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

Biochim Biophys Acta. 2015 Dec;1851(12):1587-95. doi: 10.1016/j.bbalip.2015.09.006.

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.

Keywords: ApoE; ApoL-1; HDL; LDL/VLDL; P297S; SR-B1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Antioxidants / metabolism
  • Aryldialkylphosphatase / metabolism
  • Female
  • Heterozygote*
  • Humans
  • Lipoproteins / blood*
  • Male
  • Mutation, Missense*
  • Scavenger Receptors, Class B / blood*
  • Scavenger Receptors, Class B / genetics*

Substances

  • Antioxidants
  • Lipoproteins
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Aryldialkylphosphatase
  • PON1 protein, human