ABSTRACT
Glycogen autophagy, the sequestration and degradation of cell glycogen in the autophagic vacuoles, is a selective, hormonally controlled and highly regulated process, representing a mechanism of glucose homeostasis under conditions of demand for the production of this sugar. In the newborn animals, this process is induced by glucagon secreted during the postnatal hypoglycemia and inhibited by insulin and parenteral glucose, which abolishes glucagon secretion. Hormonal action is mediated by the cAMP/protein kinase A (induction) and phosphoinositides/mTOR (inhibition) pathways that converge on common targets, such as the protein phosphatase 2A to regulate autophgosomal glycogen-hydrolyzing acid glucosidase and glycogen autophagy. Intralysosomal phosphate exchange reactions, which are affected by changes in the calcium levels and acid mannose 6- and acid glucose 6-phosphatase activities, can modify the intralysosomal composition in phosphorylated and nonphosphorylated glucose and promote the exit of free glucose through the lysosomal membrane. Glycogen autophagy-derived nonphosphorylated glucose assists the hyaloplasmic glycogen degradation-derived glucose 6-phosphate to combat postnatal hypoglycemia and participates in other metabolic pathways to secure the fine tuning of glucose homeostasis during the neonatal period.
Subject(s)
Autophagy/physiology , Glucose/metabolism , Glycogen/metabolism , Growth and Development/physiology , Homeostasis/physiology , Animals , Animals, Newborn , Humans , Infant, NewbornABSTRACT
The effects of glucagon, adrenalin or rapamycin on glycogen autophagy in the liver and heart of newborn rats were studied using biochemical determinations and electron microscopy. Glucagon or adrenalin increased autophagic activity in the hepatocytes and myocardiocytes, glycogen-hydrolyzing acid glucosidase activity in the liver and heart and degradation of glycogen inside the autophagic vacuoles. Glucagon or adrenalin also increased the maltose-hydrolyzing acid glucosidase activity in the liver, but not in the heart. Similar effects were produced in the newborn heart by rapamycin. These observations support previous studies suggesting that the cellular machinery which controls glycogen autophagy in the liver and heart of newborn animals, is regulated by the cyclic AMP and the mTOR pathways.
Subject(s)
Autophagy/drug effects , Glycogen/metabolism , Liver/metabolism , Myocardium/metabolism , Animals , Animals, Newborn , Epinephrine/pharmacology , Female , Glucagon/pharmacology , Heart/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Liver/drug effects , Liver Glycogen/metabolism , Microscopy, Electron , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/ultrastructure , Pregnancy , Rats , Rats, Wistar , Sirolimus/pharmacologyABSTRACT
The effects of rapamycin on glycogen autophagy in the newborn rat liver were studied using biochemical determinations, electron microscopy, and morphometric analysis. Rapamycin increased the fractional volume of hepatocytic autophagic vacuoles, the liver lysosomal glycogen-hydrolyzing activity of acid glucosidase, the degradation of glycogen inside the autophagic vacuoles, and decreased the activity of acid mannose 6-phosphatase. These findings suggest that rapamycin, a known inhibitor of the mammalian target of rapamycin (mTOR) signaling, induces glycogen autophagy in the newborn rat hepatocytes. mTOR may participate in the regulation of this process.
Subject(s)
Autophagy/drug effects , Immunosuppressive Agents/pharmacology , Liver Glycogen/metabolism , Liver/drug effects , Sirolimus/pharmacology , Animals , Animals, Newborn , Liver/metabolism , Liver/ultrastructure , Microscopy, Electron , RatsABSTRACT
The effects of glucagon on the ultrastructural appearance and acid glucosidase activities in the liver and heart of newborn rats were studied. Liver or heart glycogen-hydrolyzing activity of acid glucosidase increased 3 hours after birth and gradually decreased from 3 to 9 hours. Maltose-hydrolyzing activity of acid glucosidase also rose 3 hours after birth, maintained a plateau between 3 and 6 hours, and fell at 9 hours. The administration of glucagon increased autophagic activity in the hepatocytes at the age of 6 hours. Glycogen inside the autophagic vacuoles was decreased, apparently due to the increased glycogen degradation. Glycogen-hydrolyzing activity was elevated in both the liver and the heart. Maltose-hydrolyzing activity was elevated in the liver, but not in the heart. The results of this study suggest that the glycogen-hydrolyzing and maltose-hydrolyzing activities of acid glucosidase are due to different enzymes. Glucagon's effect on the glycogen-hydrolyzing acid glucosidase activity and autophagosomal morphology is similar in both the liver and the heart.
Subject(s)
Autophagy/drug effects , Glucagon/pharmacology , Glycogen/metabolism , Liver/metabolism , Myocardium/metabolism , Protein Synthesis Inhibitors/pharmacology , Animals , Animals, Newborn , Glucosidases/metabolism , Heart/drug effects , Heart/physiology , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/ultrastructure , Liver/drug effects , Liver/ultrastructure , Maltose/metabolism , Microscopy, Electron , Myocardium/ultrastructure , Rats , Time FactorsABSTRACT
Peritoneal and bronchoalveolar macrophages activated in vitro by endotoxin, exhibit alterations in the acid phosphatase activity of cell lysates when certain hormones or autacoids are present in the culture medium. They also show morphological changes concerning general appearance and acid phosphatase cytochemistry. Certain agents known to increase the intracellular levels of cyclic AMP, such as dopamine and prostaglandin E2, decreased this enzyme activity in the lysates of peritoneal macrophages. Adrenalin had no effect on this activity at 14 hours, but was found to increase the activity in the culture medium at the initial hours of incubation. Glucagon decreased whereas insulin increased acid phosphatase activity in bronchoalveolar macrophages. Serotonin or histamine, known to activate phospholipase C, increased this activity in peritoneal or bronchoalveolar macrophages. The results of this study, taken together with previously published data (Kondomerkos et al., 2003), suggest that hormones and autacoids may control certain parameters of macrophage activation including acid phosphatase activity.
Subject(s)
Acid Phosphatase/metabolism , Autacoids/pharmacology , Endotoxins/pharmacology , Hormones/pharmacology , Macrophages, Alveolar/enzymology , Macrophages, Peritoneal/enzymology , Acid Phosphatase/antagonists & inhibitors , Animals , Cells, Cultured , Coloring Agents , Culture Media , Cyclic AMP/physiology , Enzyme Inhibitors/pharmacology , Female , Hematoxylin , Hydrogen Peroxide/metabolism , In Vitro Techniques , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/ultrastructure , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/ultrastructure , Male , Rats , Rats, Wistar , Type C Phospholipases/physiologyABSTRACT
Peritoneal macrophages activated in vitro by endotoxin exhibit alterations of their capability to produce hydrogen peroxide after phorbol ester stimulation when certain hormones or autacoids are present in the culture medium. They also show morphological changes, mainly concerning cell size and nuclear appearance. Agents known to increase the intracellular levels of cyclic AMP, e.g. adrenalin and PGE2 reduce the hydrogen peroxide production. Insulin, which is known to decrease cyclic AMP levels, produces opposite results. Agents postulated to act via phospholipase C, e.g. serotonin, augment the production of hydrogen peroxide. We assume that this form of modulation may represent a regulatory mechanism of macrophage activation.
