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Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation.
Arterioscler Thromb Vasc Biol. 2005 Mar; 25(3):571-7.AT

Abstract

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.

CONCLUSIONS

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.

Authors+Show Affiliations

Division of Clinical Biochemistry, Department of Laboratory Medicine & Pathobiology, Hospital for Sick Children, University of Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15618547

Citation

Qiu, Wei, et al. "Glucosamine-induced Endoplasmic Reticulum Stress Promotes ApoB100 Degradation: Evidence for Grp78-mediated Targeting to Proteasomal Degradation." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 3, 2005, pp. 571-7.
Qiu W, Kohen-Avramoglu R, Mhapsekar S, et al. Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation. Arterioscler Thromb Vasc Biol. 2005;25(3):571-7.
Qiu, W., Kohen-Avramoglu, R., Mhapsekar, S., Tsai, J., Austin, R. C., & Adeli, K. (2005). Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(3), 571-7.
Qiu W, et al. Glucosamine-induced Endoplasmic Reticulum Stress Promotes ApoB100 Degradation: Evidence for Grp78-mediated Targeting to Proteasomal Degradation. Arterioscler Thromb Vasc Biol. 2005;25(3):571-7. PubMed PMID: 15618547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucosamine-induced endoplasmic reticulum stress promotes ApoB100 degradation: evidence for Grp78-mediated targeting to proteasomal degradation. AU - Qiu,Wei, AU - Kohen-Avramoglu,Rita, AU - Mhapsekar,Shailen, AU - Tsai,Julie, AU - Austin,Richard C, AU - Adeli,Khosrow, Y1 - 2004/12/23/ PY - 2004/12/25/pubmed PY - 2005/11/9/medline PY - 2004/12/25/entrez SP - 571 EP - 7 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 25 IS - 3 N2 - 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. CONCLUSIONS: 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/15618547/Glucosamine_induced_endoplasmic_reticulum_stress_promotes_ApoB100_degradation:_evidence_for_Grp78_mediated_targeting_to_proteasomal_degradation_ L2 - https://www.ahajournals.org/doi/10.1161/01.ATV.0000154142.61859.94?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -