1. Taking One Step Back in Familial Hypercholesterolemia: STAP1 Does Not Alter Plasma LDL (Low-Density Lipoprotein) Cholesterol in Mice and Humans
- Author
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Arthur Flohr Svendsen, Niels J. Kloosterhuis, Justina C. Wolters, Marieke Smit, Bart van de Sluis, Natalia Loaiza, Merel L. Hartgers, Geesje M. Dallinga-Thie, Mirjam H. Koster, Maaike Winkelmeijer, G. Kees Hovingh, Jan Albert Kuivenhoven, Laurens F. Reeskamp, Hans Jansen, Nicolette C. A. Huijkman, Aldo Grefhorst, Venetia Bazioti, Andrea Volta, J.W. Balder, Antoine Rimbert, Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Graduate School, Vascular Medicine, 01 Internal and external specialisms, ACS - Atherosclerosis & ischemic syndromes, Experimental Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Digestive immunity, and AGEM - Endocrinology, metabolism and nutrition
- Subjects
EXPRESSION ,medicine.medical_specialty ,Candidate gene ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Biology ,Hyperlipoproteinemia type II ,MOUSE ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,RARE ,Internal medicine ,SCORE ,medicine ,Genetics ,Hyperlipoproteinemia Type II ,Gene ,030304 developmental biology ,AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA ,0303 health sciences ,Signal transducing adaptor family member 1 ,BRDG1 ,Cholesterol ,MUTATIONS ,medicine.disease ,Atherosclerosis ,GENE ,Endocrinology ,chemistry ,LDL - Low density lipoprotein cholesterol ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine - Abstract
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.
- Published
- 2020