title: Factors controlling nascent high-density lipoprotein particle heterogeneity: ATP-binding cassette transporter A1 activity and cell lipid and apolipoprotein AI availability.
abstract: Nascent high-density lipoprotein (HDL) particles arise in different sizes. We have sought to uncover factors that control this size heterogeneity. Gel filtration, native PAGE, and protein cross-linking were used to analyze the size heterogeneity of nascent HDL produced by BHK-ABCA1, RAW 264.7, J774, and HepG2 cells under different levels of two factors considered as a ratio, the availability of apolipoprotein AI (apoAI) -accessible cell lipid, and concentration of extracellular lipid-free apoAI. Increases in the available cell lipid:apoAI ratio due to either elevated ATP-binding cassette transporter A1 (ABCA1) expression and activity or raised cell density (i.e., increasing numerator) shifted the production of nascent HDL from smaller particles with fewer apoAI molecules per particle and fewer molecules of choline-phospholipid and cholesterol per apoAI molecule to larger particles that contained more apoAI and more lipid per molecule of apoAI. A further shift to larger particles was observed in BHK-ABCA1 cells when the available cell lipid:apoAI ratio was raised still higher by decreasing the apoAI concentration (i.e., the denominator). These changes in nascent HDL biogenesis were reminiscent of the transition that occurs in the size composition of reconstituted HDL in response to an increasing initial lipid:apoAI molar ratio. Thus, the ratio of available cell lipid:apoAI is a fundamental cause of nascent HDL size heterogeneity, and rHDL formation is a good model of nascent HDL biogenesis.
authors.affiliation: Lipid Research Group, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Lyssenko
authors.forename: Margaret
authors.initials: M
authors.lastname: Nickel
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism*; D002452:Cell Count; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000032:analysis* / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D010316:Particle Size
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL; D015735:Mifepristone; D002784:Cholesterol
keywords: HDL quality; discoidal HDL; macrophage reverse cholesterol transport; reconstituted HDL
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