Lenzen R, Stark P, Kolb-Bachofen V, Strohmeyer G
Department of Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
Hepatology. 1995 May;21(5):1422-8.
In guinea pigs, glucagon choleresis is accompanied by a significant, but transient, stimulation of biliary protein secretion, which can be accounted for mainly by biliary discharge of lysosomal enzymes. To clarify whether intracellular proteolysis--a process regulated by glucagon and taking place predominantly in the lysosomes--may interact with biliary protein secretion, we determined hepatic proteolytic activity and bile secretory function during substrate deprivation, amino acid supplementation, and glucagon administration in isolated perfused guinea pig livers. To further elucidate the nature of transient lysosomal enzyme release into bile during glucagon infusion, we analyzed pericanalicular 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 acids 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 the entire infusion period and thus does not explain the transient biliary release of lysosomal enzymes. We therefore postulate that regulation of this process must be located beyond the lysosomal compartment, either involving transport processes or intracellular kinetics of lysosome formation or altered fusion kinetics at the bile canalicular membrane compartment. Metabolic and biliary effects of glucagon seem to occur independent of each other and to underly different regulatory mechanisms.
在豚鼠中，胰高血糖素引起的胆汁分泌增加伴随着胆汁蛋白质分泌的显著但短暂的刺激，这主要可归因于溶酶体酶的胆汁排出。为了阐明细胞内蛋白水解（一种由胰高血糖素调节且主要发生在溶酶体中的过程）是否可能与胆汁蛋白质分泌相互作用，我们在离体灌注的豚鼠肝脏中，在底物剥夺、氨基酸补充和给予胰高血糖素的过程中，测定了肝脏的蛋白水解活性和胆汁分泌功能。为了进一步阐明胰高血糖素输注期间溶酶体酶短暂释放到胆汁中的性质，我们通过定量电子显微镜分析了溶酶体的胆小管周围分布。结果表明，细胞内蛋白水解伴随着溶酶体酶的胆汁排泄。胰高血糖素诱导这些酶以及标记蛋白分泌到胆汁中，其发生与蛋白质分解无关，并且不能通过添加作为细胞内蛋白水解有效抑制剂的氨基酸来调节。在给予胰高血糖素期间，胆小管区域和次级溶酶体的胆小管周围分布迅速增加，在整个输注期间持续存在，因此不能解释溶酶体酶的短暂胆汁释放。因此，我们推测该过程的调节必定位于溶酶体区室之外，要么涉及转运过程，要么涉及溶酶体形成的细胞内动力学，要么涉及胆小管膜区室处改变的融合动力学。胰高血糖素在代谢和胆汁方面的作用似乎彼此独立发生，并且受不同的调节机制支配。
