Posttranscriptional Regulation of the Human ...
Type de document :
Compte-rendu et recension critique d'ouvrage
PMID :
Titre :
Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
Auteur(s) :
Zanoni, Paolo [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Panteloglou, Grigorios [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Othman, Alaa [Auteur]
Institute for Molecular Systems Biology [ETH Zurich] [IMSB]
Haas, Joël T. [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 [RNMCD]
Meier, Roger [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Rimbert, Antoine [Auteur]
ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 [ITX-lab]
University of Groningen [Groningen]
Futema, Marta [Auteur]
St George's, University of London
Khalil, Yara Abou [Auteur]
Université Saint-Joseph de Beyrouth [USJ]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Norrelykke, Simon Flyvbjerg [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Rzepiela, Andrzej Jerzy [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Stoma, Szymon [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Stebler, Michael [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
van Dijk, Freerk [Auteur]
University of Groningen [Groningen]
Wijers, Melinde [Auteur]
University of Groningen [Groningen]
Wolters, Justina Clarinda [Auteur]
University of Groningen [Groningen]
Dalila, Nawar [Auteur]
University of Copenhagen = Københavns Universitet [UCPH]
Huijkman, Nicolette C.A. [Auteur]
University of Groningen [Groningen]
Smit, Marieke [Auteur]
University of Groningen [Groningen]
Gallo, Antonio [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Carreau, Valérie [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Philippi, Anne [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Rabès, Jean Pierre H. [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil [UVSQ Santé]
AP-HP. Université Paris Saclay
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Boileau, Cathérine R. [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Visentin, Michele [Auteur]
University hospital of Zurich [Zurich]
Vonghia, Luisa [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Weyler, Jonas [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Francque, Sven M.A. [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Verrijken, An [Auteur]
University of Antwerp [UA]
Verhaegen, Ann A. [Auteur]
University of Antwerp [UA]
van Gaal, Luc F. [Auteur]
Antwerp University Hospital [Edegem] [UZA]
University of Antwerp [UA]
van Der Graaf, Adriaan [Auteur]
University of Groningen [Groningen]
van Rosmalen, Belle Vivica [Auteur]
University of Amsterdam [Amsterdam] = Universiteit van Amsterdam [UvA]
Robert, Jérôme [Auteur]
University hospital of Zurich [Zurich]
Velagapudi, Srividya [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Yalcinkaya, Mustafa [Auteur]
Columbia University [New York]
Universität Zürich [Zürich] = University of Zurich [UZH]
Keel, Michaela [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Radosavljevic, Silvija [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Geier, Andreas [Auteur]
University Hospital of Würzburg
Tybjaerg-Hansen, Anne [Auteur]
University of Copenhagen = Københavns Universitet [UCPH]
Varret, Mathilde [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Rohrer, Lucia [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Humphries, Steve E. [Auteur]
University College of London [London] [UCL]
Staels, Bart [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 [RNMCD]
van de Sluis, Bart J.A. [Auteur]
University of Groningen [Groningen]
Kuivenhoven, Jan Albert [Auteur]
University of Groningen [Groningen]
von Eckardstein, Arnold [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Panteloglou, Grigorios [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Othman, Alaa [Auteur]
Institute for Molecular Systems Biology [ETH Zurich] [IMSB]
Haas, Joël T. [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 [RNMCD]
Meier, Roger [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Rimbert, Antoine [Auteur]
ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 [ITX-lab]
University of Groningen [Groningen]
Futema, Marta [Auteur]
St George's, University of London
Khalil, Yara Abou [Auteur]
Université Saint-Joseph de Beyrouth [USJ]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Norrelykke, Simon Flyvbjerg [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Rzepiela, Andrzej Jerzy [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Stoma, Szymon [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
Stebler, Michael [Auteur]
Scientific Center for Optical and Electron Microscopy [ScopeM]
van Dijk, Freerk [Auteur]
University of Groningen [Groningen]
Wijers, Melinde [Auteur]
University of Groningen [Groningen]
Wolters, Justina Clarinda [Auteur]
University of Groningen [Groningen]
Dalila, Nawar [Auteur]
University of Copenhagen = Københavns Universitet [UCPH]
Huijkman, Nicolette C.A. [Auteur]
University of Groningen [Groningen]
Smit, Marieke [Auteur]
University of Groningen [Groningen]
Gallo, Antonio [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Carreau, Valérie [Auteur]
CHU Pitié-Salpêtrière [AP-HP]
Philippi, Anne [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Rabès, Jean Pierre H. [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil [UVSQ Santé]
AP-HP. Université Paris Saclay
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Boileau, Cathérine R. [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Visentin, Michele [Auteur]
University hospital of Zurich [Zurich]
Vonghia, Luisa [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Weyler, Jonas [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Francque, Sven M.A. [Auteur]
University of Antwerp [UA]
Antwerp University Hospital [Edegem] [UZA]
Verrijken, An [Auteur]
University of Antwerp [UA]
Verhaegen, Ann A. [Auteur]
University of Antwerp [UA]
van Gaal, Luc F. [Auteur]
Antwerp University Hospital [Edegem] [UZA]
University of Antwerp [UA]
van Der Graaf, Adriaan [Auteur]
University of Groningen [Groningen]
van Rosmalen, Belle Vivica [Auteur]
University of Amsterdam [Amsterdam] = Universiteit van Amsterdam [UvA]
Robert, Jérôme [Auteur]
University hospital of Zurich [Zurich]
Velagapudi, Srividya [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Yalcinkaya, Mustafa [Auteur]
Columbia University [New York]
Universität Zürich [Zürich] = University of Zurich [UZH]
Keel, Michaela [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Radosavljevic, Silvija [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Geier, Andreas [Auteur]
University Hospital of Würzburg
Tybjaerg-Hansen, Anne [Auteur]
University of Copenhagen = Københavns Universitet [UCPH]
Varret, Mathilde [Auteur]
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)]
Rohrer, Lucia [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Humphries, Steve E. [Auteur]
University College of London [London] [UCL]
Staels, Bart [Auteur]
Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 [RNMCD]
van de Sluis, Bart J.A. [Auteur]
University of Groningen [Groningen]
Kuivenhoven, Jan Albert [Auteur]
University of Groningen [Groningen]
von Eckardstein, Arnold [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
University hospital of Zurich [Zurich]
Titre de la revue :
Circulation research
Pagination :
80-95
Éditeur :
American Heart Association
Date de publication :
2022
ISSN :
0009-7330
Mot(s)-clé(s) en anglais :
Cardiovascular diseases
Endocytosis
Hepatocytes
Hypercholesterolemia
Spliceosomes
Endocytosis
Hepatocytes
Hypercholesterolemia
Spliceosomes
Discipline(s) HAL :
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire
Résumé en anglais : [en]
BACKGROUND: The LDLR (low-density lipoprotein receptor) 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 ...
Lire la suite >BACKGROUND: The LDLR (low-density lipoprotein receptor) 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 data sets 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 nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25, overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. CONCLUSIONS: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.Lire moins >
Lire la suite >BACKGROUND: The LDLR (low-density lipoprotein receptor) 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 data sets 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 nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25, overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. CONCLUSIONS: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.Lire moins >
Langue :
Anglais
Vulgarisation :
Non
Source :
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