Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome-Reference-Cited by-同舟云学术

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

Published:2022-01-07 Issue:1 Volume:130 Page:80-95
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circ Res

Author:

Zanoni Paolo¹²³^ORCID,Panteloglou Grigorios¹³^ORCID,Othman Alaa⁴^ORCID,Haas Joel T.⁵^ORCID,Meier Roger⁶^ORCID,Rimbert Antoine⁷⁸,Futema Marta⁹^ORCID,Abou Khalil Yara¹⁰¹¹^ORCID,Norrelykke Simon F.⁶^ORCID,Rzepiela Andrzej J.⁶,Stoma Szymon⁶,Stebler Michael⁶,van Dijk Freerk¹²,Wijers Melinde⁷,Wolters Justina C.⁷,Dalila Nawar¹³,Huijkman Nicolette C. A.⁷,Smit Marieke⁷,Gallo Antonio¹⁴^ORCID,Carreau Valérie¹⁴,Philippi Anne¹⁵,Rabès Jean-Pierre¹⁰¹⁶¹⁷,Boileau Catherine¹⁰¹⁸^ORCID,Visentin Michele¹⁹,Vonghia Luisa²⁰²¹,Weyler Jonas²⁰,Francque Sven²⁰²¹^ORCID,Verrijken An²¹²²,Verhaegen Ann²¹²²^ORCID,Van Gaal Luc²¹²²,van der Graaf Adriaan¹²^ORCID,van Rosmalen Belle V.²³^ORCID,Robert Jerome¹,Velagapudi Srividya¹²⁴³^ORCID,Yalcinkaya Mustafa¹²⁵³,Keel Michaela¹³,Radosavljevic Silvija¹³,Geier Andreas²⁶,Tybjaerg-Hansen Anne¹³,Varret Mathilde¹⁰,Rohrer Lucia¹³,Humphries Steve E.²⁷,Staels Bart⁵^ORCID,van de Sluis Bart⁷^ORCID,Kuivenhoven Jan Albert⁷^ORCID,von Eckardstein Arnold¹³^ORCID

Affiliation:

1. 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.)

2. Now with Institute of Medical Genetics, University of Zurich, Switzerland (P.Z.)

3. 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.).

4. Institute of Molecular Systems Biology, ETH Zurich, Switzerland (A.O.).

5. University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, France (J.T.H., B.S.).

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

7. 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.)

8. Now with Inserm UMR 1087/CNRS UMR 6291 IRS-UN, Nantes, France (A.R.).

9. Cardiology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s, University of London, United Kingdom (M.F.).

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

11. Laboratory of Biochemistry and Molecular Therapeutics (LBTM), Faculty of Pharmacy and Pôle technologie Santé (PTS), Saint-Joseph University, Beirut, Lebanon (Y.A.K.).

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

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

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

15. 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.).

16. AP-HP, Université Paris-Saclay, Paris, France (J.-P.R.).

17. UFR Simone Veil des Sciences de la Santé, UVSQ, Montigny-Le-Bretonneux, France (J.-P.R.).

18. AP-HP, Genetics Department, CHU Xavier Bichat, Université de Paris, France (C.B.).

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

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

21. 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.).

22. Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium (A. Verrijken, A. Verhaegen, L.V.G.).

23. Department of Surgery, Academic Medical Center, University of Amsterdam, the Netherlands (B.V.v.R.).

24. Center for Molecular Cardiology, University of Zurich, Switzerland (S.V.).

25. Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (M.Y.)

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

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

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.

Funder

EC | FP7 | FP7 Health

European Genomic Institute for Diabetes

Swiss National Science Foundation

Dutch Heart Foundation

Swiss Atherosclerosis Society

DACH Gesellschaft für Praevention

GeniusII

Fondation Maladies Rares

Agence Nationale de la Recherche

EMBO

EC | European Research Council