title: Systemic effects of AGEs in ER stress induction in vivo.
abstract: Emerging evidence indicates that accumulation of advanced glycation end products (AGEs) in human tissues may contribute to cell injury, inflammation and apoptosis through induction of endoplasmic reticulum (ER) stress. Human metabolism relies on ER homeostasis for the coordinated response of all metabolic organs by controlling the synthesis and catabolism of various nutrients. In vitro studies have demonstrated AGE-induced enhancement of unfolded protein response (UPR) in different cell types including endothelial, neuronal, pancreatic cells and podocytes, suggesting this crosstalk as an underlying pathological mechanism that contributes to metabolic diseases. In this minireview, we describe in vivo studies undertaken by our group and others that demonstrate the diverse systemic effects of AGEs in ER stress induction in major metabolic tissues such as brain, kidney, liver and pancreas of normal mice. Administration of high-AGEs content diet to normal mice for the period of 4 weeks upergulates the mRNA and protein levels of ER chaperone Bip (GRP78) indicative of UPR initiation in all major metabolic organs and induces activation of the pivotal transcription factor XBP1 that regulates glucose and lipid metabolism. Furthermore, animals with genetic ablation of UPR-activated transcription factor C/EBP homologous protein CHOP allocated in high-AGEs diet, exhibited relative resistance to UPR induction (BiP levels) and XBP1 activation in major metabolic organs. Since CHOP presents a critical mediator that links accumulation and aggregation of unfolded proteins with induction of oxidative stress and ER stress-related apoptosis, it is revealed as an important molecular target for the management of metabolic diseases.
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Chrysovalantou
authors.initials: C
authors.lastname: Mihailidou
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Christofora
authors.initials: C
authors.lastname: Grivaki
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Kostas A
authors.initials: KA
authors.lastname: Papavassiliou
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Hippokratis
authors.initials: H
authors.lastname: Kiaris
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece. cpiperi@med.uoa.gr.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.affiliation: Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75, M. Asias Street, 11527, Athens, Greece.
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D056811:Unfolded Protein Response / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1 / Q000096:biosynthesis
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse
keywords: AGEs; BiP; CHOP; ER-stress; UPR; XBP1