acids at the pyruvate carboxylation reaction through increases in the mitochondrial ATP/ADP ratios, and it helps provide the increased ATP for cytosolic reactions that is demanded by an acceleration of gluconeogenesis.