Plasma Phospholipid Transfer Protein

Föger, Bernhard; Santamarina-Fojo, Silvia; Shamburek, Robert D.; Parrot, Catherine L.; Talley, Glenda D.; Brewer, H. Bryan

doi:10.1074/jbc.272.43.27393

Cited by 129 publications

(27 citation statements)

References 47 publications

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“…On the other hand, plasma HDL levels are clearly related to the activity levels of plasma PLTP. In the highest expressing line of PLTP transgenic mice (A2), both HDL cholesterol and HDL protein (apoAI) were virtually absent from plasma, a result also found in adenoviral transfected mice that express very high levels of PLTP (17,18). This is explained by the surface activity of PLTP on phospholipids in the outer shell of the HDL particles, causing instability and increased HDL catabolism (18).…”

Section: Discussionmentioning

confidence: 87%

“…Previously, we and others suggested that overexpression of PLTP resulted in an increase in the anti-atherogenic potential of HDL, because of an increased formation of pre-␤-HDL in plasma (14,16,18). In addition, plasma from PLTP transgenic animals was more efficient in preventing the accumulation of cholesterol by cultured macrophages (14).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: High Density Lipoproteins (Hdl)mentioning

confidence: 99%

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

Haperen¹,

Tol²,

Gent³

et al. 2002

Journal of Biological Chemistry

119

122

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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...

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: High Density Lipoproteins (Hdl)mentioning

confidence: 99%

See 1 more Smart Citation

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

Haperen¹,

Tol²,

Gent³

et al. 2002

Journal of Biological Chemistry

119

122

View full text Add to dashboard Cite

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“…The role of PLTP in HDL metabolism is complex (21,22). Both PLTP knockout and PLTP overexpression in mice have been reported to be associated with low HDL (23,24). The marked downregulation of PLTP in the absence of EL is intriguing.…”

Section: Absence Of El Affects Expression Of Selected Gene Products Tmentioning

confidence: 98%

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Çilingiroğlu

Otvos

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

216

220

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High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL, metabolism, yet the evidence has been scarce and conflicting. We have inactivated EL in mice by gene targeting. EL ؊/؊ mice have elevated plasma and HDL cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an abundance of large HDL particles. There is down-regulation of the transcripts for phospholipid transfer protein, but up-regulation of those for hepatic lipase and lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase activity toward endogenous EL ؊/؊ substrate is, however, reduced by 50%. HDL clearance is decreased in EL ؊/؊ mice; both the structure of HDL and the presence of EL are factors that determine the rate of clearance. To determine EL's role in humans, we find a significant association between a single-nucleotide polymorphism 584C͞T in the EL (LIPG) gene and HDL cholesterol in a well characterized population of 372 individuals. We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans.lipoprotein metabolism ͉ atherosclerosis ͉ gene targeting

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“…(ii) Human plasma PLTP in vitro converts small HDL 3 particles into larger particles, with concomitant release of poorly lipidated apoA-I, which displays pre-␤-mobility in agarose electrophoresis (10,11). Moreover, in vivo, in both transiently expressed and transgenic mouse models of PLTP, an increased capacity of the plasma of mice overexpressing human PLTP to produce pre-␤-HDL has been demonstrated (11)(12)(13). Thus, by influencing HDL size and composition, PLTP plays an important role in HDL metabolism and modulates its anti-atherogenic potential.…”

mentioning

confidence: 99%

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

Lee

Metso

Jauhiainen

et al. 2003

Journal of Biological Chemistry

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Human atherosclerotic lesions contain mast cells filled with the neutral protease chymase. Here we studied the effect of human chymase on (i) phospholipid transfer protein (PLTP)-mediated phospholipid (PL) transfer activity, and (ii) the ability of PLTP to generate pre-␤-high density lipoprotein (HDL). Immunoblot analysis of PLTP after incubation with chymase for 6 h revealed, in addition to the original 80-kDa band, four specific proteolytic fragments of PLTP with approximate molecular masses of 70, 52, 48, and 31 kDa. This specific pattern of PLTP degradation remained stable for at least 24 h of incubation with chymase. Such proteolyzed PLTP had reduced ability (i) to transfer PL from liposome donor particles to acceptor HDL 3 particles, and (ii) to facilitate the formation of pre-␤-HDL. However, when PLTP was incubated with chymase in the presence of HDL 3 , only one major cleavage product of PLTP (48 kDa) was generated, and PL transfer activity was almost fully preserved. Moreover, chymase effectively depleted the pre-␤-HDL particles generated from HDL 3 by PLTP and significantly inhibited the high affinity component of cholesterol efflux from macrophage foam cells. These results suggest that the mast cells in human atherosclerotic lesions, by secreting chymase, may prevent PLTP-dependent formation of pre-␤-HDL particles from HDL 3 and so impair the anti-atherogenic function of PLTP.Reverse cholesterol transport is a physiologically important route for removal of excess cholesterol from the membranes of peripheral cells and its transport to the liver for secretion into the bile. This process is of special importance for macrophages, which, having no ability to regulate incoming cholesterol, are readily transformed into cholesterol-loaded foam cells. Several factors, such as apolipoproteins, lipolytic enzymes, lipid transfer proteins, and lipoprotein receptors, are involved in reverse cholesterol transport (1). Initially, efflux of cellular cholesterol is promoted by extracellular cholesterol acceptors. The primary and most efficient acceptors of cholesterol seem to be small discoidal lipid-poor pre-␤-migrating high density lipoproteins (pre-␤-HDL) 1 (2). These particles interact with the cell membrane through a microsolubilization process that leads to uptake first of phospholipids and then of cholesterol from the membrane (3). This process appears to be controlled by the ATP-binding cassette transporter protein 1 on the macrophage cell membrane (4), its transcription being regulated in part by the orphan nuclear receptor LXR. Activation of LXR in macrophages increases not only ATP-binding cassette transporter A1 but also the expression of genes encoding ABCG1 and apoE (5, 6), which may be also involved in efflux of cholesterol toward HDL. Recently, it was shown (7) that LXR activation in macrophages also up-regulates phospholipid transfer protein (PLTP) expression, but this up-regulation does not have any direct effect on cholesterol efflux from mouse peritoneal macrophages.PLTP contributes to the remodelin...

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Plasma Phospholipid Transfer Protein

Cited by 129 publications

References 47 publications

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

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

Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

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

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