EEPD1 is a novel LXR target gene in macrophages which regulates ABCA1 abundance and cholesterol efflux
EEPD1 is a novel LXR target gene in macrophages which regulates ABCA1 abundance and cholesterol efflux
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 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 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 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.
Conclusions: in 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.
ATP Binding Cassette Transporter 1/genetics, Animals, Apolipoprotein A-I/metabolism, Biological Transport, COS Cells, Cell Membrane/drug effects, Chlorocebus aethiops, Cholesterol/metabolism, Endodeoxyribonucleases/genetics, Gene Expression Profiling/methods, Gene Expression Regulation, Enzymologic, HeLa Cells, Hep G2 Cells, Humans, Ligands, Liver X Receptors/agonists, Macrophages/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RAW 264.7 Cells, RNA Interference, Transcriptome, Transfection
423-432
Nelson, Jessica Kristine
7dc3f0c8-5a67-4467-a332-efd560a0630b
Koenis, Duco Steven
2fce0429-69b3-4175-8367-dcaa1156d236
Scheij, Saskia
7863fcb2-eeba-43ab-93d5-8c9c08ad4289
Cook, Emma Clare Laura
4a22ced7-83cf-4c33-b028-0fc258e2b78f
Moeton, Martina
513f1f1d-59cd-45d9-8154-e2a676bd8c68
Santos, Ana
a6805a57-703c-464c-ab3a-929a94a82fe0
Lobaccaro, Jean-Marc Adolphe
f8e5bf69-37af-4a8f-ba35-d88bd72feaca
Baron, Silvere
38381030-32c8-42d6-b2cd-94813de21932
Zelcer, Noam
c5eff664-b107-4a7c-9823-11ccb8149fbc
March 2017
Nelson, Jessica Kristine
7dc3f0c8-5a67-4467-a332-efd560a0630b
Koenis, Duco Steven
2fce0429-69b3-4175-8367-dcaa1156d236
Scheij, Saskia
7863fcb2-eeba-43ab-93d5-8c9c08ad4289
Cook, Emma Clare Laura
4a22ced7-83cf-4c33-b028-0fc258e2b78f
Moeton, Martina
513f1f1d-59cd-45d9-8154-e2a676bd8c68
Santos, Ana
a6805a57-703c-464c-ab3a-929a94a82fe0
Lobaccaro, Jean-Marc Adolphe
f8e5bf69-37af-4a8f-ba35-d88bd72feaca
Baron, Silvere
38381030-32c8-42d6-b2cd-94813de21932
Zelcer, Noam
c5eff664-b107-4a7c-9823-11ccb8149fbc
Nelson, Jessica Kristine, Koenis, Duco Steven, Scheij, Saskia, Cook, Emma Clare Laura, Moeton, Martina, Santos, Ana, Lobaccaro, Jean-Marc Adolphe, Baron, Silvere and Zelcer, Noam
(2017)
EEPD1 is a novel LXR target gene in macrophages which regulates ABCA1 abundance and cholesterol efflux.
Arteriosclerosis, Thrombosis, and Vascular Biology, 37 (3), .
(doi:10.1161/ATVBAHA.116.308434).
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 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 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 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.
Conclusions: in 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.
Text
nelson-et-al-2017-eepd1-is-a-novel-lxr-target-gene-in-macrophages-which-regulates-abca1-abundance-and-cholesterol-efflux
- Version of Record
More information
Accepted/In Press date: 2 January 2017
e-pub ahead of print date: 12 January 2017
Published date: March 2017
Additional Information:
© 2017 The Authors.
Keywords:
ATP Binding Cassette Transporter 1/genetics, Animals, Apolipoprotein A-I/metabolism, Biological Transport, COS Cells, Cell Membrane/drug effects, Chlorocebus aethiops, Cholesterol/metabolism, Endodeoxyribonucleases/genetics, Gene Expression Profiling/methods, Gene Expression Regulation, Enzymologic, HeLa Cells, Hep G2 Cells, Humans, Ligands, Liver X Receptors/agonists, Macrophages/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RAW 264.7 Cells, RNA Interference, Transcriptome, Transfection
Identifiers
Local EPrints ID: 505356
URI: http://eprints.soton.ac.uk/id/eprint/505356
ISSN: 1079-5642
PURE UUID: 92263cd4-0c82-41ca-8a25-9b55e94a0fee
Catalogue record
Date deposited: 07 Oct 2025 16:44
Last modified: 08 Oct 2025 02:17
Export record
Altmetrics
Contributors
Author:
Jessica Kristine Nelson
Author:
Duco Steven Koenis
Author:
Saskia Scheij
Author:
Emma Clare Laura Cook
Author:
Martina Moeton
Author:
Ana Santos
Author:
Jean-Marc Adolphe Lobaccaro
Author:
Silvere Baron
Author:
Noam Zelcer
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics