title: Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin.
abstract: OBJECTIVE
  Atherosclerosis is characterized as a chronic inflammatory condition that involves cholesterol deposition in arteries. Together with scavenger receptor B1 (SR-B1), the ATP-binding cassette transporters ABCA1 and ABCG1 are the major components of macrophage cholesterol efflux. Recent studies have shown that low-grade inflammation plays a distinct regulatory role in the expression of SR-B1 and ABCA1/ABCG1. However, the mechanisms linking low-grade inflammation and cholesterol accumulation are poorly understood.
  
  
  RESULTS
  Using primary bone-marrow-derived macrophages, we demonstrate that subclinical low-dose lipopolysaccharide potently reduces the expression of SR-B1 and ABCA1/ABCG1, as well as cholesterol efflux from macrophages through interleukin-1 receptor-associated kinase 1 and Toll-interacting-protein. Low-dose lipopolysaccharide downregulates the nuclear levels of retinoic acid receptor-α, leading to their reduced binding to the promoters of SR-B1 and ABCA1/ABCG1. We observe that glycogen synthase kinase 3β activation by low-dose lipopolysaccharide through interleukin-1 receptor-associated kinase 1 and Toll-interacting-protein is responsible for reduced levels of retinoic acid receptor-α, and reduced expression of SR-B1 and ABCA1/ABCG1. Interleukin-1 receptor-associated kinase M, however, counteracts the function of interleukin-1 receptor associated kinase 1.
  
  
  CONCLUSIONS
  Collectively, our data reveal a novel intracellular network regulated by low-dose endotoxemia that disrupts cholesterol efflux from macrophages and leads to the pathogenesis of atherosclerosis.
authors.affiliation: Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Urmila
authors.initials: U
authors.lastname: Maitra
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004731:Endotoxins / Q000494:pharmacology* / Q000633:toxicity; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008074:Lipoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D051122:Scavenger Receptors, Class B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D004731:Endotoxins; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C485837:Tollip protein, mouse; C044101:endotoxin, Escherichia coli; D002784:Cholesterol; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507772:Irak3 protein, mouse; D038362:Glycogen Synthase Kinase 3