AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages

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Iborra, Rodrigo Tallada ^[1] ; Machado-Lima, Adriana ^{[2, 1]} ; Okuda, Ligia Shimabukuro ^[1] ; Pinto, Paula Ramos ^[1] ; Nakandakare, Edna Regina ^[1] ; Machado, Ubiratan Fabres ^[3] ; Correa-Giannella, Maria Lucia ^{[4, 5]} ; Pickford, Russell ^[6] ; Woods, Tom ^[7] ; Brimble, Margaret A. ^[7] ; Rye, Kerry-Anne ^[8] ; Lu, Rui ^[9] ; Yokoyama, Shinji ^[9] ; Passarelli, Marisa ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Lipides, LIM 10, Av Dr Arnaldo 455, Room 3305, BR-01246000 Sao Paulo, SP - Brazil

^[2] Univ Sao Judas Tadeu, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Carboidratos & Radioimunoinsaio, LIM 18, Sao Paulo - Brazil

^[5] Univ Nove Julho, Programa posgrad Med, Sao Paulo - Brazil

^[6] Univ New South Wales, Bioanalyt Mass Spectrometry Facil, Sydney, NSW - Australia

^[7] Univ Auckland, Sch Chem Sci, Auckland - New Zealand

^[8] Univ New South Wales, Fac Med, Sch Med Sci, Lipid Res Grp, Sydney, NSW - Australia

^[9] Chubu Univ, Nutr Hlth Sci Res Ctr, Kasugai, Aichi - Japan

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF DIABETES AND ITS COMPLICATIONS; v. 32, n. 1, p. 1-10, JAN 2018.
• Citações Web of Science: 2

Resumo

Background and aims: Advanced glycation end products (AGEs) induce cellular oxidative/endoplasmic reticulum stress and inflammation. We investigated its underlying mechanisms for atherogenesis focusing on regulation of ABCA1 protein decay in macrophages. Methods: The ABCA1 decay rate was evaluated in macrophages after treatment with LXR agonist and by incubation with control (C) or AGE-albumin concomitant or not with cycloheximide, MG-132, ammonium chloride and calpain inhibitors were utilized to inhibit, respectively, proteasome, lysosome and ABCA1 proteolysis at cell surface. ABCA1 was determined by immunoblot and the protein decay rate calculated along time by the slope of the linear regression. Ubiquitination level was determined in ABCA1 immunoprecipitated from whole cell lysate or bulk cell membrane. AGE effect was also analyzed in THP-1 cells transfected with siRNA-RAGE. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/MS. One-way ANOVA and Student t test were utilized to compare results. Results: CML and PYR-albumin were higher in AGE-albumin as compared to C. AGE-albumin reduced ABCA1 in J774 and THP-1 macrophages (20-30%) and induced a higher ABCA1 ubiquitination and a faster protein decay rate that was dependent on the presence of AGE during the kinetics of measurement in the presence of cycloheximide. Proteasomal inhibition restored and lysosomal inhibition partially recovered ABCA1 in cells treated with AGE-albumin. Calpain inhibition was not able to rescue ABCA1. RAGE knockdown prevented the reduction in ABCA1 elicited by AGE. Conclusions: AGE-albumin.diminishes ABCA1 by accelerating its degradation through the proteasomal and lysosomal systems. This may increase lipid accumulation in macrophages by diminishing cholesterol efflux via RAGE signaling contributing to atherosclerosis in diabetes mellitus. (C) 2017 Elsevier Inc. All rights reserved. (AU)

• Processo FAPESP: 12/19112-0 - Participação do eixo rage/age sobre o acúmulo de lípides em macrófagos induzido por albumina modificada por glicação avançada - contribuição do controle glicêmico no diabete melito
• Beneficiário: Adriana Machado Saldiba de Lima
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/26256-1 - Tráfego intracelular do receptor de HDL ABCA-1 em macrófagos tratados com albumina modificada por glicação: a influência do controle glicêmico no transporte reverso de colesterol
• Beneficiário: Rodrigo Tallada Iborra
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 16/15603-0 - Desvendando mecanismos envolvidos no controle glicêmico e nas complicações crônicas do Diabetes mellitus: contribuições à saúde humana
• Beneficiário: Ubiratan Fabres Machado
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 12/12088-7 - Controle glicêmico e remoção de colesterol de macrófagos mediada por ABCA-1: papel da albumina modificada por glicação avançada
• Beneficiário: Rodrigo Tallada Iborra
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/02854-7 - Função anti-inflamatória da apolipoproteína A-IV no diabete melito e seu reflexo sobre o transporte reverso de colesterol de macrófagos: influência da modificação por glicação avançada
• Beneficiário: Ligia Shimabukuro Okuda
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/21072-5 - Influência do controle glicêmico ou do estágio da nefropatia sobre o transporte reverso de colesterol no Diabete melito: papel da memória metabólica induzida pela albumina modificada por glicação avançada
• Beneficiário: Marisa Passarelli
• Modalidade de apoio: Auxílio à Pesquisa - Regular