Regulation of gluconeogenesis from pyruvate and lactate in the isolated perfused rat liver.
The effects of glucagon and the alpha-adrenergic agonist, phenylephrine, on the rate of 14CO2 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 14CO2 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 phosphoenolpyruvate carboxykinase reaction, inhibited the rates of 14CO2 production and glucose production from [1-14C]lactate by 50% and 100%, respectively. Furthermore, 3-mercaptopicolinate blocked the glucagon- and phenylephrine-stimulated 14CO2 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 14CO2 production from [1-14C]lactate is a result of increased metabolic flux through the phosphoenolpyruvate carboxykinase reaction, and phenylephrine-stimulated gluconeogenesis from pyruvate is regulated at step(s) between phosphoenolpyruvate and glucose.
D000818:Animals; D002245:Carbon Dioxide / Q000096:biosynthesis; D005934:Glucagon / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis; D007773:Lactates / Q000378:metabolism*; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010071:Oxaloacetates / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010848:Picolinic Acids / Q000494:pharmacology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism*; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D007773:Lactates; D010071:Oxaloacetates; D010848:Picolinic Acids; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D002245:Carbon Dioxide; D010656:Phenylephrine; D019344:Lactic Acid; C008363:3-mercaptopicolinic acid; D019289:Pyruvic Acid; D005934:Glucagon; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose