{"doi":"10.1016/j.jlr.2024.100505","title":"Does small HDL’s function improve when lipid-lowering alters its composition?","abstract":"Metabolic syndrome associates with a markedly increased risk for cardiovascular disease (CVD) and very frequently with dyslipidemia, which is characterized by elevated plasma triglycerides and lower levels of high-density lipoprotein-cholesterol (HDL-C). Low HDL-C levels were long thought to contribute causally to increased CVD risk, but more recent studies have led to the realization that HDL’s cardioprotective functions do not always correlate with its cholesterol content and that increasing HDL-C levels therapeutically is not necessarily beneficial. This may be because HDL is a complex mixture of particles ranging from ∼7 nm to ∼14 nm in diameter (1Rosenson R.S. Brewer Jr., H.B. Chapman M.J. Fazio S. Hussain M.M. Kontush A. et al.HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.Clin. Chem. 2011; 57: 392-410Crossref PubMed Scopus (388) Google Scholar) and because total cholesterol mass varies more than 2-fold depending on particle size. As might be expected, the larger HDLs carry more cholesterol per particle than do smaller HDLs. HDL subspecies can be defined in multiple ways: by size, by protein composition, or by density, with small HDLs generally being denser due to their relatively high protein content and low lipid content per particle compared with the larger HDLs. Isopycnic density ultracentrifugation can isolate five HDL subpopulations ranging from the large most buoyant HDL2b followed by HDL2a, HDL3a, HDL3b, and the densest and smallest HDL3c (2Chapman M.J. Orsoni A. Mellett N.A. Nguyen A. Robillard P. Shaw J.E. et al.Statin treatment remodels the HDL subclass lipidome and proteome in hypertriglyceridemia.J. Lipid Res. 2023; 65100494Google Scholar) as shown in Fig. 1. HDL populations can also be sized by calibrated differential ion mobility analysis (3Hutchins P.M. Ronsein G.E. Monette J.S. Pamir N. Wimberger J. He Y. et al.Quantification of HDL particle concentration by calibrated ion mobility analysis.Clin. Chem. 2014; 60: 1393-1401Crossref PubMed Scopus (67) Google Scholar). This method directly measures the sizes and absolute concentrations of individual HDL particles. HDL populations measured by ion mobility analysis can be classified as large-HDL (L-HDL, which is roughly similar to HDL2b), medium-HDL (M-HDL), small-HDL (S-HDL), and very-small- or extra-small HDL (XS-HDL). The latter is roughly similar to HDL3c (1Rosenson R.S. Brewer Jr., H.B. Chapman M.J. Fazio S. Hussain M.M. Kontush A. et al.HDL measures, particle heterogeneity, proposed nomenclature, and relation to atherosclerotic cardiovascular events.Clin. Chem. 2011; 57: 392-410Crossref PubMed Scopus (388) Google Scholar). It is becoming increasingly clear that the various HDL subpopulations differ in composition and cardioprotective ability. Small HDL particles are best able to mediate cholesterol efflux from macrophages via the transporter ABCA1 (4Du X.M. Kim M.J. Hou L. Le Goff W. Chapman M.J. Van Eck M. et al.HDL particle size is a critical determinant of ABCA1-mediated macrophage cellular cholesterol export.Circ. Res. 2015; 116: 1133-1142Crossref PubMed Scopus (225) Google Scholar, 5He Y. Pavanello C. Hutchins P.M. Tang C. Pourmousa M. Vaisar T. et al.Flipped C-terminal ends of apoA1 promote ABCA1-dependent cholesterol efflux by small HDLs.Circulation. 2023; https://doi.org/10.1161/CIRCULATIONAHA.123.065959Crossref Scopus (0) Google Scholar)—the most studied of HDL’s cardioprotective effects. A recent model proposes that apolipoprotein A-I (APOA1), the major structural protein in HDL, interacts better with ABCA1 when it resides in small HDL particles because small HDLs contain less phospholipid (smaller phospholipid surface area). Therefore, APOA1’s C-termini are flipped off the surface, freeing them to engage ABCA1 (5He Y. Pavanello C. Hutchins P.M. Tang C. Pourmousa M. Vaisar T. et al.Flipped C-terminal ends of apoA1 promote ABCA1-dependent cholesterol efflux by small HDLs.Circula","journal":"Journal of Lipid Research","year":2024,"id":493438,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":313702,"name":"Tomáš Vaisar","orcid":"0000-0002-7406-6606","position":1,"is_corresponding":false},{"id":299555,"name":"Karin Bornfeldt","orcid":"0000-0001-9208-6523","position":2,"is_corresponding":false},{"id":306422,"name":"Jay W. Heinecke","orcid":null,"position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-19T02:09:03.883685Z","pmid":"38246236","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":[]}