title: Ligation of RAGE with ligand S100B attenuates ABCA1 expression in monocytes.
abstract: OBJECTIVE
  ATP Binding Cassette Transporter (ABC) A1 is one of the key regulators of HDL synthesis and reverse cholesterol transport. Activation of Receptors for Advanced Glycation End products (RAGE) is involved in the pathogenesis of diabetes, and its complications. The aim of the present study is to examine the effect of RAGE ligand S100B on ABCA1 expression.
  
  
  METHODS
  S100B mediated regulation of LXR target genes like ABCA1, ABCG1, ABCG8, LXR-α and LXR-β in THP-1 cells was analyzed by real-time PCR, RT-PCR and western blots. ABCA1 mRNA expression in monocytes from diabetic patients was studied. Effect of LXR ligand on S100B induced changes in LXR target genes was also studied. Luciferase reporter assay was used for S100B induced ABCA1 promoter regulation.
  
  
  RESULTS
  S100B treatment resulted in a significant 2-3 fold reduction (p<0.01) in ABCA1 and ABCG1 mRNA in dose and time dependent manner in THP1 cells. ABCA1 protein level was also significantly (p<0.01) reduced. S100B-induced reduction on ABCA1 mRNA expression was blocked by treating THP-1 cell with anti-RAGE antibody. Reduced ABCA1 mRNA levels seen in peripheral blood monocytes from diabetes patients showed the in-vivo relevance of our in-vitro results. Effect of S100B on ABCA1 and ABCG1 expression was reversed by LXR ligand treatment. S100B treatment showed significant 2 fold (p<0.01) decrease in T1317 induced ABCA1 promoter activation.
  
  
  CONCLUSIONS
  These results show for the first time that ligation of RAGE with S100B can attenuate the expression of ABCA1 and ABCG1 through the LXRs. This could reduce ApoA-I-mediated cholesterol efflux from monocytes.
authors.affiliation: Diabetes and Cardiovascular Research Laboratory, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India.
authors.forename: Prabhakaran
authors.initials: P
authors.lastname: Kumar
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Raghavan
authors.forename: Gobinath
authors.initials: G
authors.lastname: Shanmugam
authors.forename: Narkunaraja
authors.initials: N
authors.lastname: Shanmugam
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D002469:Cell Separation; D003920:Diabetes Mellitus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D000071518:Liver X Receptors; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000235:genetics; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology*; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C416946:ABCG8 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D009414:Nerve Growth Factors; D057093:Orphan Nuclear Receptors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D012313:RNA; D008156:Luciferases
keywords: ABCA1; AGE; ATP-Binding Cassette transporter A1; Advanced Glycation end products; Diabetes; LDL; LXR; Liver X Receptors; THP-1 cells; low density lipoprotein