Acceleration of Gluconeogenesis from Lactate by Lysine By NEAL W . CORNELL , PATRICIA LUND , REGINALD HEMs and HANS A

This paper reports experimental results that show that lysine at low concentrations can accelerate hepatic gluconeogenesis from lactate. The effect is catalytic. Although the mechanism of action of lysine is still unknown it is probable that lysine plays an important role in the regulation of liver metabolism. The lysine effect was discovered in the course of experiments on histidine metabolism in the isolated perfused rat liver. Although histidine is a glucogenic amino acid and is readily degraded by the perfused liver it formed no glucose. This was taken to suggest that histidine (like tryptophan) might inhibit gluconeogenesis, and indeed histidine was found to have such an effect, at 2mM, on gluconeogenesis from lactate. These findings were confirmed in experiments with isolated liver cells prepared by the method of Berry & Friend (1969), to which Dr. M. N. Berry had introduced us during a recent stay in this laboratory. Since the isolated cells are a more convenient experimental material than the perfused liver (because many parallel tests can be carried out on a homogeneous suspension of cells from one liver), and having convinced ourselves that the metabolic properties (oxygen consumption, gluconeogenesis from a variety of substrates, urea synthesis, ketogenesis, glycolysis, fructolysis, the redox state of the NAD couple in cytoplasm andmitochondria, selectivemembrane permeability, i.e. relative impermeability to diand tricarboxylic acids) of the isolated cells (unlike those of slices; see Krebs, 1970) are quantitatively similar to those of perfused liver, we followed up the investigation of the histidine effect in the first instance in the isolated cells. Ornithine, which causes the NH3 derived from histidine to be converted into urea, was found to counteract the inhibition of gluconeogenesis from lactate but lysine (tested in order to examine the specificity of the ornithine effect) proved even more effective. Controls revealed that lysine also accelerates the rate of gluconeogenesis from lactate in the absence of histidine, and moreover lysine was found to affect several other metabolic processes involving lactate.