RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

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 <i>Ager</i> null and wild-type (WT) mice, or THP-1 transfected with siRNA-<i>AGER,</i> 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 <i>Ager</i> null cells, in which the cholesterol efflux and lipid staining were, respectively, higher and lower when compared to WT cells. In WT, <i>Ager</i>, <i>Nox4</i> and <i>Nfkb1,</i> mRNA increased and <i>Scd1</i> and <i>Abcg1</i> diminished after treatment with DM1 and DM2 albumin. In <i>Ager</i> null cells treated with DM-albumin, <i>Nox4</i>, <i>Scd1</i> and <i>Nfkb1</i> were reduced and <i>Jak2</i> and <i>Abcg1</i> increased. In <i>AGER</i>-silenced THP-1, <i>NOX4</i> and <i>SCD1</i> mRNA were reduced and <i>JAK2</i> and <i>ABCG1</i> were increased even after treatment with AGE or DM-albumin. RAGE mediates the deleterious effects of AGE-albumin in macrophage cholesterol efflux.