Increased Risk of Atherosclerosis by Elevated Plasma Levels of Phospholipid Transfer Protein

Abstract

Plasma phospholipid transfer protein (PLTP) is thought to be involved in the remodeling of high density lipoproteins (HDL), which are atheroprotective. It is also involved in the metabolism of very low density lipoproteins (VLDL). Hence, PLTP is thought to be an important factor in lipoprotein metabolism and the development of atherosclerosis. We have overexpressed PLTP in mice heterozygous for the low density lipoprotein (LDL) receptor, a model for atherosclerosis. We show that increased PLTP activity results in a dose-dependent decrease in HDL, and a moderate stimulation of VLDL secretion (<1.5-fold). The mice were given a high fat, high cholesterol diet, which resulted in hypercholesterolemia in all animals. HDL concentrations were dramatically reduced in PLTP-overexpressing animals when compared with LDL receptor controls, whereas VLDL ؉ LDL cholesterol levels were identical. Susceptibility to atherosclerosis was increased in a PLTP doseresponsive manner. We conclude that PLTP increases susceptibility to atherosclerosis by lowering HDL concentrations, and therefore we suggest that an increase in PLTP is a novel, long term risk factor for atherosclerosis in humans. High density lipoproteins (HDL)1 are believed to be protective against the development of atherosclerosis because they mediate reverse cholesterol transport, i.e. the transfer of cholesterol from peripheral tissues to the liver (1, 2). However, our understanding of the molecular details and key regulatory proteins involved is incomplete (3-5). One effector of this process is the ATP-binding cassette ABCA1, which is functionally deficient in Tangier disease (reviewed in Ref. 6). The high incidence of coronary artery disease in Tangier patients suggests an essential, protective role of HDL-mediated reverse cholesterol transport in the development of atherosclerosis (7).However, recent results suggest that the contribution of ABCA1 to overall reverse cholesterol transport and its role in atherogenesis are primarily related to its function in macrophages (8 -10). Therefore, other potential key proteins in reverse cholesterol transport are of interest, including PLTP (11-13).Previously, we generated transgenic mice overexpressing human PLTP and showed that plasma from these animals is more effective in preventing accumulation of cholesterol by cultured macrophages (14). We and others therefore suggested an antiatherogenic effect for PLTP (14 -16). On the other hand, overexpression of PLTP results in a decrease of plasma HDL levels (14, 17, 18), which could be an atherogenic effect. Thus, it is unclear whether the net effect of high PLTP activity levels would be atherogenic or anti-atherogenic. The complete absence of PLTP activity in PLTP knockout mice inhibits HDL maturation, which results in reduced levels of plasma HDL caused by accelerated decay (19,20). Still, PLTP knockout mice showed decreased atherosclerosis (21). This could be partly explained by the discovery of a novel, intracellular function of PLTP in hepatocytes; it was found that PLTP def...

Degradation of Phospholipid Transfer Protein (PLTP) and PLTP-generated Pre-β-high Density Lipoprotein by Mast Cell Chymase Impairs High Affinity Efflux of Cholesterol from Macrophage Foam Cells

“…Also in mice with adenovirus-mediated overexpression of PLTP, increased levels of pre-␤-HDL were observed (12,13). In contrast, PLTP deficiency in hyperlipidemic mice models has resulted in decreased atherosclerosis that was explained via the effects on VLDL secretion (41), and strong overexpression of PLTP in mice heterozygous for the LDL receptor has been shown to increase the susceptibility to atherosclerosis (42). However, both the overexpression and gene knockout models are quite extreme conditions, and therefore, depending on the metabolic status, PLTP may display anti-or proatherogenic properties.…”

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

“…These include the transfer of phospholipids from triglyceride-rich lipoproteins to high-density lipoproteins (HDL) during lipolysis (Tall et al 1985), the remodeling of HDL-particles (Jauhiainen et al 1993;Tu et al 1993), the stimulation of hepatic very low-density lipoprotein (VLDL) secretion (Jiang et al , 2001Lie et al 2002;van Haperen et al 2002), and the modification of the inflammatory and oxidative state of lipoproteins Jiang et al 2002;Schlitt et al 2005;Yan et al 2004;Yang et al 2003).…”

“…Overexpression of human PLTP in lowdensity lipoprotein receptor (LDLR) deficient mice resulted in a dose-responsive increase in susceptibility to atherosclerosis . 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).…”

“…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). However, it is important to notice that PLTP is a lipid transfer protein and thus very sensitive to changes in lipaemia (Rye et al 1998).…”

Haplotypes in the phospholipid transfer protein gene are associated with obesity-related phenotypes: the Québec Family Study

“…18,19 In addition, several mouse studies have suggested that genes influencing body fatness in mice reside on chromosome 2 in a region homologous to human chromosome 20q. [20][21][22] Finally, it has been shown that PLPT facilitates the production of triglyceride-rich apoB-containing lipoproteins 23,24 and the transport of lipids from cells, 25 which are central functions of lipid homeostasis. Based on these observations, we hypothesize that PLTP modulates the level of adiposity.…”