TY - JOUR
T1 - Pharmacologic perturbation of rat liver lysosomes
T2 - Effects on release of lysosomal enzymes and of lipids into bile
AU - Sewell, Richard B.
AU - Grinpukel, Susan A.
AU - Zinsmeister, Alan R.
AU - LaRusso, Nicholas F.
N1 - Funding Information:
This work was supported by the National Health and Medical Research Council of Australia, by grants DK24031, DK34988, and RR585 from the National Institutes of Health, and by the Mayo Foundation. Doctor Sewell was an Australian Postdoctoral National Health and Medical Research Council Fellow. Part of this work was presented at an American Gastroenterological Association meeting and was published in abstract form (121.
PY - 1988/10
Y1 - 1988/10
N2 - Hepatocyte lysosomes disassemble materials derived from intracellular sources, including lipid-containing membranes, by a process called autophagy. In addition, hepatocyte lysosomes can release their contents into bile by exocytosis. Therefore, using both in vivo and in vitro models, we tested the hypothesis that acute pharmacologic induction of autophagy would modify the biliary excretion of lysosomal protein and of lipids. We treated rats with a single dose of chloroquine (10 mg/kg), glucagon (1 mg/kg), or control solutions and collected bile via bile fistulas. Both chloroquine and glucagon immediately caused a marked and parallel decrease in biliary excretion of three lysosomal enzymes, N-acetyl-β-glucosaminidase, β-glucuronidase, and β-galactosidase, to 25%-30% of baseline values (p < 0.01). This decrease was sustained for 2 h after glucagon and 4 h after chloroquine administration. In contrast, biliary lipid changes were minor: a slight lowering of biliary cholesterol secretion after chloroquine (p < 0.05), but no change in biliary bile acids, cholesterol, and phospholipid secretion after glucagon. Changes in biliary excretion of lysosomal enzymes accompanying chloroquine and glucagon administration were associated with morphologic evidence of autophagy as assessed by electron microscopy and by increased fragility of hepatic lysosomes as assessed by latency of N-acetyl-β-glucosaminidase. These in vivo changes in biliary lysosomal enzyme excretion induced by chloroquine and glucagon were confirmed in vitro using the isolated perfused rat liver. Thus, acute induction of autophagy results in conservation of hepatic lysosomal protein and has virtually no effect on biliary lipid excretion.
AB - Hepatocyte lysosomes disassemble materials derived from intracellular sources, including lipid-containing membranes, by a process called autophagy. In addition, hepatocyte lysosomes can release their contents into bile by exocytosis. Therefore, using both in vivo and in vitro models, we tested the hypothesis that acute pharmacologic induction of autophagy would modify the biliary excretion of lysosomal protein and of lipids. We treated rats with a single dose of chloroquine (10 mg/kg), glucagon (1 mg/kg), or control solutions and collected bile via bile fistulas. Both chloroquine and glucagon immediately caused a marked and parallel decrease in biliary excretion of three lysosomal enzymes, N-acetyl-β-glucosaminidase, β-glucuronidase, and β-galactosidase, to 25%-30% of baseline values (p < 0.01). This decrease was sustained for 2 h after glucagon and 4 h after chloroquine administration. In contrast, biliary lipid changes were minor: a slight lowering of biliary cholesterol secretion after chloroquine (p < 0.05), but no change in biliary bile acids, cholesterol, and phospholipid secretion after glucagon. Changes in biliary excretion of lysosomal enzymes accompanying chloroquine and glucagon administration were associated with morphologic evidence of autophagy as assessed by electron microscopy and by increased fragility of hepatic lysosomes as assessed by latency of N-acetyl-β-glucosaminidase. These in vivo changes in biliary lysosomal enzyme excretion induced by chloroquine and glucagon were confirmed in vitro using the isolated perfused rat liver. Thus, acute induction of autophagy results in conservation of hepatic lysosomal protein and has virtually no effect on biliary lipid excretion.
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U2 - 10.1016/0016-5085(88)90187-4
DO - 10.1016/0016-5085(88)90187-4
M3 - Article
C2 - 3137115
AN - SCOPUS:0023677531
SN - 0016-5085
VL - 95
SP - 1088
EP - 1098
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -