A reexamination of the role of the cytosolic alanine aminotransferase in hepatic gluconeogenesis.
The relative importance of the mitochondrial and cytosolic alanine aminotransferase isozymes for providing pyruvate from alanine for further metabolism in the mitochondrial compartment was examined in the isolated perfused rat liver. The experimental rationale employed depends upon the supposition that gluconeogenesis from alanine and the decarboxylation of infused [1-14C]alanine should be diminished by pyruvate transport inhibitors (e.g., alpha-cyanocinnamate) in proportion to the contribution of the cytosolic alanine aminotransferase for generating pyruvate. alpha-Cyanocinnamate inhibited the endogenous rate of glucose production in perfused livers derived from 24-h-fasted rats. The rate of [1-14C]alanine decarboxylation at low (1 mM) and high (10 mM) perfusate alanine concentrations was inhibited by 9.5 and 42%, respectively, in the presence of alpha-cyanocinnamate. In livers from fasted animals perfused with either 1 or 10 mM alanine, alpha-cyanocinnamate caused a substantial increase in the rates of both lactate and pyruvate production. Elevating the hepatic ketogenic rate during infusion of acetate in livers, perfused with alanine, stimulated both the rates of alanine decarboxylation and glucose production; the extent of stimulation of these two metabolic parameters was determined to be a function of the alanine concentration in the perfusate. The stimulation of the rate of alanine decarboxylation during acetate-induced ketogenesis was reversed by co-infusion of alpha-cyanocinnamate with simultaneous increases in the rates of lactate and pyruvate production. The results indicate that during rapid ketogenesis, cytosolic transamination of alanine contributes at least 19% (at 1 mM alanine) and 55% (at 10 mM alanine) of the pyruvate for gluconeogenesis.
D000085:Acetates / Q000494:pharmacology; D019342:Acetic Acid; D000409:Alanine / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism*; D000818:Animals; D002245:Carbon Dioxide / Q000096:biosynthesis; D002934:Cinnamates / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D005943:Gluconeogenesis; D007527:Isoenzymes / Q000378:metabolism*; D007657:Ketone Bodies / Q000096:biosynthesis; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008099:Liver / Q000201:enzymology*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D027501:Monocarboxylic Acid Transporters; D010477:Perfusion; D011773:Pyruvates / Q000096:biosynthesis; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D000085:Acetates; D002934:Cinnamates; D007527:Isoenzymes; D007657:Ketone Bodies; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D011773:Pyruvates; C018253:alpha-cyanocinnamate; D002245:Carbon Dioxide; D019344:Lactic Acid; D019289:Pyruvic Acid; D000410:Alanine Transaminase; D000409:Alanine; D019342:Acetic Acid