{"doi":"10.1016/j.jlr.2021.100099","title":"Apolipoprotein A-I modulates HDL particle size in the absence of apolipoprotein A-II","abstract":"Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 and 91 , respectively. Unexpectedly, isotope dilution MS/MS with [ 15 N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two \"settings\"-large and small-that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.","journal":"Journal of Lipid Research","year":2021,"id":168721,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":30,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":698803,"name":"Scott E Street","orcid":null,"position":1,"is_corresponding":false},{"id":313702,"name":"Tomáš Vaisar","orcid":"0000-0002-7406-6606","position":2,"is_corresponding":false},{"id":530446,"name":"Rachel Hart","orcid":"0009-0005-3454-7922","position":3,"is_corresponding":false},{"id":698804,"name":"Jay Jerome","orcid":null,"position":4,"is_corresponding":false},{"id":698263,"name":"Zsuzsanna Kuklenyik","orcid":"0000-0001-9801-7705","position":5,"is_corresponding":false},{"id":313698,"name":"Noémie Clouet-Foraison","orcid":"0000-0002-3966-2453","position":6,"is_corresponding":false},{"id":698264,"name":"Carissa Thornock","orcid":"0000-0002-8676-2748","position":7,"is_corresponding":false},{"id":484343,"name":"Shimpi Bedi","orcid":"0000-0003-3277-7845","position":8,"is_corresponding":false},{"id":406587,"name":"Amy S. Shah","orcid":"0000-0001-7297-139X","position":9,"is_corresponding":false},{"id":304683,"name":"Jere P. Segrest","orcid":"0000-0002-0676-7996","position":10,"is_corresponding":false},{"id":306422,"name":"Jay W. Heinecke","orcid":null,"position":11,"is_corresponding":false},{"id":304680,"name":"W. Sean Davidson","orcid":"0000-0003-2756-2989","position":12,"is_corresponding":false},{"id":698262,"name":"John Melchior","orcid":"0000-0003-3781-2566","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-18T23:46:06.853307Z","pmid":"34324889","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}