title: EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux.
abstract: OBJECTIVE
  The sterol-responsive nuclear receptors, liver X receptors α (LXRα,NR1H3) and β (LXRβ,NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transportersABCA1andABCG1to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study.
  
  
  RESULTS
  We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression ofEEPD1blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages.
  
  
  CONCLUSIONS
  In this study, we identifyEEPD1as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1.
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Jessica Kristine
authors.initials: JK
authors.lastname: Nelson
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Duco Steven
authors.initials: DS
authors.lastname: Koenis
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Emma Clare Laura
authors.initials: EC
authors.lastname: Cook
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Martina
authors.initials: M
authors.lastname: Moeton
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Ana
authors.initials: A
authors.lastname: Santos
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Jean-Marc Adolphe
authors.initials: JA
authors.lastname: Lobaccaro
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.).
authors.forename: Silvere
authors.initials: S
authors.lastname: Baron
authors.affiliation: From the Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (J.K.N., D.S.K., S.S., E.C.L.C., M.M., A.S., N.Z.); and Université Clermont Auvergne, CNRS, Inserm, GReD, Clermont-Ferrand, France (J.-M.A.L., S.B.). n.zelcer@amc.uva.nl.
authors.forename: Noam
authors.initials: N
authors.lastname: Zelcer
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D059467:Transcriptome; D014162:Transfection
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D002784:Cholesterol; D004706:Endodeoxyribonucleases; D008024:Ligands; D000071518:Liver X Receptors; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C505693:APOA1 protein, human; C000605211:Nr1h2 protein, mouse; C000605214:Nr1h3 protein, mouse; C000608105:EEPD1 protein, human
keywords: ABCA1; LXR; cholesterol efflux; cholesterol metabolism; macrophages; nuclear receptors