The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion
Year: 2026
Type: article
Abstract: BACKGROUND AND AIMS: Decreased removal and increased production of apolipoprotein B (apoB) containing lipoproteins cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease. By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit low density lipoprotein (LDL) uptake into Huh-7 hepatocarcinoma cells. This study investigated the underlying mechanism and the role of impaired COPI function for hypercholesterolemia. METHODS: Targeted loss of function experiments in vitro as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes were performed. RESULTS: Silencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and reduced cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol. While patients and mice carrying rare immunopathogenic missense variants of the WD40- or appendage domains of COPA and COPG1, respectively, had normal LDL-cholesterol levels, rare variants altering other domains of these proteins were enriched among patients with hypercholesterolemia. The hepatic knockdown of Copg1 increased the concentrations of nonHDL-cholesterol in plasma and triglycerides in the liver of mice. CONCLUSIONS: The COPI coatomer regulates LDLR activity and apoB secretion as well as hepatic lipid content. Deficiency of Copg1 in mice and some but not all rare damaging COPI gene variants in humans are associated with higher LDL-cholesterol levels.
Source: Atherosclerosis
Authors: Grigorios Panteloglou, Jérôme Robert, Marieke Smit, Nicolette Huijkman, Niels Kloosterhuis, Christopher S. Law, Brian Woods, Alaa Othman, Marcus E. Kleber, Graciela E. Delgado, Patrizia Tarugi, Museer A. Lone, Justina Clarinda Wolters, Antoine Rimbert, Anja Kerksiek, Dieter Lütjohann, Lucia Rohrer, Paolo Zanoni, Sofia Kakava, Stephanie Häusler, Eveline Schlumpf, Marta Futema, Steve E. Humphries, Janet Chou, Winfried März, Raif S. Geha, Anthony K. Shum, Jan Albert Kuivenhoven, Bart van de Sluis, Arnold von Eckardstein
Institutions: University of Zurich, University Hospital Zurich, University Medical Center Groningen, University of Groningen, University of California, San Francisco, Boston Children's Hospital, Harvard University, ETH Zurich, Functional Genomics Center Zurich, Heidelberg University, Medizinische Fakultät Mannheim, University of Modena and Reggio Emilia, Centre National de la Recherche Scientifique, Inserm, Institut du Thorax, Nantes Université, University Hospital Bonn, City St George's, University of London, University College London, Medical University of Graz
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,020
Funders: Fondazione Cassa di Risparmio di Modena, Dutch Cardiovascular Alliance, British Heart Foundation, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, ZonMw, Hartstichting, Universität Zürich, SystemsX.ch, Aard- en Levenswetenschappen, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, National Institute of Allergy and Infectious Diseases, FP7 Health
OpenAlex ID: W7163394499