title: Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha.
abstract: BACKGROUND
  In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood.
  
  
  RESULTS
  Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages.
  
  
  CONCLUSIONS
  Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1.
authors.affiliation: Department of Physiology, National Yang-Ming University, Taipei 112, Taiwan. tslee@ym.edu.tw
authors.forename: Kuo-Yun
authors.initials: KY
authors.lastname: Lu
authors.forename: Li-Chieh
authors.initials: LC
authors.lastname: Ching
authors.forename: Kuo-Hui
authors.initials: KH
authors.lastname: Su
authors.forename: Yuan-Bin
authors.initials: YB
authors.lastname: Yu
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Yu-Chu
authors.initials: YC
authors.lastname: Huang
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Cheng
authors.forename: Ching-Chian
authors.initials: CC
authors.lastname: Pan
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004921:Erythropoietin / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000096:biosynthesis; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics
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; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002316:Cardiotonic Agents; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; C099252:oxidized low density lipoprotein; D004921:Erythropoietin