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Journal of Lipid Research, Vol. 47, 1749-1761, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
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 (110 mM glucosamine) reduction was observed in VLDL-apoB-100 secretion in primary hepatocytes (24.267.3%) and rat McA-RH7777 cells (23.289.5%). 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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