title: In type 2 diabetes mellitus glycated albumin alters macrophage gene expression impairing ABCA1-mediated cholesterol efflux.
abstract: Advanced glycation end products (AGE) are elevated in diabetes mellitus (DM) and predict the development of atherosclerosis. AGE-albumin induces oxidative stress, which is linked to a reduction in ABCA-1 and cholesterol efflux. We characterized the glycation level of human serum albumin (HSA) isolated from poorly controlled DM2 (n = 11) patients compared with that of control (C, n = 12) individuals and determined the mechanism by which DM2-HSA can interfere in macrophage lipid accumulation. The HSA glycation level was analyzed by MALDI/MS. Macrophages were treated for 18 h with C- or DM2-HSA to measure the (14) C-cholesterol efflux, the intracellular lipid accumulation and the cellular ABCA-1 protein content. Agilent arrays (44000 probes) were used to analyze gene expression, and the differentially expressed genes were validated by real-time RT-PCR. An increased mean mass was observed in DM2-HSA compared with C-HSA, reflecting the condensation of at least 5 units of glucose. The cholesterol efflux mediated by apo AI, HDL3 , and HDL2 was impaired in DM2-HSA-treated cells, which was related to greater intracellular lipid accumulation. DM2-HSA decreased Abcg1 mRNA expression by 26%. Abca1 mRNA was unchanged, although the final ABCA-1 protein content decreased. Compared with C-HAS-treated cells, NADPH oxidase 4 mRNA expression increased in cells after DM2-HSA treatment. Stearoyl-Coenzyme A desaturase 1, janus kinase 2, and low density lipoprotein receptor mRNAs were reduced by DM2-HSA. The level of glycation that occurs in vivo in DM2-HSA-treated cells selectively alters macrophage gene expression, impairing cholesterol efflux and eliciting intracellular lipid accumulation, which contribute to atherogenesis, in individuals with DM2.
authors.affiliation: Lipids Laboratory (LIM 10), Faculty of Medical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Machado-Lima
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Iborra
authors.forename: Raphael S
authors.initials: RS
authors.lastname: Pinto
authors.forename: Gabriela
authors.initials: G
authors.lastname: Castilho
authors.forename: Camila H
authors.initials: CH
authors.lastname: Sartori
authors.forename: Erika R
authors.initials: ER
authors.lastname: Oliveira
authors.forename: Ligia S
authors.initials: LS
authors.lastname: Okuda
authors.forename: Edna R
authors.initials: ER
authors.lastname: Nakandakare
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto
authors.forename: Ubiratan F
authors.initials: UF
authors.lastname: Machado
authors.forename: Maria Lucia C
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.forename: Pietro
authors.initials: P
authors.lastname: Traldi
authors.forename: Simona
authors.initials: S
authors.lastname: Porcu
authors.forename: Marco
authors.initials: M
authors.lastname: Roverso
authors.forename: Annunziata
authors.initials: A
authors.lastname: Lapolla
authors.forename: Marisa
authors.initials: M
authors.lastname: Passarelli
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000328:Adult; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D017127:Glycation End Products, Advanced; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D012709:Serum Albumin / Q000235:genetics / Q000378:metabolism*; D000093423:Glycated Serum Albumin
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D002784:Cholesterol; D000093423:Glycated Serum Albumin