INTERRELATIONSHIPS BETWEEN UREOGENESIS AND GLUCONEOGENESIS IN PERFUSED-RAT-LIVER

Stimulation of ureogenesis by ornithine and/or NH4Cl inhibited glucone ogenesis from lactate but not from equimolar concentrations of pyruvat e in perfused rat liver. Neither a shortage of energy nor a decrease i n alpha-ketoglutarate availability seems to be responsible for this in hibition. With lactate as substrate the extracellular concentration of pyruvate attained was is-approximately-equal-to 0.15 mM that assuming reflects its cytosolic concentration it would be limiting for its mit ochondrial transport. Stimulation of ureogenesis from NH4Cl enhances f lux through pyruvate dehydrogenase. Furthermore, activation of pyruvat e dehydrogenase by dichloroacetate led to stimulation of ureogenesis a nd inhibition of glucose production. Conversely, inhibition of pyruvat e dehydogenase flux by fatty acid enhanced glucose production and inhi bited ureogenesis. Thus, ornithine and/or NH4Cl seem to inhibit lactat e to glucose flux by shifting the mitochondrial partitioning of pyruva te from carboxylation towards decarboxylation with the result of a dec reased oxaloacetate formation. Gluconeogenic substrates enhanced the h epatic uptake of ornithine. However, no correlation seems to exist bet ween the uptake of ornithine, ornithine-induced stimulation of ureogen esis and total rates of urea production. Ornithine produced a concentr ation-dependent acidification of the hepatic outflow perfusate, sugges ting that it may be transported in exchange for H+.