title: CD1d serves as a surface receptor for oxidized cholesterol induction of peroxisome proliferator-activated receptor-γ.
abstract: OBJECTIVE
  The cluster of differentiation-1d (CD1d) recognizes and presents the lipid antigens to NK-T lymphocytes. Atherosclerotic lesions contain atherogenic lipids, mainly cholesterol and its oxides. Peroxisome proliferator-activated receptor-γ (PPARγ) is also known to exist in atherosclerotic lesions, participating in regulation of lipid metabolism. The current study tested whether CD1d acts as a surface receptor that mediates induction and activation of PPARγ by oxysterols commonly found in atherosclerotic lesions.
  
  
  RESULTS
  CD1d overexpression in HEK 293 cells transfected with CD1d cDNA was confirmed by fluorescence, flow cytometry, Western blotting and mRNA expression. Tritiated ((3)H) 7-ketocholesterol (7K) was used for lipid binding assays. Radioactive assessment demonstrated an increased 7K-binding activity HEK 293 cells with CD1d overexpression. The 7K binding could be blocked by another oxysterol, 25-hydroxycholesterol, but not by native free cholesterol. Addition of CD1d:IgG dimer protein or an anti-CD1d antibody, but not control IgG, significantly diminished 7K binding to CD1d-expressing HEK 293 cells. CD1d deficiency markedly diminished the 7K-binding in macrophages and smooth muscle cells. Western blot and gel shift assays demonstrated that CD1d-mediated 7K binding induced expression and activation of PPARγ. The PPARγ agonist PGJ2 enhances the 7K stimulatory effect on PPARγ expression and activity but the antagonist GW9662 inhibits the 7K effect on the CD1d-expressing cells.
  
  
  CONCLUSIONS
  CD1d acts as a cell surface receptor that recognizes and binds oxysterols and initializes a pathway connecting oxysterol binding to PPARγ activation.
authors.affiliation: Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Health Science Center at Houston, USA.
authors.forename: Corina
authors.initials: C
authors.lastname: Rosales
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Daming
authors.initials: D
authors.lastname: Tang
authors.affiliation: Center for Cardiovascular Biology and Atherosclerosis Research, University of Texas Health Science Center at Houston, USA; Texas Heart Institute, Houston, TX 77030, USA. Electronic address: yong-jian.geng@uth.tmc.edu.
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism*; D050197:Atherosclerosis / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry*; D017931:DNA Primers / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D007653:Ketocholesterols / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000737:chemistry*; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D013261:Sterols / Q000737:chemistry
chemical_list: D055610:Antigens, CD1d; C526877:CD1D protein, human; D017931:DNA Primers; D006888:Hydroxycholesterols; D007074:Immunoglobulin G; D007653:Ketocholesterols; D008055:Lipids; D047495:PPAR gamma; D013261:Sterols; C007997:25-hydroxycholesterol; D002784:Cholesterol; C003001:7-ketocholesterol; D010100:Oxygen
keywords: Atherosclerosis; Lipid antigens; Oxysterols; PPARγ