Inducible expression of phospholipid transfer protein (PLTP) in transgenic mice: acute effects of PLTP on lipoprotein metabolism

TY - JOUR

T1 - Inducible expression of phospholipid transfer protein (PLTP) in transgenic mice

T2 - acute effects of PLTP on lipoprotein metabolism

AU - Moerland, Matthijs

AU - Anghelescu, Nora

AU - Samyn, Hannelore

AU - van Haperen, Rien

AU - van Gent, Teus

AU - Strouboulis, John

AU - van Tol, Arie

AU - Grosveld, Frank

AU - de Crom, Rini

PY - 2007/8

Y1 - 2007/8

N2 - One main determinant in high-density lipoprotein (HDL) metabolism is phospholipid transfer protein (PLTP), a plasma protein that is associated with HDL. In transgenic mice overexpressing human PLTP we found that elevated plasma PLTP levels dose-dependently increased the susceptibility to diet-induced atherosclerosis. This could be mainly due to the fact that most functions of PLTP are potentially atherogenic, such as decreasing plasma HDL levels. To further elucidate the role of PLTP in lipoprotein metabolism and atherosclerosis we generated a novel transgenic mouse model that allows conditional expression of human PLTP. In this mouse model a human PLTP encoding sequence is controlled by a Tet-On system. Upon induction of PLTP expression, our mouse model showed a strongly increased PLTP activity (from 3.0 +/- 0.6 to 11.4 +/- 2.8 AU, p < 0.001). The increase in PLTP activity resulted in an acute decrease in plasma cholesterol of 33% and a comparable decrease in phospholipids. The decrease in total plasma cholesterol and phospholipids was caused by a 35% decrease in HDL-cholesterol level and a 41% decrease in HDL-phospholipid level. These results demonstrate the feasibility of our mouse model to induce an acute elevation of PLTP activity, which is easily reversible. As a direct consequence of an increase in PLTP activity, HDL-cholesterol and HDL-phospholipid levels strongly decrease. Using this mouse model, it will be possible to study the effects of acute elevation of PLTP activity on lipoprotein metabolism and pre-existing atherosclerosis.

AB - One main determinant in high-density lipoprotein (HDL) metabolism is phospholipid transfer protein (PLTP), a plasma protein that is associated with HDL. In transgenic mice overexpressing human PLTP we found that elevated plasma PLTP levels dose-dependently increased the susceptibility to diet-induced atherosclerosis. This could be mainly due to the fact that most functions of PLTP are potentially atherogenic, such as decreasing plasma HDL levels. To further elucidate the role of PLTP in lipoprotein metabolism and atherosclerosis we generated a novel transgenic mouse model that allows conditional expression of human PLTP. In this mouse model a human PLTP encoding sequence is controlled by a Tet-On system. Upon induction of PLTP expression, our mouse model showed a strongly increased PLTP activity (from 3.0 +/- 0.6 to 11.4 +/- 2.8 AU, p < 0.001). The increase in PLTP activity resulted in an acute decrease in plasma cholesterol of 33% and a comparable decrease in phospholipids. The decrease in total plasma cholesterol and phospholipids was caused by a 35% decrease in HDL-cholesterol level and a 41% decrease in HDL-phospholipid level. These results demonstrate the feasibility of our mouse model to induce an acute elevation of PLTP activity, which is easily reversible. As a direct consequence of an increase in PLTP activity, HDL-cholesterol and HDL-phospholipid levels strongly decrease. Using this mouse model, it will be possible to study the effects of acute elevation of PLTP activity on lipoprotein metabolism and pre-existing atherosclerosis.

KW - Animals

KW - Female

KW - Humans

KW - Lipids/blood

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic/physiology

KW - Phospholipid Transfer Proteins/drug effects

KW - Protein Synthesis Inhibitors/pharmacology

KW - RNA, Messenger/analysis

KW - Tetracycline/pharmacology

U2 - 10.1007/s11248-007-9094-y

DO - 10.1007/s11248-007-9094-y

M3 - Article

C2 - 17437182

SN - 0962-8819

VL - 16

SP - 503

EP - 513

JO - Transgenic Research

JF - Transgenic Research

IS - 4

ER -