Inducible expression of phospholipid transfer protein (PLTP) in transgenic mice: acute effects of PLTP on lipoprotein metabolism.
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.
Moerland
Matthijs
M
Department of Cell Biology and Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands.
Anghelescu
Nora
N
Samyn
Hannelore
H
van Haperen
Rien
R
van Gent
Teus
T
Strouboulis
John
J
van Tol
Arie
A
Grosveld
Frank
F
de Crom
Rini
R
D000818:Animals; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000502:physiology*; D049294:Phospholipid Transfer Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D013752:Tetracycline / Q000494:pharmacology
D008055:Lipids; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C510091:phospholipid transfer protein, mouse; D013752:Tetracycline