Human Plasma Phospholipid Transfer Protein Increases the Antiatherogenic Potential of High Density Lipoproteins in Transgenic Mice

Abstract

Abstract-Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoprotein particles and alters high density lipoprotein (HDL) subfraction patterns in vitro, but its physiological function is poorly understood. Transgenic mice that overexpress human PLTP were generated. Compared with wild-type mice, these mice show a 2.5-to 4.5-fold increase in PLTP activity in plasma. This results in a 30% to 40% decrease of plasma levels of HDL cholesterol. Incubation of plasma from transgenic animals at 37°C reveals a 2-to 3-fold increase in the formation of pre-␤-HDL compared with plasma from wild-type mice. Although pre-␤-HDL is normally a minor subfraction of HDL, it is known to be a very efficient acceptor of peripheral cell cholesterol and a key mediator in reverse cholesterol transport. Further experiments show that plasma from transgenic animals is much more efficient in preventing the accumulation of intracellular cholesterol in macrophages than plasma from wild-type mice, despite lower total HDL concentrations. It is concluded that PLTP can act as an antiatherogenic factor preventing cellular cholesterol overload by generation of pre-␤-HDL.

Influence of leptin and insulin on lipid transfer proteins in human hepatoma cell line, HepG2

“…The role of PLTP in lipoprotein metabolism, especially HDL metabolism, was shown in PLTP-knock out mice and in mice overexpressing PLTP. Both, overexpression of PLTP 37,48,49 and targeted mutation of PLTP 50 led to a dramatic reduction of HDL-cholesterol (HDL-C) in plasma, although through different mechanisms; it was hypothesized 50 that PLTP knock-out reduced HDL due to decreased transfer of surface components from TG-rich lipoproteins into HDL and altered stability of HDL particles. Overexpression of PLTP, it was hypothesized, 49 accelerates HDL catabolism leading to a decrease of HDL levels.…”

“…Both, overexpression of PLTP 37,48,49 and targeted mutation of PLTP 50 led to a dramatic reduction of HDL-cholesterol (HDL-C) in plasma, although through different mechanisms; it was hypothesized 50 that PLTP knock-out reduced HDL due to decreased transfer of surface components from TG-rich lipoproteins into HDL and altered stability of HDL particles. Overexpression of PLTP, it was hypothesized, 49 accelerates HDL catabolism leading to a decrease of HDL levels. In the latter situation, despite low HDL levels, increased formation of pre-ß-HDL was observed 49 as was enhanced efficiency of plasma in preventing the accumulation of intracellular cholesterol, 49 both effects potentially promoting an antiatherogenic situation.…”

“…Overexpression of PLTP, it was hypothesized, 49 accelerates HDL catabolism leading to a decrease of HDL levels. In the latter situation, despite low HDL levels, increased formation of pre-ß-HDL was observed 49 as was enhanced efficiency of plasma in preventing the accumulation of intracellular cholesterol, 49 both effects potentially promoting an antiatherogenic situation.…”

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

“…Most functions of PLTP are potentially atherogenic: overexpression of human PLTP dose-dependently decreases HDL levels, resulting in a more atherogenic lipoprotein profile (Albers et al 1996;van Haperen et al 2002); overexpression of human PLTP stimulates VLDL secretion by the liver (Lie et al 2002;van Haperen et al 2002); lipoprotein oxidizability increases following adenoviral overexpression of PLTP in atherosclerosis-prone mice (Jiang et al 2002;Yang et al 2003). On the other hand, PLTP has anti-atherogenic potential as well, because it increases the formation of preb-HDL, an HDL subfraction that is a very efficient acceptor of cellular cholesterol and therefore an important mediator in reverse cholesterol transport (Jiang et al 1996;Lie et al 2001;van Haperen et al 2000). Apparently, PLTP displays both pro-and anti-atherogenic properties, of which the experimental approaches used so far demonstrate that the net effect is proatherogenic (Desrumaux et al 2003;Jiang et al 2001;Lie et al 2004;van Haperen et al 2002;Yang et al 2003).…”

La protéine plasmatique de transfert des phospholipides (PLTP) : un nouveau facteur athérogène

“…Alors que c'est dans ce contexte que la PLTP a été initialement étudiée, des données plus récentes ont indiqué qu'elle peut être également impliquée dans le flux sortant du cholestérol cellulaire, les transfert de vitamine E et la sécrétion des VLDL (very low density lipoproteins) par le foie (Figure 1). La PLTP est exprimée naturellement à des niveaux éle-vés chez la souris et, de ce fait, les effets additifs résultant de l'expression de la PLTP humaine à des concentrations physiologiques ont été relativement modérés chez la souris transgénique [1,3,4]. Ils ont néanmoins permis de valider l'hypothèse selon laquelle la PLTP joue un rôle important dans le métabolisme intravasculaire des HDL [1,3,4].…”