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Journal of Lipid Research, Vol. 47, 1749-1761, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Mechanisms of glucosamine-induced suppression of the hepatic assembly and secretion of apolipoprotein B-100-containing lipoproteins

Wei Qiu, Rita Kohen Avramoglu, Angela C. Rutledge, Julie Tsai and Khosrow Adeli¹

Division of Clinical Biochemistry, Department of Clinical Biochemistry and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Published, JLR Papers in Press, May 3, 2006.

¹ To whom correspondence should be addressed. e-mail: k.adeli{at}utoronto.ca

Glucosamine-induced endoplasmic reticulum (ER) stress was recently shown to specifically reduce apolipoprotein B-100 (apoB-100) secretion by enhancing the proteasomal degradation of apoB-100. Here, we examined the mechanisms linking glucosamine-induced ER stress and apoB-lipoprotein biogenesis. Trypsin sensitivity studies suggested glucosamine-induced changes in apoB-100 conformation. Endoglycosidase H studies of newly synthesized apoB-100 revealed glucosamine induced N-linked glycosylation defects resulting in reduced apoB-100 secretion. We also examined glucosamine-induced changes in VLDL assembly and secretion. A dose-dependent (1–10 mM glucosamine) reduction was observed in VLDL-apoB-100 secretion in primary hepatocytes (24.2–67.3%) and rat McA-RH7777 cells (23.2–89.5%). Glucosamine also inhibited the assembly of larger VLDL-, LDL-, and intermediate density lipoprotein-apoB-100 but did not affect smaller HDL-sized apoB-100 particles. Glucosamine treatment during the chase period (posttranslational) led to a 24% reduction in apoB-100 secretion (P < 0.01; n = 4) and promoted post-ER apoB degradation. However, the contribution of post-ER apoB-100 degradation appeared to be quantitatively minor. Interestingly, the glucosamine-induced posttranslational reduction in apoB-100 secretion could be partially prevented by treatment with desferrioxamine or vitamin E. Together, these data suggest that cotranslational glucosamine treatment may cause defects in apoB-100 N-linked glycosylation and folding, resulting in enhanced proteasomal degradation. Posttranslationally, glucosamine may interfere with the assembly process of apoB lipoproteins, leading to post-ER degradation via nonproteasomal pathways.

Supplementary key words very low density lipoprotein • hepatocytes • apolipoprotein B degredation • proteasome • glycosylation

Abbreviations: ALLN, N-acetyl-leucinyl-leucinyl-nor-leucinal; apoB-100, apolipoprotein B-100; BFA, brefeldin A; DFX, desferrioxamine; ER, endoplasmic reticulum; IDL, intermediate density lipoprotein; MTP, microsomal triglyceride transfer protein; PERPP, postendoplasmic reticulum presecretory proteolysis; TBARS, thiobarbituric acid-reactive substances

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