EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux
The sterol-responsive nuclear receptors, liver X receptors α (LXRα, ) and β (LXRβ, ), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters and to promote efflux of exces...
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| Vydáno v: | Arteriosclerosis, thrombosis, and vascular biology Ročník 37; číslo 3; s. 423 - 432 |
|---|---|
| Hlavní autoři: | , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.03.2017
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| ISSN: | 1524-4636 |
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| Abstract | The sterol-responsive nuclear receptors, liver X receptors α (LXRα,
) and β (LXRβ,
), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters
and
to 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.
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 (
) 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 of
blunts 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.
In this study, we identify
as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. |
|---|---|
| AbstractList | The sterol-responsive nuclear receptors, liver X receptors α (LXRα,
) and β (LXRβ,
), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters
and
to 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.
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 (
) 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 of
blunts 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.
In this study, we identify
as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. OBJECTIVEThe 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 transporters ABCA1 and ABCG1 to 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.APPROACH AND RESULTSWe 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 of EEPD1 blunts 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.CONCLUSIONSIn this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1. |
| Author | Cook, Emma Clare Laura Lobaccaro, Jean-Marc Adolphe Nelson, Jessica Kristine Scheij, Saskia Baron, Silvere Zelcer, Noam Koenis, Duco Steven Santos, Ana Moeton, Martina |
| Author_xml | – sequence: 1 givenname: Jessica Kristine surname: Nelson fullname: Nelson, Jessica Kristine organization: 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.) – sequence: 2 givenname: Duco Steven surname: Koenis fullname: Koenis, Duco Steven organization: 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.) – sequence: 3 givenname: Saskia surname: Scheij fullname: Scheij, Saskia organization: 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.) – sequence: 4 givenname: Emma Clare Laura surname: Cook fullname: Cook, Emma Clare Laura organization: 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.) – sequence: 5 givenname: Martina surname: Moeton fullname: Moeton, Martina organization: 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.) – sequence: 6 givenname: Ana surname: Santos fullname: Santos, Ana organization: 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.) – sequence: 7 givenname: Jean-Marc Adolphe surname: Lobaccaro fullname: Lobaccaro, Jean-Marc Adolphe organization: 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.) – sequence: 8 givenname: Silvere surname: Baron fullname: Baron, Silvere organization: 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.) – sequence: 9 givenname: Noam surname: Zelcer fullname: Zelcer, Noam email: n.zelcer@amc.uva.nl organization: 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 |
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| Keywords | ABCA1 nuclear receptors macrophages cholesterol efflux cholesterol metabolism LXR |
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| PublicationTitle | Arteriosclerosis, thrombosis, and vascular biology |
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| Snippet | The sterol-responsive nuclear receptors, liver X receptors α (LXRα,
) and β (LXRβ,
), are key determinants of cellular cholesterol homeostasis. LXRs are... OBJECTIVEThe sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and β (LXRβ, NR1H2), are key determinants of cellular cholesterol... |
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| SubjectTerms | Animals Apolipoprotein A-I - metabolism ATP Binding Cassette Transporter 1 - genetics ATP Binding Cassette Transporter 1 - metabolism Biological Transport Cell Membrane - drug effects Cell Membrane - enzymology Chlorocebus aethiops Cholesterol - metabolism COS Cells Endodeoxyribonucleases - genetics Endodeoxyribonucleases - metabolism Gene Expression Profiling - methods Gene Expression Regulation, Enzymologic HeLa Cells Hep G2 Cells Humans Ligands Liver X Receptors - agonists Liver X Receptors - deficiency Liver X Receptors - genetics Liver X Receptors - metabolism Macrophages - drug effects Macrophages - enzymology Male Mice Mice, Inbred C57BL Mice, Knockout RAW 264.7 Cells RNA Interference Transcriptome Transfection |
| Title | EEPD1 Is a Novel LXR Target Gene in Macrophages Which Regulates ABCA1 Abundance and Cholesterol Efflux |
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