Serum glycoproteins in the liver diseases. V. Desialylated glycoproteins in chronic hepatitis

The membranes of the liver cell have been described as a protein mosaic within a lipid bilayer. Among the various pieces in this design are receptor proteins capable of recognizing and binding specific ligands. These receptors define much of the differentiated state of hepatocytes providing them with many specific functions. One of the most extensively studied of these receptor proteins is the hepatic binding protein or HBP. This membrane glycoprotein is responsible for the endocytosis of galactose-terminating glycoproteins leading to their lysosomal catabolism. While no physiologic function has yet been ascribed to HBP, its study has provided many insights into the biology and pathobiology of the liver. DISCOVERYThe path that led to discovery of HBP began with the development of a novel procedure to incorporate tritium selectively into the galactosyl residues of serum glycoprotein (1). Since most serum glycoproteins' carbohydrate moieties terminate in sialic acid, this residue was enzymatically removed to expose the penultimate galactose. The desialylated glycoproteins were then treated with galactose oxidase to yield an active aldehyde group in their galactosyl residues which could be reduced with tritiated borohydride. Application of this procedure to the serum copper-protein, ceruloplasmin, yielded a preparation which was indistinguishable from the native protein except, of course, for the absence of sialic acid. However, when this desialylated glycoprotein was injected, it no longer was viable in the circulation (2).The penultimate galactosyl residues, exposed by removal of sialic acid, were shown to be the critical determinants of this rapid clearance phenomena (3, 4). Enzymatic oxidation or removal of the terminal galactosyl residues significantly prolonged the intravascular survival of desialylated ceruloplasmin. The unique nature of this model was extended beyond galactose-directed clearance by the observation that sequestration of desiAddress reprint requests to: Richard J. Stockert, Ph.D., Ullmann, Room 517,

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The role of capillarization in hepatic failure: Studies in carbon tetrachloride-induced cirrhosis

Martínez-Hernández

Martinez

1991

Hepatology

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During the cirrhotic process, the hepatic microvascular phenotype is transformed from sinusoids (discontinuous capillaries) into continuous capillaries. This transformation has been termed capillarization. Many hepatic functions depend on the rapid, bidirectional exchange of macromolecules between plasma and hepatocytes. To determine whether capillarization contributes to hepatic failure in cirrhosis, we decided to study the plasma clearance (125I) and hepatocyte uptake (electron microscopy) of three tracers in normal and cirrhotic rats. The tracers chosen were a hemeundecapeptide with peroxidatic activity (fluid-phase pinocytosis), asialofetuin (receptor-mediated endocytosis of a medium size protein) and ferritin (receptor-mediated endocytosis of a large size protein). The results demonstrate a decreased hepatocyte uptake of hemeundecapeptide; a significant delay in plasma clearance of asialofetuin; and a minor delay in plasma clearance of ferritin, but a striking trapping of ferritin in the cirrhotic capillary basement membrane. The delayed plasma clearance in cirrhosis cannot be ascribed to a decreased number of surface receptors because, in isolated hepatocytes, the number of molecules bound per cell was equivalent in normal and cirrhotic livers. These findings support the concept of capillarization, with the formation of continuous diffusion and filtration barriers between plasma and hepatocytes, representing a significant hindrance to the bidirectional macromolecular exchange normally taking place between these two compartments. Furthermore, at least in the case of ferritin, the capillary basement membrane of cirrhotic livers seems to be the major filtration barrier. This hindrance to hepatocyte uptake, and presumably also to secretion, may be the cause (or at least a major determinant) of the hepatic failure characteristic of cirrhosis.

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Serum glycoproteins in the liver diseases. V. Desialylated glycoproteins in chronic hepatitis

Cited by 7 publications

References 7 publications

Hepatic Recognition and Catabolism of Serum Glycoproteins

Hepatic Recognition and Catabolism of Serum Glycoproteins

Hepatic Binding Protein: The Galactose-Specific Receptor of Mammalian Hepatocytes

The role of capillarization in hepatic failure: Studies in carbon tetrachloride-induced cirrhosis

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