Glucagon-induced autophagy and proteolysis in rat liver: mediation by selective deprivation of intracellular amino acids.

Abstract

Amino acid deprivation and glucagon are both potent inducers of autophagy and proteolysis in liver. Because glucagon enhanced the metabolic utilization of some amino acids, the catabolic response to both of these stimuli could be achieved by a lowering of intracellular amino acid pools. Glucagon could also act independently of amino acids. To clarify the mode of hormonal action and also the relationship between the 2 cellular responses, livers from fed rats were perfused, with and without glucagon, with plasma amino acids over a concentration range of 0-10 times normal. Individual amino acid constancy at each level was ensured by perfusion in the single-pass mode. Amino acids alone strongly regulated autophagy and proteolysis in a coordinated fashion; maximal suppression was achieved at twice normal concentrations; both effects increased rapidly to maximum at less than normal concentration. Corresponding effects of glucagon could be elicited only at intermediate amino acid levels. None was noted at 4 and 10 times normal; at 0, hormonal stimulation was minimal. The amino acid inhibition was selective because it did not block cyclic AMP production or glycogenolysis. Intracellular pool measurements and systematic alteration of perfusate amino acid composition indicated that the autophagic and proteolytic effects of glucagon are mediated by a hormonally induced depletion of glycine, alanine, glutamate and glutamine; of these, glutamine alone is the most effective. The stimulation of intracellular protein degradation in liver is a manifestation of deprivation-induced autophagy which results from a decrease in certain intracellular glucogenic amino acids, notably glutamine.