Effects of inflammation and dexamethasone on various aspects of glycoprotein biosynthesis

Sarkar, Mohan Lal (1987) Effects of inflammation and dexamethasone on various aspects of glycoprotein biosynthesis. Doctoral (PhD) thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (29MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

The concentration of acute-phase proteins in plasma is significantly increased in response to inflammatory agents. Almost all acute-phase proteins are glycoproteins in which the carbohydrate moiety is attached to the peptide through an asparagine nitrogen and are synthesized via dolichol-linked intermediates. Dexamethasone, a potent synthetic glucocorticoid, has been shown to influence the biosynthesis of these acute-phase glycoproteins in experiments with animals and in vitro. -- This thesis concerns various aspects of the glycosylation of acute-phase proteins during inflammation and dexamethasone treatment in the rat. -- Turpentine-induced inflammation caused increased sialyl and galactosyltransferase activities in the liver, while in serum, only the sialyltransferase activity was increased. -- The formation of several dolichol-linked intermediates such as dolichol phosphate mannose, dolichol pyrophosphate N-acetyl chitobiose and dolichol pyrophosphate oligosaccharides was increased in cultured hepatocytes, or their homogenates, isolated from inflamed rats. Dexamethasone treatment of hepatocytes from control and inflamed animals also caused an increased formation of these intermediates. The increase in the formation of dolichol-linked intermediates in inflammation was attributed to increased endogenous dolichol phosphate levels. In contrast, the increased levels of the intermediates in dexamethasone treatment were not due to the endogenous dolichol phosphate but were most likely due to the induction of glycosyltransferases involved in glycoprotein biosynthesis. These conclusions were based on the results obtained from the following experiments: 1) estimation of the endogenous dolichol phosphate, 2) formation of dolichol phosphate mannose in presence of increasing amounts of exogenous dolichol phosphate, and 3) formation of dolichol and dolichol phosphate from mevalonate. -- Experiments in hepatocytes with actinomycin D and cycloheximide suggested that the increase in dolichol-linked intermediates was dependent on the increased synthesis of glycosylatable polypeptides of the acute-phase proteins. -- Nucleotide sugar pyrophosphatase activities were increased only in dexamethasone treated hepatocytes, whereas, the nucleotide sugar levels remained unaltered during both inflammation and dexamethasone treatment. The present study showing increased synthesis of dolichol-linked intermediates during the biosynthesis of acute-phase proteins in response to inflammation and dexamethasone treatment has provided new information on the role of the dolichol pathway in glycoprotein synthesis.

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