دورية أكاديمية
Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
| العنوان: | Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome |
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| المؤلفون: | Zanoni, Paolo, Panteloglou, Grigorios, Othman, Alaa, Haas, Joel T, Meier, Roger, Rimbert, Antoine, Futema, Marta, Abou-Khalil, Yara, Nørrelykke, Simon Flyvbjerg, Rzepiela, Andrzej J, Stoma, Szymon, Stebler, Michael, van Dijk, Freerk, Wijers, Melinde, Wolters, Justina C, Dalila, Nawar, Huijkman, Nicolette C A, Smit, Marieke, Gallo, Antonio, Carreau, Valerie, Philippi, Anne, Rabès, Jean-Pierre, Boileau, Catherine, Visentin, Michele, Vonghia, Luisa, Weyler, Jonas, Francque, Sven, Verrijken, An, Verhaegen, Ann, Van Gaal, Luc, von Eckardstein, Arnold |
| المصدر: | Zanoni, Paolo; Panteloglou, Grigorios; Othman, Alaa; Haas, Joel T; Meier, Roger; Rimbert, Antoine; Futema, Marta; Abou-Khalil, Yara; Nørrelykke, Simon Flyvbjerg; Rzepiela, Andrzej J; Stoma, Szymon; Stebler, Michael; van Dijk, Freerk; Wijers, Melinde; Wolters, Justina C; Dalila, Nawar; Huijkman, Nicolette C A; Smit, Marieke; Gallo, Antonio; Carreau, Valerie; Philippi, Anne; Rabès, Jean-Pierre; Boileau, Catherine; Visentin, Michele; Vonghia, Luisa; Weyler, Jonas; Francque, Sven; Verrijken, An; Verhaegen, Ann; Van Gaal, Luc; et al; von Eckardstein, Arnold (2022). Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome. Circulation Research, 130(1):80-95. |
| بيانات النشر: | Lippincott Williams & Wilkins |
| سنة النشر: | 2022 |
| المجموعة: | University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| مصطلحات موضوعية: | Institute of Clinical Chemistry, Institute of Medical Genetics, Zurich Center for Integrative Human Physiology (ZIHP), Center for Molecular Cardiology, 570 Life sciences, biology, 610 Medicine & health |
| الوصف: | Background: The low-density lipoprotein receptor (LDLR) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of datasets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in non-transfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in non-alcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and three rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared to overexpression of wild type RBM25, overexpression of the three rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of post-transcriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels. Keywords: cardiovascular diseases, endocytosis, hepatocytes, hypercholesterolemia, spliceosomes |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf; other |
| اللغة: | English |
| تدمد: | 0009-7330 |
| العلاقة: | https://www.zora.uzh.ch/id/eprint/209782/1/CIRCRESAHA.120.318141_%281%29.pdfTest; https://www.zora.uzh.ch/id/eprint/209782/3/318141_uncut_gel_blots.pdfTest; https://www.zora.uzh.ch/id/eprint/209782/5/318141_online.pdfTest; https://www.zora.uzh.ch/id/eprint/209782/6/318141_online_data_set.csvTest; info:pmid/34809444; urn:issn:0009-7330 |
| DOI: | 10.5167/uzh-209782 |
| DOI: | 10.1161/CIRCRESAHA.120.318141 |
| الإتاحة: | https://doi.org/10.5167/uzh-20978210.1161/CIRCRESAHA.120.318141Test https://www.zora.uzh.ch/id/eprint/209782Test/ https://www.zora.uzh.ch/id/eprint/209782/1/CIRCRESAHA.120.318141_%281%29.pdfTest https://www.zora.uzh.ch/id/eprint/209782/3/318141_uncut_gel_blots.pdfTest https://www.zora.uzh.ch/id/eprint/209782/5/318141_online.pdfTest https://www.zora.uzh.ch/id/eprint/209782/6/318141_online_data_set.csvTest |
| حقوق: | info:eu-repo/semantics/closedAccess |
| رقم الانضمام: | edsbas.22DD7491 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00097330 |
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| DOI: | 10.5167/uzh-209782 |