title: Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study.
abstract: Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL. Overexpressing human PLTP in mice increases the susceptibility to atherosclerosis. In human plasma, high-active and low-active forms of PLTP exist. To elucidate the contribution of phospholipid transfer activity to changes in lipoprotein metabolism and atherogenesis, we developed mice expressing mutant PLTP, still able to associate with HDL but lacking phospholipid transfer activity. In mice heterozygous for the LDL receptor, effects of the mutant and normal human PLTP transgene (mutPLTP tg and PLTP tg, respectively) were compared. In PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. In contrast, in mutPLTP tg mice, lipid levels were not different from controls. Furthermore, hepatic VLDL-TG secretion was stimulated in PLTP tg mice, but not in mutPLTP tg mice. When mice were fed a cholesterol-enriched diet, atherosclerotic lesion size in PLTP tg mice was increased more than 2-fold compared with control mice, whereas in mutPLTP tg mice, there was no change. Our findings demonstrate that PLTP transfer activity is essential for the development of atherosclerosis in PLTP transgenic mice, identifying PLTP activity as a possible target to prevent atherogenesis, independent of plasma PLTP concentration.
authors: Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Hannelore
authors: H
authors: Samyn
authors: Matthijs
authors: M
authors: Moerland
authors: Teus
authors: T
authors: van Gent
authors: Rien
authors: R
authors: van Haperen
authors: Jari
authors: J
authors: Metso
authors: Frank
authors: F
authors: Grosveld
authors: Matti
authors: M
authors: Jauhiainen
authors: Arie
authors: A
authors: van Tol
authors: Rini
authors: R
authors: de Crom
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D008079:Lipoproteins, VLDL; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; C510091:phospholipid transfer protein, mouse