RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes

Abstract

Diabetes exacerbates cardiovascular disease, at least in part through suppression of macrophage cholesterol efflux and levels of the cholesterol transporters ATP binding cassette transporter A1 (ABCA1) and ABCG1. The receptor for advanced glycation end products (RAGE) is highly expressed in human and murine diabetic atherosclerotic plaques, particularly in macrophages. We tested the hypothesis that RAGE suppresses macrophage cholesterol efflux and probed the mechanisms by which RAGE downregulates ABCA1 and ABCG1. Macrophage cholesterol efflux to apolipoprotein A1 and HDL and reverse cholesterol transport to plasma, liver, and feces were reduced in diabetic macrophages through RAGE. In vitro, RAGE ligands suppressed ABCG1 and ABCA1 promoter luciferase activity and transcription of ABCG1 and ABCA1 through peroxisome proliferator–activated receptor-γ (PPARG)–responsive promoter elements but not through liver X receptor elements. Plasma levels of HDL were reduced in diabetic mice in a RAGE-dependent manner. Laser capture microdissected CD68+ macrophages from atherosclerotic plaques of Ldlr−/− mice devoid of Ager (RAGE) displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus Ager-expressing Ldlr−/− mice independently of glycemia or plasma levels of total cholesterol and triglycerides. Antagonism of RAGE may fill an important therapeutic gap in the treatment of diabetic macrovascular complications.

RAGE Against the ABCs

“…Laser-capture microdissection of CD68 + macrophages from atherosclerotic plaques of Ldlr 2/2 Rage 2/2 mice displayed higher levels of Abca1, Abcg1, and Pparg mRNA transcripts versus RAGE-expressing Ldlr 2/2 mice independent of glycemic and lipid control (12). However, a recent comparison revealed only Abca1 transcripts were suppressed in plaque macrophages from diabetic mice (3).…”

“…In vivo macrophage reverse cholesterol transport (RCT) studies reveal diabetes significantly impairs this process, which was restored when RAGE was deleted (12). Supporting the downregulation of ABCA1/G1, lower HDL levels are observed in diabetic mice and the deletion of RAGE returns HDL levels to normal.…”

“…1). While the experiments by Daffu et al (12) reveal that RAGE plays a role in suppressing ABCA1/G1 expression under normoglycemic conditions, nondiabetic Rage 2/2 mice display normal cholesterol levels, suggesting that this is perhaps specific to macrophages, which do not significantly contribute to the circulating pool of HDL (18).…”

“…Interestingly, restoration of ABCA1/G1 has no effect on the ability of macrophages to be retained or egress from the lesion and points to a major role in the influx of monocytes to the atherosclerotic plaque that should be considered when developing targets in the setting of diabetes (3). Nonetheless, Daffu et al (12) rightly conclude that the RAGE signaling axis may fill an important therapeutic gap in the treatment of diabetic macrovascular complications, particularly by this previously unexplored mechanism linking cholesterol metabolism. (12).…”

“…Nonetheless, Daffu et al (12) rightly conclude that the RAGE signaling axis may fill an important therapeutic gap in the treatment of diabetic macrovascular complications, particularly by this previously unexplored mechanism linking cholesterol metabolism. (12). In the setting of diabetes, RAGE ligands (i.e., AGE, S100A8/A9) become more abundant and there is enhanced RAGE expression on macrophages.…”