Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.

Cholesterol / metabolism HEK293 Cells Hep G2 Cells Humans Lipoproteins, LDL / metabolism Liver / metabolism Mutation Nuclear Proteins / genetics RNA Splicing Receptors, LDL / genetics Spliceosomes / metabolism
cardiovascular diseases endocytosis hepatocytes hypercholesterolemia spliceosomes

Journal

Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103

Informations de publication

Date de publication:
07 01 2022
Historique:
pubmed: 24 11 2021
medline: 26 2 2022
entrez: 23 11 2021
Statut: ppublish

Résumé

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. 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. 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 We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of

Sections du résumé

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
CONCLUSIONS
We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of

Identifiants

DOI: 10.1161/CIRCRESAHA.120.318141 PMID: 34809444
pubmed: 34809444
doi: 10.1161/CIRCRESAHA.120.318141
doi:

Substances chimiques

LUC7L3 protein, human 0
Lipoproteins, LDL 0
Nuclear Proteins 0
Receptors, LDL 0
Cholesterol 97C5T2UQ7J

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

80-95

Subventions

Organisme : British Heart Foundation
ID : RG3008
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG008/08
Pays : United Kingdom

Auteurs

Paolo Zanoni (P)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Now with Institute of Medical Genetics, University of Zurich, Switzerland (P.Z.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
ORCID: 0000-0001-9397-1989

Grigorios Panteloglou (G)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
ORCID: 0000-0002-7672-7623

Alaa Othman (A)

Institute of Molecular Systems Biology, ETH Zurich, Switzerland (A.O.).
ORCID: 0000-0002-0092-5594

Joel T Haas (JT)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.).
ORCID: 0000-0002-0028-5988

Roger Meier (R)

Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
ORCID: 0000-0002-5544-0156

Antoine Rimbert (A)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).
Now with Inserm UMR 1087/CNRS UMR 6291 IRS-UN, Nantes, France (A.R.).

Marta Futema (M)

Cardiology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, United Kingdom (M.F.).
ORCID: 0000-0002-2120-2088

Yara Abou Khalil (Y)

LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy and Pôle technologie Santé (PTS), Saint-Joseph University, Beirut, Lebanon (Y.A.K.).
ORCID: 0000-0002-3361-3570

Simon F Norrelykke (SF)

Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
ORCID: 0000-0001-8302-526X

Andrzej J Rzepiela (AJ)

Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).

Szymon Stoma (S)

Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).

Michael Stebler (M)

Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).

Freerk van Dijk (F)

Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.).

Melinde Wijers (M)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).

Justina C Wolters (JC)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).

Nawar Dalila (N)

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.D., A.T.-H.).

Nicolette C A Huijkman (NCA)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).

Marieke Smit (M)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).

Antonio Gallo (A)

AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.).
ORCID: 0000-0002-8887-994X

Valérie Carreau (V)

AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.).

Anne Philippi (A)

Université de Paris, Faculté de Médecine Paris-Diderot, UMR-S958 Paris, France; Now with Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France (A.P.).

Jean-Pierre Rabès (JP)

LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
AP-HP, Université Paris-Saclay, Paris, France (J.-P.R.).
UFR Simone Veil des Sciences de la Santé, UVSQ, Montigny-Le-Bretonneux, France (J.-P.R.).

Catherine Boileau (C)

LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
AP-HP, Genetics Department, CHU Xavier Bichat, Université de Paris, France (C.B.).
ORCID: 0000-0002-0371-7539

Michele Visentin (M)

Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland (M. Visentin).

Luisa Vonghia (L)

Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).
Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine, University of Antwerp, Belgium (L.V., J.W., S.F., A. Verrijken, A. Verhaegen, L.V.G.).

Jonas Weyler (J)

Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).

Sven Francque (S)

Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).
Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine, University of Antwerp, Belgium (L.V., J.W., S.F., A. Verrijken, A. Verhaegen, L.V.G.).
ORCID: 0000-0002-7527-4714

An Verrijken (A)

Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine, University of Antwerp, Belgium (L.V., J.W., S.F., A. Verrijken, A. Verhaegen, L.V.G.).
Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).

Ann Verhaegen (A)

Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine, University of Antwerp, Belgium (L.V., J.W., S.F., A. Verrijken, A. Verhaegen, L.V.G.).
Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).
ORCID: 0000-0001-5970-182X

Luc Van Gaal (L)

Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine, University of Antwerp, Belgium (L.V., J.W., S.F., A. Verrijken, A. Verhaegen, L.V.G.).
Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).

Adriaan van der Graaf (A)

Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.).
ORCID: 0000-0002-8898-8484

Belle V van Rosmalen (BV)

Department of Surgery, Academic Medical Center, University of Amsterdam, the Netherlands (B.V.v.R.).
ORCID: 0000-0002-4507-7189

Jerome Robert (J)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).

Srividya Velagapudi (S)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Molecular Cardiology, University of Zurich, Switzerland (S.V.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
ORCID: 0000-0002-7211-4141

Mustafa Yalcinkaya (M)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (M.Y.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).

Michaela Keel (M)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).

Silvija Radosavljevic (S)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).

Andreas Geier (A)

Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany (A. Geier).

Anne Tybjaerg-Hansen (A)

Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.D., A.T.-H.).

Mathilde Varret (M)

LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).

Lucia Rohrer (L)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).

Steve E Humphries (SE)

Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, United Kingdom (S.E.H.).

Bart Staels (B)

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.).
ORCID: 0000-0002-3784-1503

Bart van de Sluis (B)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).
ORCID: 0000-0003-3039-4365

Jan Albert Kuivenhoven (JA)

Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (A.R., M.W., J.C.W., N.C.A.H., M. Smit, B.v.d.S., J.A.K.).
ORCID: 0000-0002-9346-2719

Arnold von Eckardstein (A)

Institute for Clinical Chemistry, University and University Hospital Zurich, Switzerland (P.Z., G.P., J.R., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
Center for Integrative Human Physiology, University of Zurich, Switzerland (P.Z., G.P., S.V., M.Y., M.K., S.R., L.R., A.v.E.).
ORCID: 0000-0002-1666-2266

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Classifications MeSH

questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Cellules HepG2 › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Lipoprotéines LDL › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Système digestif › Foie › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux lipoprotéines › Récepteurs aux lipoprotéines LDL › Posttranscriptional Regulation of the Human...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Structures nucléaires › Espace intranucléaire › Splicéosomes › Posttranscriptional Regulation of the Human...