Regulation of gluconeogenesis from pyruvate and lactate in the isolated perfused rat liver

Abstract

The effects of glucagon and the α-adrenergic agonist, phenylephrine, on the rate of 14CO 2 production and gluconeogenesis from [1- 14C]lactate and [1- 14C]pyruvate were investigated in isolated perfused livers of 24-h-fasted rats. Both glucagon and phenylephrine stimulated the rate of 14CO 2 production from [1- 14C]lactate but not from [1- 14C]pyruvate. Neither glucagon nor phenylephrine affected the activation state of the pyruvate dehydrogenase complex in perfused livers derived from 24-h-fasted rats. 3-Mercaptopicolinate, an inhibitor of the phospho enolpyruvate carboxykinase reaction, inhibited the rates of 14CO 2 production and glucose production from [1- 14C]lactate by 50% and 100%, respectively. Furthermore, 3-Mercaptopicolinate blocked the glucagon- and phenylephrine-stimulated 14CO 2 production from [1- 14C]lactate. Additionally, measurements of the specific radioactivity of glucose synthesized from [1- 14C]lactate, [1- 14C]pyruvate and [2- 14C]pyruvate indicated that the 14C-labeled carboxyl groups of oxaloacetate synthesized from 1- 14C-labeled precursors were completely randomized and pyruvate → oxaloacetate → pyruvate substrate cycle activity was minimal. The present study also demonstrates that glucagon and phenylephrine stimulation of the rate of 14CO 2 production from [1- 14C]lactate is a result of increased metabolic flux through the phospho enolpyruvate carboxykinase reaction, and phenylephrine-stimulated gluconeogenesis from pyruvate is regulated at step(s) between phospho enolpyruvate and glucose.