Abstract
We addressed the involvement of the receptor for advanced glycation end products (RAGE) in the impairment of the cellular cholesterol efflux elicited by glycated albumin. Albumin was isolated from type 1 (DM1) and type 2 (DM2) diabetes mellitus (HbA1c > 9%) and non-DM subjects (C). Moreover, albumin was glycated in vitro (AGE-albumin). Macrophages from Ager null and wild-type (WT) mice, or THP-1 transfected with siRNA-AGER, were treated with C, DM1, DM2, non-glycated or AGE-albumin. The cholesterol efflux was reduced in WT cells exposed to DM1 or DM2 albumin as compared to C, and the intracellular lipid content was increased. These events were not observed in Ager null cells, in which the cholesterol efflux and lipid staining were, respectively, higher and lower when compared to WT cells. In WT, Ager, Nox4 and Nfkb1, mRNA increased and Scd1 and Abcg1 diminished after treatment with DM1 and DM2 albumin. In Ager null cells treated with DM-albumin, Nox4, Scd1 and Nfkb1 were reduced and Jak2 and Abcg1 increased. In AGER-silenced THP-1, NOX4 and SCD1 mRNA were reduced and JAK2 and ABCG1 were increased even after treatment with AGE or DM-albumin. RAGE mediates the deleterious effects of AGE-albumin in macrophage cholesterol efflux.
Highlights
In diabetes mellitus (DM), disturbances in the reverse cholesterol transport (RCT) are related to the pathophysiology of atherosclerosis
By utilizing bone marrow-derived macrophages (BMDM) from Ager null mice and THP-1 cells with AGER knockdown, we demonstrate that receptor for advanced glycation end products (RAGE) mediates the reduction in cholesterol efflux induced by Advanced glycation end products (AGEs) albumin by modulating macrophage gene expression
In order to access the role of RAGE in the disturbances of cholesterol efflux elicited by glycated albumin drawn from those patients when compared to albumin from control subjects, bone marrow-derived macrophages (BMDM) from WT and Ager null mice were utilized after cholesterol overloading
Summary
In diabetes mellitus (DM), disturbances in the reverse cholesterol transport (RCT) are related to the pathophysiology of atherosclerosis. AGE adversely affects ABCA1 and G1-mediated cholesterol efflux [4,5] by reducing ABCA1 protein levels in macrophages without changing Abca mRNA [6,7]. We demonstrated that AGE albumin, isolated from both type 1 and 2 DM subjects’ serum, alters the transcription of genes involved in ABCA1 expression and activity in macrophages, such as Scd (Stearoyl-Coenzyme A desaturase 1), Jak (Janus kinase 2) and Nox (NADPH oxidase 4) [15,16], leading to intracellular lipid accumulation. We tested the hypothesis that AGER silencing suppresses the reduction in macrophage cholesterol efflux induced by AGE albumin and rescues the gene expression profile. By utilizing bone marrow-derived macrophages (BMDM) from Ager null mice and THP-1 cells with AGER knockdown, we demonstrate that RAGE mediates the reduction in cholesterol efflux induced by AGE albumin by modulating macrophage gene expression
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