title: Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
abstract: 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.
authors.affiliation: Occupational and Environmental Medicine Center, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Electronic address: stefan.ljunggren@liu.se.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Ljunggren
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: H.Levels@amc.uva.nl.
authors.forename: Johannes H M
authors.initials: JH
authors.lastname: Levels
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: G.K.Hovingh@amc.uva.nl.
authors.forename: Kees
authors.initials: K
authors.lastname: Hovingh
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: A.G.Holleboom@amc.uva.nl.
authors.forename: Adriaan G
authors.initials: AG
authors.lastname: Holleboom
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: mennovergeer@hotmail.com.
authors.forename: Menno
authors.initials: M
authors.lastname: Vergeer
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Athens, Greece. Electronic address: largyri@bio.demokritos.gr.
authors.forename: Letta
authors.initials: L
authors.lastname: Argyri
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Athens, Greece. Electronic address: xristinaki.1987@hotmail.com.
authors.forename: Christina
authors.initials: C
authors.lastname: Gkolfinopoulou
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Athens, Greece. Electronic address: achroni@bio.demokritos.gr.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: jasierts@yahoo.com.
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Sierts
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: j.j.kastelein@amc.uva.nl.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Pediatrics, section for Molecular Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address: j.a.kuivenhoven@umcg.nl.
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Electronic address: mats.lindahl@liu.se.
authors.forename: Mats
authors.initials: M
authors.lastname: Lindahl
authors.affiliation: Occupational and Environmental Medicine Center, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. Electronic address: helen.m.karlsson@liu.se.
authors.forename: Helen
authors.initials: H
authors.lastname: Karlsson
mesh_terms: D019943:Amino Acid Substitution; D000975:Antioxidants / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D020125:Mutation, Missense; D051122:Scavenger Receptors, Class B / Q000097:blood* / Q000235:genetics*
chemical_list: D000975:Antioxidants; D008074:Lipoproteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
keywords: ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1