Factors affecting the metabolic control of cytosolic and lysosomal glycogen levels in the liver

Abstract

Although glycogen is a chemically homogeneous material it is polydisperse, exhibiting a broad molecular weight spectrum and a metabolic lability that is molecular weight dependent. The lower molecular weight (β-particle) glycogen was found to be extremely labile, while the higher molecular weight (α-particle) exhibited a far lower metabolic activity, indicating that it may act as a glycogen store for mobilisation in stress situations. These observations, coupled to the existence of Pompe’s Disease, a glycogen storage disease involving the lysosomal system, supports the hypothesis that α - and β -particulate glycogen may be partially separated from one another within the cell i.e. compartmentalised. By the use of a rapid differential centrifugation technique it was possible to show, both physiochemically and ultrastructurally, the existence of glycogen of a very large molecular size associated with the lysosomal fraction. This glycogen exhibited a different molecular weight distribution from that isolate from the liver as a whole i.e. cytosol + lysosomal. It is suggested that appreciably more than 10% of cellular glycogen is located within the lysosomes and that this is of predominantly high molecular weight. The size-distribution of liver glycogen was shown to be distinctly affected by the anti-inflammatory drugs, salicylate and Indomethacin. By measurement of the incorporation of radioactive glucose into glycogen, salicylate was shown to have a depressing effect on overall liver glycogen metabolism. These effects appear to arise from a stabilisation of the lysosomal membrane by the drugs. The incorporation, via liposomes, of purified anti-1,4-α-glucosidase antibodies into the liver lysosomes of normal Wistar rats and rats with a genetic deficiency of phosphorylase kinase, caused a distinct decrease in 1,4-α-glucosidase activity and in the content of high molecular weight glycogen. These changes were enhanced by prolonged liposomal-antibody treatment and suggested that a possible feedback control mechanism operates in the incorporation of glycogen into lysosomes. The 1-4- α -glucosidase inhibitor, Acarbose, when injected intraperitoneally into normal and phosphorylase kinase-deficient rats similarly disturbed liver lysosomal metabolism, causing distinct and persistent inhibition of enzymes and acute disturbances of lysosomal glycogen metabolism. Again a feedback control mechanism appears to operate, which effects cytosolic carbohydrate metabolism. The biochemical effects closely resembled those occurring in Pompe’s disease and were confirmed by electron microscopy. A model for the adult form of the lysosomal storage disease has been suggested.