Taking One Step Back in Familial Hypercholesterolemia
| Autor: | Loaiza, Natalia, Hartgers, Merel, Reeskamp, Laurens, Balder, Jan-Willem, Rimbert, Antoine, Bazioti, Venetia, Wolters, Justina, Winkelmeijer, Maaike, Jansen, Hans, Dallinga-Thie, Geesje, Volta, Andrea, Huijkman, Nicolette, Smit, Marieke, Kloosterhuis, Niels, Koster, Mirjam, F Svendsen, Arthur, Van De Sluis, Bart, Hovingh, G Kees, Grefhorst, Aldo, Kuivenhoven, Jan Albert, Jansen, Hans P.G., F. Svendsen, Arthur, Hovingh, G. Kees |
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| Přispěvatelé: | unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Pediatrics and Laboratory Medicine [Groningen, The Netherlands], University Medical Center Groningen [Groningen] (UMCG), Biometris, Wageningen University and Research [Wageningen] (WUR), Department of Vascular Medicine, Emma Children’s Hospital Academic Medical Centre, Department of Pediatrics, Molecular Genetics Section, University of Amsterdam [Amsterdam] (UvA) |
| Rok vydání: | 2020 |
| Předmět: |
Male
mice [SDV]Life Sciences [q-bio] Hypercholesterolemia Monocytes Hyperlipoproteinemia Type II Translational Sciences Cell Line Tumor Animals Humans genetics Lymphocytes Apolipoproteins B Adaptor Proteins Signal Transducing Mice Knockout B-Lymphocytes cholesterol Cholesterol LDL Hep G2 Cells Atherosclerosis Lipids Disease Models Animal Receptors LDL ComputingMethodologies_DOCUMENTANDTEXTPROCESSING lipids (amino acids peptides and proteins) Female |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology Arteriosclerosis, Thrombosis, and Vascular Biology, American Heart Association, 2020, pp.ATVBAHA119313470. ⟨10.1161/ATVBAHA.119.313470⟩ |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/ATVBAHA.119.313470⟩ |
| Popis: | Supplemental Digital Content is available in the text. Objective: STAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1−/−) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1−/− mice was transplanted to Ldlr−/− mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol. Conclusions: Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene. |
| Databáze: | OpenAIRE |
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