Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1

Stefan A. Ljunggren, Johannes H. M. Levels, Kees Hovingh, Adriaan G. Holleboom, Menno Vergeer, Letta Argyri, Christina Gkolfinopoulou, Angeliki Chroni, Jeroen A. Sierts, John J. Kastelein, Jan Albert Kuivenhoven, Mats Lindahl, Helen Karlsson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

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. (C) 2015 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)1587-1595
Number of pages9
JournalBiochimica et biophysica acta-Molecular and cell biology of lipids
Volume1851
Issue number12
DOIs
Publication statusPublished - Dec-2015

Keywords

  • ApoE
  • ApoL-1
  • HDL
  • LDL/VLDL
  • P297S
  • SR-B1
  • HIGH-DENSITY-LIPOPROTEIN
  • 2-DIMENSIONAL GEL-ELECTROPHORESIS
  • CHOLESTEROL EFFLUX CAPACITY
  • CORONARY-HEART-DISEASE
  • ESTER TRANSFER PROTEIN
  • SR-BI
  • APOLIPOPROTEIN L
  • SUBCLINICAL ATHEROSCLEROSIS
  • CARDIOVASCULAR-DISEASE
  • MASS-SPECTROMETRY

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