title: Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway.
abstract: Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL's size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL's content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL's content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL's ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL's APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA pamir@ohsu.edu.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pamir
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hutchins
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Graziella
authors.initials: G
authors.lastname: Ronsein
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Vaisar
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL.
authors.forename: Godfrey S
authors.initials: GS
authors.lastname: Getz
authors.affiliation: Department of Genetics, University of California at Los Angeles, Los Angeles, CA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D002784:Cholesterol; D008075:Lipoproteins, HDL; C577833:Abca1 protein, mouse
keywords: ATP binding cassette transporter A1; apolipoprotein E; atherosclerosis; cardiovascular risk; high density lipoprotein; mass spectrometry