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

Autor:	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.)., 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.)., Othman A; Institute of Molecular Systems Biology, ETH Zurich, Switzerland (A.O.)., Haas JT; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.)., 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)., 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.)., Futema M; Cardiology Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, United Kingdom (M.F.)., 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.)., 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)., 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)., 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)., 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)., van Dijk F; Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.)., 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.)., 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.)., 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.)., 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.)., 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.)., Gallo A; AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.)., Carreau V; AP-HP, Endocrinology and Metabolism Department, Human Research Nutrition Center, Pitié-Salpêtrière Hospital, Paris, France (A. Gallo, V.C.)., 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.)., 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.)., 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.)., Visentin M; Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland (M. Visentin)., 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.)., Weyler J; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium (L.V., J.W., S.F.)., 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.)., 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.)., 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.)., 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.)., van der Graaf A; Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (F.v.D., A.v.d.G.)., van Rosmalen BV; Department of Surgery, Academic Medical Center, University of Amsterdam, the Netherlands (B.V.v.R.)., 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.)., 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.)., 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.)., 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.)., 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.)., Geier A; Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany (A. Geier)., 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.)., 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)., 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.)., Humphries SE; Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, United Kingdom (S.E.H.)., Staels B; University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.)., 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.)., 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.)., 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.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2022 Jan 07; Vol. 130 (1), pp. 80-95. Date of Electronic Publication: 2021 Nov 23.
DOI:	10.1161/CIRCRESAHA.120.318141
Abstrakt:	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.
Databáze:	MEDLINE
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