Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity

Nathalie Pamir, Calvin Pan, Deanna L. Plubell, Patrick M. Hutchins, Chongren Tang, Jake Wimberger, Angela Irwin, Thomas Q. De Aguiar Vallim, Jay W. Heinecke, Aldons J. Lusis

Research output: Contribution to journalArticle

Abstract

HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local cis-acting regulation, termed cis-protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL's properties, such as protection against CAD.

Original languageEnglish (US)
Pages (from-to)594-608
Number of pages15
JournalJournal of lipid research
Volume60
Issue number3
DOIs
StatePublished - Jan 1 2019

Fingerprint

Proteome
Proteins
Cholesterol Esters
Quantitative Trait Loci
Sterols
Coronary Artery Disease
Cholesterol
Apolipoproteins C
Apolipoprotein A-II
Protein Interaction Maps
Inbred Strains Mice
Macrophages
Nanoparticles
HDL Cholesterol
Chemical analysis
Phospholipids
Phenotype

Keywords

  • High density lipoprotein
  • Single nucleotide polymorphism
  • Sterol efflux

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Pamir, N., Pan, C., Plubell, D. L., Hutchins, P. M., Tang, C., Wimberger, J., ... Lusis, A. J. (2019). Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity. Journal of lipid research, 60(3), 594-608. https://doi.org/10.1194/jlr.M090555

Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity. / Pamir, Nathalie; Pan, Calvin; Plubell, Deanna L.; Hutchins, Patrick M.; Tang, Chongren; Wimberger, Jake; Irwin, Angela; De Aguiar Vallim, Thomas Q.; Heinecke, Jay W.; Lusis, Aldons J.

In: Journal of lipid research, Vol. 60, No. 3, 01.01.2019, p. 594-608.

Research output: Contribution to journalArticle

Pamir, N, Pan, C, Plubell, DL, Hutchins, PM, Tang, C, Wimberger, J, Irwin, A, De Aguiar Vallim, TQ, Heinecke, JW & Lusis, AJ 2019, 'Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity' Journal of lipid research, vol. 60, no. 3, pp. 594-608. https://doi.org/10.1194/jlr.M090555
Pamir, Nathalie ; Pan, Calvin ; Plubell, Deanna L. ; Hutchins, Patrick M. ; Tang, Chongren ; Wimberger, Jake ; Irwin, Angela ; De Aguiar Vallim, Thomas Q. ; Heinecke, Jay W. ; Lusis, Aldons J. / Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity. In: Journal of lipid research. 2019 ; Vol. 60, No. 3. pp. 594-608.
@article{d3a13ea7f2ca4c09818ac99e28e990f2,
title = "Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity",
abstract = "HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local cis-acting regulation, termed cis-protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL's properties, such as protection against CAD.",
keywords = "High density lipoprotein, Single nucleotide polymorphism, Sterol efflux",
author = "Nathalie Pamir and Calvin Pan and Plubell, {Deanna L.} and Hutchins, {Patrick M.} and Chongren Tang and Jake Wimberger and Angela Irwin and {De Aguiar Vallim}, {Thomas Q.} and Heinecke, {Jay W.} and Lusis, {Aldons J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1194/jlr.M090555",
language = "English (US)",
volume = "60",
pages = "594--608",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "3",

}

TY - JOUR

T1 - Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity

AU - Pamir, Nathalie

AU - Pan, Calvin

AU - Plubell, Deanna L.

AU - Hutchins, Patrick M.

AU - Tang, Chongren

AU - Wimberger, Jake

AU - Irwin, Angela

AU - De Aguiar Vallim, Thomas Q.

AU - Heinecke, Jay W.

AU - Lusis, Aldons J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local cis-acting regulation, termed cis-protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL's properties, such as protection against CAD.

AB - HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local cis-acting regulation, termed cis-protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL's properties, such as protection against CAD.

KW - High density lipoprotein

KW - Single nucleotide polymorphism

KW - Sterol efflux

UR - http://www.scopus.com/inward/record.url?scp=85064262793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064262793&partnerID=8YFLogxK

U2 - 10.1194/jlr.M090555

DO - 10.1194/jlr.M090555

M3 - Article

VL - 60

SP - 594

EP - 608

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 3

ER -