dc.contributor |
Háskóli Íslands |
dc.contributor |
University of Iceland |
dc.contributor.author |
Bindesbøll, Christian |
dc.contributor.author |
Aas, Aleksander |
dc.contributor.author |
Ogmundsdottir, Margret H |
dc.contributor.author |
Pankiv, Serhiy |
dc.contributor.author |
Reine, Trine |
dc.contributor.author |
Zoncu, Roberto |
dc.contributor.author |
Simonsen, Anne |
dc.date.accessioned |
2020-11-02T12:25:21Z |
dc.date.available |
2020-11-02T12:25:21Z |
dc.date.issued |
2020-03-11 |
dc.identifier.citation |
Bindesbøll, C., Aas, A., Ogmundsdottir, M.H. et al. NBEAL1 controls SREBP2 processing and cholesterol metabolism and is a susceptibility locus for coronary artery disease. Scientific Reports 10, 4528 (2020). https://doi.org/10.1038/s41598-020-61352-0 |
dc.identifier.issn |
2045-2322 |
dc.identifier.uri |
https://hdl.handle.net/20.500.11815/2154 |
dc.description |
Publisher's version (útgefin grein) |
dc.description.abstract |
Dysregulated cholesterol homeostasis promotes the pathology of atherosclerosis, myocardial infarction and strokes. Cellular cholesterol is mainly regulated at the transcriptional level by SREBP2, but also through uptake of extracellular cholesterol from low density lipoproteins (LDL) via expression of LDL receptors (LDLR) at the cell surface. Identification of the mechanisms involved in regulation of these processes are thus key to understand the pathology of coronary artery disease. Here, we identify the large and poorly characterized BEACH domain protein Neurobeachin-like (NBEAL) 1 as a Golgi- associated protein required for regulation of cholesterol metabolism. NBEAL1 is most abundantly expressed in arteries. Genetic variants in NBEAL1 are associated with decreased expression of NBEAL1 in arteries and increased risk of coronary artery disease in humans. We show that NBEAL1 regulates cholesterol metabolism by modulating LDLR expression in a mechanism involving interaction with SCAP and PAQR3 and subsequent SREBP2-processing. Thus, low expression of NBEAL1 may lead to increased risk of coronary artery disease by downregulation of LDLR levels. |
dc.description.sponsorship |
The authors would like to acknowledge the following funding sources; the Research Council of Norway (Project Number 221831 and through its Centres of Excellence funding scheme project number 262652), the Peder Sather Grant Program, the Icelandic Research Fund (Project Number 184727-051), and the South-Eastern Norway Regional Health Authority. We would like to thank Dr. Laura Rodriguez de la Ballina for technical assistance using CellProfiler and Thu Van Pham for isolating HUVECs. We thank Thorhildur Juliusdottir for valuable comments and assistance using the Toppar software. Plasmids were kindly provided from Prof. Yan Chen (MYC-PAQR3, MYC-SCAP), Prof. Andrew Brown (pCMV-PLAP-BP2). Prof. Hitoshi Shimano (pGL2-LDLR-luc, pGL2-HMGCS-luc, pGL2-FAS-luc). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. |
dc.format.extent |
4528 |
dc.language.iso |
en |
dc.publisher |
Springer Science and Business Media LLC |
dc.relation.ispartofseries |
Scientific Reports;10(1) |
dc.rights |
info:eu-repo/semantics/openAccess |
dc.subject |
NBEAL1 |
dc.subject |
SREBP2 |
dc.subject |
Cholesterol |
dc.subject |
Coronary artery disease |
dc.subject |
Kólesteról |
dc.subject |
Gen |
dc.subject |
Kransæðasjúkdómar |
dc.title |
NBEAL1 controls SREBP2 processing and cholesterol metabolism and is a susceptibility locus for coronary artery disease |
dc.type |
info:eu-repo/semantics/article |
dcterms.license |
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
dc.description.version |
Peer Reviewed |
dc.identifier.journal |
Scientific Reports |
dc.identifier.doi |
10.1038/s41598-020-61352-0 |
dc.relation.url |
https://www.nature.com/articles/s41598-020-61352-0 |
dc.contributor.department |
Læknadeild (HÍ) |
dc.contributor.department |
Faculty of Medicine (UI) |
dc.contributor.department |
Lífvísindasetur (HÍ) |
dc.contributor.department |
Biomedical Center (UI) |
dc.contributor.school |
Heilbrigðisvísindasvið (HÍ) |
dc.contributor.school |
School of Health Sciences (UI) |