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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:571.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Glucosamine-Induced Endoplasmic Reticulum Stress Promotes ApoB100 Degradation

Evidence for Grp78-Mediated Targeting to Proteasomal Degradation

Wei Qiu; Rita Kohen-Avramoglu; Shailen Mhapsekar; Julie Tsai; Richard C. Austin; Khosrow Adeli

From the Division of Clinical Biochemistry (W.Q.,R.K.-A., S.M., J.T., K.A.), the Department of Laboratory Medicine & Pathobiology, Hospital for Sick Children, University of Toronto, Ontario, Canada; and the Department of Pathology and Molecular Medicine (R.C.A.), McMaster University, Hamilton, Ontario, Canada.

Correspondence to Khosrow Adeli, Division of Clinical Biochemistry, DPLM, Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8. E-mail k.adeli{at}utoronto.ca

Objective— To investigate the role of glucosamine-mediated endoplasmic reticulum (ER) stress and Grp78 (BiP) in the intracellular degradation of apolipoprotein B100 (apoB100) in cultured hepatocytes.

Methods and Results— Glucosamine treatment (2.5 to 10 mmol/L) of HepG2 cells increased levels of the ER chaperones, 78-kDa glucose-regulated protein (Grp78) and Grp94, in a dose-dependent manner and led to significant decreases in both cellular and secreted apoB100 by up to 97% (P<0.01). In contrast, no changes were observed in ER resident (ER60, PTP-1B) or secretory (albumin, apoE) control proteins. Glucosamine-induced apoB degradation was similarly observed in primary hamster hepatocytes and McA-RH7777 cells. Glucosamine treatment led to reduced tranlocational efficiency of apoB100 in the ER and enhanced its ubiquitination and proteasomal degradation. Adenoviral overexpression of Grp78 also led to significantly decreased levels of newly synthesized apoB100 in a dose-dependent manner (P<0.01). Grp78-induced downregulation of apoB100 was sensitive to inhibition by the proteasome inhibitor, lactacystin, but not lysosomal protease inhibitors, E64 and leupeptin, suggesting that overexpression of Grp78 selectively induced proteasomal degradation of apoB100.

Conclusion— These findings suggest that binding and retention by Grp78 may play a critical role in proteasomal targeting and the ER quality-control of misfolded apoB. Interaction with core lipoprotein lipids may facilitate apoB transport out of the ER by reducing Grp78-mediated ER retention.

The role of Grp78 (BiP) in the intracellular degradation of apolipoprotein B100 (apoB100) was investigated in cultured hepatocytes after glucosamine-induced ER stress and Grp78 overexpression. Our findings suggest that binding and retention by Grp78 may play a critical role in proteasomal targeting and the ER quality-control of misfolded apoB.

Key Words: apolipoprotein B • degradation • glucosamine • Grp78 • proteasome

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