Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1
Open accessAbstract
The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1(P297S) mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1(P297S) heterozygotes.Lipoproteins from six SR-B1(P297S) carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.The SR-B1(P297S) mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.
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Mutations of SR-BI (P279S, P376L) are associated with both significant increases in HDL-C and increased cardiovascular risk.
“Only recently, mutations of scavenger receptor (SR-BI) (P279S, P376L) have been described which are associated with both significant increases in HDL-C and increased cardiovascular risk [38–40].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [39]
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HDL cholesterol: reappraisal of its clinical relevance
März, W., Kleber, M. E., Scharnagl, H., Speer, T., Zewinger, S., Ritsch, A., Parhofer, K. G., von Eckardstein, A., Landmesser, U., & Laufs, U. (2017) · Clinical Research in Cardiology · doi:10.1007/s00392-017-1106-1 · Cited by 275 · see citing works
- Authors
- Ljunggren, S. A., Levels, J. H. M., Hovingh, K., Holleboom, A. G., Vergeer, M., Argyri, L., Gkolfinopoulou, C., Chroni, A., Sierts, J. A., Kastelein, J. J., Kuivenhoven, J. A., Lindahl, M., & Karlsson, H.
- Affiliations
- Linköping University (SE)
- Amsterdam UMC Location University of Amsterdam (NL)
- National Centre of Scientific Research "Demokritos" (GR)
- University Medical Center Groningen (NL)
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 1851
- Issue
- 12
- Pages
- 1587-1595
- ISSN
- 1388-1981 (ISSN-L)
- OpenAlex
- W2189806027
- Cited by
- 19
- References
- 45
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- green
- urn.kb.se
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- EU's Sixth Framework Program (037631)
- European Union (FP7-603091-2)
- CardioVascular Research Initiative (CVON2011-16)
- Research Council of South East Sweden (FORSS-3755)
- County Council of Östergötland
- Faculty of Health Sciences in Linköping
- NWO (91612122, 91613031)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- scavenger receptor class B type I, heterozygous carriers, lipoprotein composition, HDL cholesterol, apolipoprotein E, HDL antioxidant activity, paraoxonase 1, HDL cholesterol efflux, cholesterol absorption, lipoprotein metabolism
- MeSH terms
- Antioxidants, Female, Heterozygote, Humans, Lipoproteins, Male, Amino Acid Substitution, Mutation, Missense, Aryldialkylphosphatase, Scavenger Receptors, Class B
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