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.
N1 - Publisher Copyright:
© 2019 Pamir et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2019
Y1 - 2019
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
C2 - 30622162
AN - SCOPUS:85064262793
SN - 0022-2275
VL - 60
SP - 594
EP - 608
JO - Journal of lipid research
JF - Journal of lipid research
IS - 3
ER -