Interrelationships between ureogenesis and gluconeogensis in perfused rat liver

Stimulation of ureogenesis by ornithine and/or NH4Cl inhibited gluconeogenesis from lactate but not from equimolar concentrations of pyruvate in perfused rat liver. Neither a shortage of energy nor a decrease in α-ketoglutarate availability seems to be responsible for this inhibition. With lactate as substrate the extracellular concentration of pyruvate attained was ≊0.15 mM that assuming reflects its cytosolic concentration it would be limiting for its mitochondrial transport. Stimulation of ureogenesis from NH4Cl enhances flux through pyruvate dehydrogenase. Furthermore, activation of pyruvate dehydrogenase by dichloroacetate led to stimulation of ureogenesis and inhibition of glucose production. Conversely, inhibition of pyruvate dehydogenase flux by fatty acid enhanced glucose production and inhibited ureogenesis. Thus, ornithine and/or NH4Cl seem to inhibit lactate to glucose flux by shifting the mitochondrial partitioning of oyruvate from carboxylation towards decarboxylation with the result of a decreaased oxaloacetate formation. Gluconeogenic substrates enhanced the hepatic uptake of ornithine. However, no correlation seems to exist between the uptake of ornithine, ornithine-induced stimulation of ureogenesis and total rates of urea production. Ornithine produced a concentration-dependent acidification of the hepatic outflow perfusate, suggesting that it may be transported in exchange for H+.This work has been supported, in part, by grants from Dirección General de Ciencia y Tecnología (PB87-0280), Comisión Interministerial de Ciencia y Tecnología (SAL91-0509) and Comunidad de Madrid (C249/90). G.C. holds a fellowship from the Spanish Ministerio de Educación y Ciencia