GLUCAGON EFFECT ON INTRACELLULAR PROTEOLYSIS AND PERICANALICULAR LOCATION OF HEPATOCYTE LYSOSOMES IN ISOLATED-PERFUSED GUINEA-PIG LIVERS

In guinea pigs, glucagon choleresis is accompanied by a significant, b ut transient, stimulation of biliary protein secretion, which can be a ccounted for mainly by biliary discharge of lysosomal enzymes. To clar ify whether intracellular proteolysis-a process regulated by glucagon and taking place predominantly in the lysosomes-may interact with bili ary protein secretion, we determined hepatic proteolytic activity and bile secretory function during substrate deprivation, amino acid suppl ementation, and glucagon administration in isolated perfused guinea pi g livers. To further elucidate the nature of transient lysosomal enzym e release into bile during glucagon infusion, we analyzed pericanalicu lar distribution of lysosomes by quantitative electron microscopy. The results demonstrate that intracellular proteolysis is accompanied by biliary excretion of lysosomal enzymes. Glucagon-induced secretion of these enzymes as well as labeled proteins into bile occurs independent of protein breakdown and cannot be modulated by addition of amino aci ds as potent inhibitors of intracellular proteolysis. During glucagon administration, bile canalicular area and pericanalicular distribution of secondary lysosomes show a rapid increase, which persists during t he entire infusion period and thus does not explain the transient bili ary release of lysosomal enzymes. We therefore postulate that regulati on of this process must be located beyond the lysosomal compartment, e ither involving transport processes or intracellular kinetics of lysos ome formation or altered fusion kinetics at the bile canalicular membr ane compartment. Metabolic and biliary effects of glucagon seem to occ ur independent of each other and to underly different regulatory mecha nisms.