The biosynthesis and secretion of human interleukin-6 (IL-6) was studied in monocyte cultures stimulated with endotoxin.
Type III hyperlipoproteinemia (HLP) is a multifactorial disorder associated with homozygosity for the apolipoprotein (apo) E-2 allele. Factors which may promote the development of HLP include lipoprotein lipase (LPL) and hyperinsulinemia. These factors were investigated in eight patients with type III HLP and in nine normolipidemic controls. In vitro the interaction of apoE with LPL was analyzed in cell binding assays. All type III HLP patients showed delayed triglyceride (TG) clearance and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparable to apoE3/3 controls. HLP patients showed lower LPL activity and mass than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mutation in three patients and a -93 T-G substitution combined with an Asp 9-->Asn mutation in one control subject. In addition to LPL abnormalities, postprandial hyperinsulinemia was observed in five out of eight patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven out of eight patients with type III HLP showed LPL abnormalities and/or postprandial hyperinsulinemia. Together with the in vitro data these findings support a coordinate effect of apoE and LPL for the manifestation of type III HLP. Hyperinsulinemia appears to be an additional factor important for disease expression.
The initial plasma clearance and organ distribution of al-acid glycoprotein and a,-macroglobulin carrying different types of oligosaccharide, side chains was studied in rats. The differently glycosylated proteins were synthesized by rat hepatocytes in culture in the presence of tunicamycin (unglycosylated form), swainsonine (hybrid type), or 1 -deoxymannojirimycin (high-mannose type). Deglycosylated glycoproteins (Asn-GlcNAc) were obtained by endoglucosaminidase H treatment of high-mannose-type glycoproteins.Ten minutes after intravenous injection 3% of complex type, 26% of hybrid type, 84% of high-mannose type. 64% of unglycosylated and 80% of deglycosylated al-acid glycoprotein disappeared from the plasma. The respective values for a,-macroglobulin were 26%, 42%, 59% and 67%. When the clearance of total hepatic secretory proteins was examined, major differences between glycosylated and unglycosylated (g1yco)proteins were found, particularly in the case of low-molecular-mass polypeptides.Whereas complex-type a,-acid glycoprotein and a,-macroglobulin showed no accumulation in various organs, hybrid-type al-acid glycoprotein and a,-macroglobulin were present in spleen and liver. High-mannose-type a,-acid glycoprotein and a,-macroglobulin also accumulated mainly in spleen and liver. Spleen had the highest specific activity; liver, due to its larger organ mass, represented the major organ for the uptake of high-mannosetype glycoproteins. Competition experiments with mannan and GlcNAc -bovine-serum-albumin showed a mannose/GlcNAc receptor-mediated removal. Whereas unglycosylated a,-acid glycoprotein was taken up by the kidney, unglycosylated clz-macroglobulin was found in the spleen. Deglycosylated glycoproteins (Asn-GlcNAc) were removed from the plasma via two different mechanisms: firstly, clearance by the kidney similar to the unglycosylated glycoproteins ; secondly, clearance by a mannose/GlcNAc receptor-mediated uptake mainly into the spleen.We conclude that N-linked oligosaccharide side chains are important for the plasma survival of hepatic secretory glycoproteins and that unphysiologically glycosylated forms are cleared by different mechanisms.A general mechanism for the clearance of plasma proteins does not exist. Several clearance systems have been described for specific proteins, for example complexes of al-proteinase inhibitor with proteases [I] or of a,-macroglobulin with proteases [2, 31 are more rapidly cleared than the native protease inhibitors. Aldehyde-modified proteins are taken up by a scavenger receptor on macrophages or macrophage-derived cells Most plasma proteins are glycoproteins carrying N-linked oligosaccharide side chains of the complex type. Two types of reactions involved in the clearance of glycoproteins modified in their oligosaccharide side chains have been described. Galactose-terminated (asia1o)-glycoproteins are removed from the circulation by a specific hepatocyte receptor [8, 91. Glycoproteins terminated by mannose, N-acetyl-glucosamine or fucose are recognized by a receptor ...
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