title: Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport.
abstract: Phospholipid transfer protein (PLTP) may affect macrophage reverse cholesterol transport (mRCT) through its role in the metabolism of HDL. Ex vivo cholesterol efflux capacity and in vivo mRCT were assessed in PLTP deletion and PLTP overexpression mice. PLTP deletion mice had reduced HDL mass and cholesterol efflux capacity, but unchanged in vivo mRCT. To directly compare the effects of PLTP overexpression and deletion on mRCT, humanPLTPwas overexpressed in the liver of wild-type animals using an adeno-associated viral (AAV) vector, and control and PLTP deletion animals were injected with AAV-null. PLTP overexpression and deletion reduced plasma HDL mass and cholesterol efflux capacity. Both substantially decreased ABCA1-independent cholesterol efflux, whereas ABCA1-dependent cholesterol efflux remained the same or increased, even though preβ HDL levels were lower. Neither PLTP overexpression nor deletion affected excretion of macrophage-derived radiocholesterol in the in vivo mRCT assay. The ex vivo and in vivo assays were modified to gauge the rate of cholesterol efflux from macrophages to plasma. PLTP activity did not affect this metric. Thus, deviations in PLTP activity from the wild-type level reduce HDL mass and ex vivo cholesterol efflux capacity, but not the rate of macrophage cholesterol efflux to plasma or in vivo mRCT.
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Xin
authors.initials: X
authors.lastname: Bi
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cipollari
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: William R
authors.initials: WR
authors.lastname: Lagor
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Szapary
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Billheimer
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104. Electronic address: nilys@upenn.edu.
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Lyssenko
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; Department of Medicine and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood*; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D053442:High-Density Lipoproteins, Pre-beta / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D049294:Phospholipid Transfer Proteins / Q000096:biosynthesis / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D008076:Cholesterol, HDL; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D002784:Cholesterol
keywords: ATP binding cassette transporter A1; animal models; atherosclerosis; high density lipoprotein/metabolism; macrophages; phospholipid transfer protein activity