RAGE Suppresses ABCG1-Mediated Macrophage Cholesterol Efflux in Diabetes

Diabetes. 2015 Dec;64(12):4046-60. doi: 10.2337/db15-0575. Epub 2015 Aug 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Aorta / immunology
  • Aorta / metabolism
  • Aorta / pathology
  • Biological Transport
  • Cell Line
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Diabetic Angiopathies / blood
  • Diabetic Angiopathies / immunology
  • Diabetic Angiopathies / metabolism*
  • Diabetic Angiopathies / pathology
  • Glycation End Products, Advanced / blood
  • Glycation End Products, Advanced / metabolism*
  • Humans
  • Ligands
  • Lipoproteins / antagonists & inhibitors
  • Lipoproteins / genetics
  • Lipoproteins / metabolism
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice, Knockout
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Plaque, Atherosclerotic / blood
  • Plaque, Atherosclerotic / immunology
  • Plaque, Atherosclerotic / metabolism
  • Plaque, Atherosclerotic / pathology
  • Promoter Regions, Genetic
  • Receptor for Advanced Glycation End Products / agonists*
  • Receptor for Advanced Glycation End Products / blood
  • Receptor for Advanced Glycation End Products / genetics
  • Receptor for Advanced Glycation End Products / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • ABCG1 protein, human
  • ABCG1 protein, mouse
  • AGER protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Ager protein, mouse
  • Glycation End Products, Advanced
  • Ligands
  • Lipoproteins
  • PPAR gamma
  • Receptor for Advanced Glycation End Products
  • Recombinant Proteins
  • Cholesterol