| Title: | The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion |
| Journal: | Atherosclerosis |
| Published: | 1 Aug 2026 |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2026.121887 |
Publication 21102
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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.</p>
30 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
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