title: Resistin increases lipid accumulation by affecting class A scavenger receptor, CD36 and ATP-binding cassette transporter-A1 in macrophages.
abstract: OBJECTIVE
  Resistin promotes macrophage-foam cell formation, but the mechanisms are unclear. In macrophages, lipid uptake is regulated by scavenger receptors (SR-A and CD36), while the cholesterol efflux is regulated by SR-BI, ATP-binding cassette transporter-A1 (ABCA1) and ABCG1. We investigated the mechanisms underlying the dysregulation by resistin of these regulators leading to promotion of lipid accumulation in bone marrow-derived macrophages.
  
  
  METHODS
  Western blotting, real-time PCR and oil red O staining were performed.
  
  
  RESULTS
  Resistin exacerbated lipid accumulation in oxLDL-treated macrophages. Resistin treatment of oxLDL-untreated macrophages showed increased SR-A and CD36 mRNA and protein levels, and decreased ABCA1 protein level, while having no effect on SR-BI or ABCG1 expression. Up-regulation of SR-A and CD36 by resistin resulted from activation of AP-1 and PPARgamma, respectively, and this was confirmed by the lack of activation of either after AP-1 inhibition using curcumin or SP600125, or PPARgamma inhibition using GW9662, respectively. The down-regulation of ABCA1 by resistin was not accompanied by a reduced mRNA level or an activation of LXRalpha/RXR, but resulted from enhanced protein degradation as revealed by the abolition of the down-regulation after inhibition of the proteasome pathway using ALLN or MG-132. A combined inhibition by SP600125, GW9662 and ALLN prevented resistin-induced exacerbation of lipid accumulation in oxLDL-treated macrophages.
  
  
  CONCLUSIONS
  Resistin promotes foam cell formation via dysregulation of SR-A, CD36 and ABCA1. SR-A and CD36 are transcriptionally up-regulated by resistin through AP-1 and PPARgamma, respectively, whereas ABCA1 is down-regulated by resistin through proteasome-mediated enhancement of protein degradation.
authors.affiliation: Institute of Physiology, School of Medicine, National Yang-Ming University, Taiwan.
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.forename: Chun-Yueh
authors.initials: CY
authors.lastname: Lin
authors.forename: Jin-Yi
authors.initials: JY
authors.lastname: Tsai
authors.forename: Yuh-Lin
authors.initials: YL
authors.lastname: Wu
authors.forename: Kuo-Hui
authors.initials: KH
authors.lastname: Su
authors.forename: Kuo-Yun
authors.initials: KY
authors.lastname: Lu
authors.forename: Sheng-Huang
authors.initials: SH
authors.lastname: Hsiao
authors.forename: Ching-Chian
authors.initials: CC
authors.lastname: Pan
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.forename: Yung-Pei
authors.initials: YP
authors.lastname: Hsu
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D018955:CD36 Antigens / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; C008132:Cd36 protein, rat; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D052243:Resistin; C499622:Retn protein, rat; D051117:Scavenger Receptors, Class A; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D046988:Proteasome Endopeptidase Complex