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Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome.
Zanoni, Paolo; Panteloglou, Grigorios; Othman, Alaa; Haas, Joel T; Meier, Roger; Rimbert, Antoine; Futema, Marta; Abou Khalil, Yara; Norrelykke, Simon F; 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, Valérie; Philippi, Anne; Rabès, Jean-Pierre; Boileau, Catherine; Visentin, Michele; Vonghia, Luisa; Weyler, Jonas; Francque, Sven; Verrijken, An; Verhaegen, Ann; Van Gaal, Luc; van der Graaf, Adriaan; van Rosmalen, Belle V; Robert, Jerome; Velagapudi, Srividya; Yalcinkaya, Mustafa; Keel, Michaela; Radosavljevic, Silvija; Geier, Andreas; Tybjaerg-Hansen, Anne; Varret, Mathilde; Rohrer, Lucia; Humphries, Steve E; Staels, Bart; van de Sluis, Bart; Kuivenhoven, Jan Albert; von Eckardstein, Arnold.
Afiliação
  • 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.).
  • Panteloglou G; Now with Institute of Medical Genetics, University of Zurich, Switzerland (P.Z.).
  • Othman A; 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.).
  • Haas JT; 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.).
  • Meier R; 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.).
  • Rimbert A; Institute of Molecular Systems Biology, ETH Zurich, Switzerland (A.O.).
  • Futema M; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.).
  • Abou Khalil Y; Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
  • Norrelykke SF; 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.).
  • Rzepiela AJ; Now with Inserm UMR 1087/CNRS UMR 6291 IRS-UN, Nantes, France (A.R.).
  • Stoma S; Cardiology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, United Kingdom (M.F.).
  • Stebler M; LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
  • van Dijk F; Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy and Pôle technologie Santé (PTS), Saint-Joseph University, Beirut, Lebanon (Y.A.K.).
  • Wijers M; Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
  • Wolters JC; Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
  • Dalila N; Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
  • Huijkman NCA; Scientific center for optical and electron microscopy (ScopeM), ETH Zurich, Switzerland (R.M., S.F.N., A.J.R., S.S., M. Stebler).
  • Smit M; Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.).
  • Gallo 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.).
  • Carreau V; 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.).
  • Philippi A; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (N.D., A.T.-H.).
  • Rabès JP; 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.).
  • Boileau C; 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.).
  • Visentin M; AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.).
  • Vonghia L; AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.).
  • Weyler J; 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.).
  • Francque S; LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
  • Verrijken A; AP-HP, Université Paris-Saclay, Paris, France (J.-P.R.).
  • Verhaegen A; UFR Simone Veil des Sciences de la Santé, UVSQ, Montigny-Le-Bretonneux, France (J.-P.R.).
  • Van Gaal L; LVTS-INSERM UMRS 1148 and University of Paris, CHU Xavier Bichat, Paris, France (Y.A.K., J.-P.R., C.B., M. Varret).
  • van der Graaf A; AP-HP, Genetics Department, CHU Xavier Bichat, Université de Paris, France (C.B.).
  • van Rosmalen BV; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland (M. Visentin).
  • Robert J; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).
  • Velagapudi S; 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.).
  • Yalcinkaya M; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).
  • Keel M; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.).
  • Radosavljevic S; 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.).
  • Geier 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.).
  • Tybjaerg-Hansen A; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).
  • Varret M; 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.).
  • Rohrer L; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).
  • Humphries SE; 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.).
  • Staels B; Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).
  • van de Sluis B; Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.).
  • Kuivenhoven JA; Department of Surgery, Academic Medical Center, University of Amsterdam, the Netherlands (B.V.v.R.).
  • 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.).
Circ Res ; 130(1): 80-95, 2022 01 07.
Article em En | MEDLINE | ID: mdl-34809444
ABSTRACT

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.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Receptores de LDL / Proteínas Nucleares / Splicing de RNA Limite: Humans Idioma: En Revista: Circ Res Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Receptores de LDL / Proteínas Nucleares / Splicing de RNA Limite: Humans Idioma: En Revista: Circ Res Ano de publicação: 2022 Tipo de documento: Article