Control of Gluconeogenesis from Amino Acids in the Perfused Rat Liver

Gluconeogenesis from amino acids was investigated with isolated rat livers perfused with Krebs bicarbonate buffer containing bovine red cells and serum albumin. In livers from fasted rats perfused with a mixture of amino acids at various multiples of their normal plasma concentrations, glucose production was half-maximal at normal amino acid concentrations and approached saturation at three times normal concentrations. Urea production also rose with increasing concentrations of amino acids, but was not saturated at four times normal levels. It is concluded that the rate of release of amino acids from peripheral tissues can be important in controlling hepatic gluconeogenesis. In livers perfused with physiological levels of amino acids, glucagon increased alanine conversion to glucose 3.5-fold and produced changes in the steady state concentrations of intermediates of the gluconeogenic pathway which indicated stimulation of the conversion of pyruvate to phosphopyruvate. With high concentrations of alanine, transamination became a significant rate-limiting step for gluconeogenesis. Under these conditions glucagon or cyclic 3',5'-AMP increased alanine conversion to glucose 2- to 3-fold, and the changes in intermediates indicated that they also stimulated the transport of alanine into the cell. Maximum gluconeogenesis from alanine was reached only when the perfusate concentration of alanine was 20 times the normal, physiological level. Glucagon stimulated both glucose and urea production from the amino acid mixture at all amino acid concentrations studied. Urea production was also stimulated by epinephrine and cyclic 3',5'-AMP in livers perfused with or without amino acids. It is proposed that glucagon and possibly catecholamines play a role in the physiological regulation of gluconeogenesis from amino acids by increasing the formation of cyclic 3',5'AMP, which acts to stimulate both the transport of amino acids into the hepatic cell and the conversion of pyruvate to P-pyruvate.