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Journal of Lipid Research, Vol. 50, 1814-1823, September 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling

Wei Qiu, Qiaozhu Su, Angela C. Rutledge, Jing Zhang and Khosrow Adeli¹

Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Ontario, M5G 1X8, Canada

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

Glucosamine impairs hepatic apolipoprotein B100 (apoB100) production by inducing endoplasmic reticulum (ER) stress and enhancing cotranslational and posttranslational apoB100 degradation (Qiu, W., R. K. Avramoglu, A. C. Rutledge, J. Tsai, and K. Adeli. Mechanisms of glucosamine-induced suppression of the hepatic assembly and secretion of apolipoprotein B-100-containing lipoproteins. J. Lipid Res. 2006. 47: 1749–1761). Here, we report that glucosamine also regulates apoB100 protein synthesis via ER-stress-induced PERK activation. Short-term (4 h) glucosamine treatment of HepG2 cells reduced both cellular (by 62%) and secreted apoB100 (by 43%) without altering apoB100 mRNA. Treatment with proteasomal inhibitors only partially prevented the suppressive effects of glucosamine, suggesting that mechanisms other than proteasomal degradation may also be involved. Glucosamine-induced ER stress was associated with a significantly reduced apoB100 synthesis with no significant change in posttranslational decay rates, suggesting that glucosamine exerted its effect early during apoB biosynthesis. The role of PERK and its substrate, -subunit of eukaryotic initiation factor 2 (eIF2), in the suppressive effects of glucosamine on apoB synthesis was then investigated. Coexpression of apoB15 (normally resistant to intracellular degradation) with wild-type double stranded (ds) RNA activated protein kinase (PKR)-like endoplasmic reticulum kinase (PERK) in COS-7 cells resulted in a dramatic reduction in the levels of newly synthesized apoB15. Interestingly, cotransfection with apoB15 and a kinase inactive PERK mutant (K618A) increased apoB15 expression. In addition, short-term glucosamine treatment stimulated an increase in phosphorylation of PERK and eIF2. Taken together, these data suggest that in addition to the induction of ER-associated degradation and other degradative pathways, ER stress is associated with suppression of apoB synthesis via a PERK-dependent mechanism.

Supplementary key words -subunit of eukaryotic initiation factor 2 • glucose-regulated protein 78 • degradation

Abbreviations: ALLN, N-acetyl-leucinyl-leucinyl-nor-leucinal; apoB, apolipoprotein B; ATF, activating transcription factor; eIF2, -subunit of eukaryotic translational initiation factor 2; ER, endoplasmic reticulum; ERAD, endoplasmic-reticulum-associated degradation; IRE1, inositol requirement 1; lactacystin, clasto-lactocystin β-lactone; MTP, microsomal triglyceride transfer protein; PERK, PKR-like endoplasmic reticulum kinase; PKR, double stranded (ds) RNA activated protein kinase; WT, wild-type

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