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A more recent version of this article appeared on August 1, 2006

Papers In Press, published online ahead of print May 3, 2006
J. Lipid Res., doi:10.1194/jlr.M500363-JLR200
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Submitted on August 11, 2005
Revised on April 26, 2006
Accepted on May 3, 2006

Mechanisms of glucosamine-induced suppression of hepatic assembly and secretion of apolipoprotein B100-containing lipoproteins

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

Clinical Biochemistry, Hospital for Sick Children, Toronto, Ontario M5G1X8

Corresponding Author: khosrow.adeli{at}sickkids.ca

Glucosamine-induced endoplasmic reticulum (ER) stress was recently shown to specifically reduce apolipoprotein B100 (apoB100) secretion by enhancing proteasomal degradation of apoB100 in cultured hepatocytes. In the present study, we have examined the mechanisms linking glucosamine-induced ER stress and apoB-lipoprotein biogenesis. Trypsin sensitivity studies of radiolabeled apoB100 showed different fragmentation patterns for untreated and glucosamine-treated HepG2 cells, suggesting glucosamine-induced changes in apoB100 conformation. Endoglycosidase H studies of newly-synthesized apoB100 revealed glucosamine induced N-linked glycosylation defects resulting in reduced apoB100 secretion. We also examined glucosamine-induced changes in VLDL assembly and secretion. Following 16 h glucosamine treatment, there was a dose-dependent reduction in VLDL-apoB100 secretion in primary hepatocytes (24.2-67.3% at 1-10 mM doses) and rat McA-RH7777 cells (23.2-89.5% at 1-10 mM doses). Glucosamine also inhibited the assembly of larger VLDL-apoB100, as well as LDL-apoB100 and IDL-apoB100 particles, but did not affect smaller HDL-size apoB100 particles. The formation of apoB48-containing lipoproteins in McA-RH7777 cells was unchanged by glucosamine treatment, suggesting that the glucosamine effect was specific to the assembly of larger apoB100 molecules. Glucosamine treatment during the chase period (post-translational) led to a 24% reduction in apoB100 secretion (p < 0.01, n=4) and appeared to promote post-ER apoB degradation. However, it should be noted that the contribution of post-ER apoB100 degradation is only observed in the absence of proteosomal activity and is quantitatively minor. Interestingly, the glucosamine-induced post-translational reduction in apoB100 secretion by primary hamster hepatocytes could be partially prevented by treatment with desferrioxamine or vitamin E. Taken together, these data suggest that co-translational glucosamine treatment may cause defects in apoB100 N-linked glycosylation and folding, resulting in enhanced proteasomal degradation. Post-translationally, glucosamine may interfere with the assembly process of VLDL, IDL, and LDL lipoprotein subclasess, leading to post-ER degradation via non-proteasomal pathways.


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