title: Elevation of systemic PLTP, but not macrophage-PLTP, impairs macrophage reverse cholesterol transport in transgenic mice.
abstract: Phospholipid transfer protein (PLTP) is a multifunctional protein synthesized by various cell types and secreted into the plasma. Plasma PLTP is able to transfer phospholipids between lipoproteins and modulate HDL particles. Mice with overexpression of human PLTP have an increased ability to generate pre beta-HDL, reduced total HDL levels and an increased susceptibility to atherosclerosis. As the macrophage is a key component of the atherosclerotic lesion and an important site of PLTP expression, we investigated the role of systemic and peripheral PLTP in macrophage cholesterol efflux and reverse cholesterol transport (RCT) in vivo. We used an assay in which (3)H-labelled cholesterol-loaded macrophages were injected intraperitoneally into recipient mice, and radioactivity was quantified in plasma, liver and faeces. Firstly, wild type macrophages were injected into wild type, PLTP transgenic (PLTPtg) and apoAI transgenic (apoAItg) mice. While plasma (3)H-tracer levels in apoAItg mice were increased compared with wild type mice, they were reduced in PLTPtg mice. Moreover, overexpression of PLTP significantly decreased faecal (3)H-tracer levels compared with wild type and apoAItg mice. Secondly, wild type mice were injected with peritoneal macrophages derived from PLTPtg or wild type mice. No significant difference in the amount of (3)H-tracer in plasma, liver or faeces was found between the two groups of mice. Our findings demonstrate that macrophage cholesterol efflux and RCT to faeces is impaired in PLTP transgenic mice, and that elevation of macrophage-PLTP does not affect RCT, indicating that higher systemic PLTP levels may promote atherosclerosis development by decreasing the rate of macrophage RCT.
authors.affiliation: Department of Cell Biology & Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Samyn
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moerland
authors.forename: Teus
authors.initials: T
authors.lastname: van Gent
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Arie
authors.initials: A
authors.lastname: van Tol
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology*; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000637:transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D053442:High-Density Lipoproteins, Pre-beta; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D002784:Cholesterol