Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

Jari Metso,Teus Van Gent,Frank Grosveld,Matthijs Moerland,Hannelore Samyn,Arie Van Tol,Rini De Crom,Matti Jauhiainen,Rien Van Haperen

doi:10.1194/jlr.m800080-jlr200

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.

Highlights

Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL
We investigate the importance of PLTP transfer activity in lipoprotein metabolism, pre-bHDL formation, hepatic VLDL secretion, and the development of atherosclerosis, by comparing mice expressing human PLTP with and without transfer activity with their control littermates
Mutant PLTP transgenic mice were generated as described for PLTP transgenic mice, but a mutation was introduced in the cDNA sequence of the construct

Summary

Introduction

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 PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study. PLTP-deficient mice have markedly reduced HDL levels [12] These mice are more resistant to atherosclerosis development; this is partly attributable to diminished secretion and lower levels of apolipoprotein B (apoB)-containing lipoproteins and to the increase in bioavailability of vitamin E in these particles [13, 14]. When overexpressing human PLTP in mice, elevation of plasma PLTP activity levels results in a dose-dependent decrease in HDL levels, despite an increased production of pre-b-HDL particles [15]. How elevated PLTP levels lead to increased atherosclerosis is still not fully understood

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