title: ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - reversal by a chemical chaperone.
abstract: ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes.
authors.affiliation: Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Castilho
authors.forename: Ligia S
authors.initials: LS
authors.lastname: Okuda
authors.forename: Raphael S
authors.initials: RS
authors.lastname: Pinto
authors.forename: Rodgiro T
authors.initials: RT
authors.lastname: Iborra
authors.forename: Edna R
authors.initials: ER
authors.lastname: Nakandakare
authors.forename: Celio X
authors.initials: CX
authors.lastname: Santos
authors.forename: Francisco R
authors.initials: FR
authors.lastname: Laurindo
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D017127:Glycation End Products, Advanced; D015151:Immunoblotting; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018832:Molecular Chaperones / Q000494:pharmacology*; D012709:Serum Albumin / Q000494:pharmacology*; D000093423:Glycated Serum Albumin
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017127:Glycation End Products, Advanced; D018832:Molecular Chaperones; D012709:Serum Albumin; D000093423:Glycated Serum Albumin