title: 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.
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Gurdip
authors.initials: G
authors.lastname: Daffu
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Shen
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Laura
authors.initials: L
authors.lastname: Senatus
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Devi
authors.initials: D
authors.lastname: Thiagarajan
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Andisheh
authors.initials: A
authors.lastname: Abedini
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Carmen
authors.initials: C
authors.lastname: Hurtado Del Pozo
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, and Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.affiliation: Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY annmarie.schmidt@nyumc.org.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D000067759:Receptor for Advanced Glycation End Products / Q000819:agonists* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; C000593871:AGER protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C000593873:Ager protein, mouse; D017127:Glycation End Products, Advanced; D008024:Ligands; D008074:Lipoproteins; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D011994:Recombinant Proteins; D002784:Cholesterol