LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1.
Macrophages facilitate clearance of cholesterol from the body via reverse cholesterol transport (RCT). The first event in RCT is internalization of modified low density lipoprotein by macrophages, upon which PPARgamma1 and LXRalpha signaling pathways are turned on, leading to the transactivation of a cascade of genes (e.g. ABCA1 and ABCG1), whose products promote macrophage cholesterol efflux. Down-regulation of macrophage cholesterol efflux mediators leads to an imbalance in cholesterol homeostasis, promoting foam cell formation. Lipopolysaccharide (LPS) has been shown to suppress PPARgamma1 and its downstream target genes in macrophages, inducing foam cell formation; a key mechanism proposed to underlie bacterial infection-induced atherosclerosis. Herein, we show that adipocyte enhancer-binding protein 1 (AEBP1) is up-regulated during monocyte differentiation. Moreover, we provide experimental evidence suggesting that AEBP1 expression is induced by LPS, and that LPS-induced down-regulation of pivotal macrophage cholesterol efflux mediators, leading to foam cell formation, is largely mediated by AEBP1. Although AEBP1-independent pathways seem to contribute to these LPS effects, such pathways can only mediate lesser and delayed effects of LPS on macrophage cholesterol efflux and development of foam cells. We speculate that AEBP1 may serve as a potential therapeutic target for the prevention/treatment of bacterial infection-induced atherosclerosis.
Majdalawieh
Amin
A
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada.
Ro
Hyo-Sung
HS
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D039481:CD11b Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D016466:CHO Cells; D002268:Carboxypeptidases / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008074:Lipoproteins / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C112918:Aebp1 protein, mouse; D039481:CD11b Antigen; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D017455:Receptors, IgE; D012097:Repressor Proteins; D002784:Cholesterol; D002268:Carboxypeptidases