INTERRELATIONS BETWEEN UREOGENESIS AND GLUCONEOGENESIS IN ISOLATED HEPATOCYTES - ROLE OF ANION TRANSPORT AND COMPETITION FOR ENERGY

Glucose synthesis from lactate plus pyruvate and from lactate plus alanine was measured in the presence or absence of 1 mM-oleate or 2 mM-octanoate at low (2 mM) or high (8 mM) concentrations of NH4Cl. Both fatty acids alone or with 2 mM-NH4Cl doubled glucose production from lactate plus pyruvate. Glucose synthesis from lactate plus alanine, in the presence of oleate, was decreased 16% by 2 mM-NH4Cl. In the presence of fatty acids, 8 mM-NH4Cl decreased gluconeogenesis by 60-65% from both lactate plus pyruvate and lactate plus alanine. This inhibition was correlated with a high accumulation of aspartate and a drastic decrease in 2-oxoglutarate and malate in the cells. In the presence of 2 mM- or 8 mM-NH4Cl, oleate and glucogenic precursors, the addition of 2.5 mM-ornithine stimulated urea synthesis. This was paralleled by a decrease of 16% in glucose synthesis from lactate plus pyruvate in the presence of 2 mM-NH4Cl and had no effect at 8 mM-NH4Cl. In the system producing glucose from lactate plus alanine, ornithine completely reversed the inhibition caused by 2 mM-NH4Cl and only partly that by 8 mM-NH4Cl. Gluconeogenesis from pyruvate was also inhibited by 2 mM-NH4Cl in the presence of oleate or ethanol. This was due to the decrease of malate, which is the C4 precursor of glucose in this system. The limitation of gluconeogenesis by 2-oxoglutarate and malate concentrations in the liver cell and the competition for energy between glucose and urea synthesis is discussed.