Net mass transfer of plasma cholesteryl esters and lipid transfer proteins in normolipidemic patients with peripheral vascular disease

Rühling, K.; Lang, A.; Richard, Florence; Tol, Arie van; Eisele, Bernhard; Herzberg, Victoria L.; Till, U

doi:10.1016/s0026-0495(99)90144-0

Cited by 20 publications

(11 citation statements)

References 40 publications

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“…A similar positive association of LCAT was also observed in patients with angiographically proven CHD[111]. These results are in contrast, however, to multiple earlier papers describing either a negative or no association between LCAT activity and CHD[112–114]. These seemingly contradictory results may potentially be explained by the fact that most of these studies are relatively small and do not examine the other proteins and enzymes in the RCT pathway, which can potentially alter the effect of LCAT on atherosclerosis.…”

Section: Lcat and Cardiovascular Diseasesupporting

confidence: 50%

Lecithin: cholesterol acyltransferase – from biochemistry to role in cardiovascular disease

Rousset

Vaisman²,

Amar³

et al. 2009

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

168

136

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Purpose of review We discuss the latest findings on the biochemistry of lecithin:cholesterol acyltransferase (LCAT), the effect of LCAT on atherosclerosis, clinical features of LCAT deficiency, and the impact of LCAT on cardiovascular disease from human studies. Recent findings Although there has been much recent progress in the biochemistry of LCAT and its effect on HDL metabolism, its role in the pathogenesis of atherosclerosis is still not fully understood. Studies from various animal models have revealed a complex interaction between LCAT and atherosclerosis that may be modified by diet and by other proteins that modify lipoproteins. Furthermore, the ability of LCAT to lower apoB appears to be the best way to predict its effect on atherosclerosis in animal models. Recent studies on patients with LCAT deficiency have shown a modest but significant increase incidence of cardiovascular disease consistent with a beneficial effect of LCAT on atherosclerosis. The role of LCAT in the general population, however, have not revealed a consistent association with cardiovascular disease. Summary Recent research findings from animal and humans studies have revealed a potential beneficial role of LCAT in reducing atherosclerosis but additional studies are necessary to better establish the linkage between LCAT and cardiovascular disease.

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Section: Lcat and Cardiovascular Diseasesupporting

confidence: 50%

Lecithin: cholesterol acyltransferase – from biochemistry to role in cardiovascular disease

Rousset

Vaisman²,

Amar³

et al. 2009

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

168

136

View full text Add to dashboard Cite

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“…The reductions in CER are likely due to variations in HDL particle size distribution and changes in structure of the apoA-I on the HDL particles, altering the manner in which apoA-I and LCAT interact as LCAT binds to a HDL particle. The relationship between LCAT activity and RCT or cardiovascular disease is uncertain at this time with several studies concluding that higher levels of LCAT activity are associated with increased incidences of cardiovascular disease (29,30), while others describe either a negative or no correlation between LCAT activity and cardiovascular disease or RCT (31–33). In our experiments, the two groups with the lowest CER, mouse-H apoA-I- and LacZ-expressing mice, had the highest and lowest amount of 3 H-radioactivity in the feces, respectively (Figure 2B).…”

Section: Discussionmentioning

confidence: 99%

Influence of Apolipoprotein A-I Domain Structure on Macrophage Reverse Cholesterol Transport in Mice

Alexander

Vedhachalam

Sankaranarayanan

et al. 2011

ATVB

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Objective-The goal of this study was to determine the influence of apolipoprotein A-I (apoA-I) tertiary structure domain properties on the antiatherogenic properties of the protein. Two chimeric hybrids with the N-terminal domains swapped (human-mouse apoA-I and mouse-human apoA-I) were expressed in apoA-I-null mice with adeno-associated virus (AAV) and used to study macrophage reverse cholesterol transport (RCT) in vivo. Methods and Results-The different apoA-I variants were expressed in apoA-I-null mice that were injected with [H 3 ]cholesterol-labeled J774 mouse macrophages to measure RCT. Significantly more cholesterol was removed from the macrophages and deposited in the feces via the RCT pathway in mice expressing mouse-H apoA-I compared with all other groups. Analysis of the individual components of the RCT pathway demonstrated that mouse-H apoA-I promoted ATP-binding cassette transporter A1-mediated cholesterol efflux more efficiently than all other variants, as well as increasing the rate of cholesterol uptake into liver cells. Conclusion-The structural domain properties of apoA-I affect the ability of the protein to mediate macrophage RCT.Replacement of the N-terminal helix bundle domain in the human apoA-I with the mouse apoA-I counterpart causes a gain of function with respect to macrophage RCT, suggesting that engineering some destabilization into the N-terminal helix bundle domain or increasing the hydrophobicity of the C-terminal domain of human apoA-I would enhance the antiatherogenic properties of the protein. Key Words: apolipoproteins Ⅲ cardiovascular disease prevention Ⅲ lipoproteins A polipoprotein A-I (apoA-I) is the major protein component of high-density lipoprotein (HDL), and its level in plasma is inversely associated with the risk of cardiovascular disease. [1][2][3] The antiatherogenic properties of apoA-I arise primarily through its role as a mediator of reverse cholesterol transport (RCT), a process by which excess cholesterol is removed from peripheral tissues and transported to the liver for catabolism. 4,5 ApoA-I has been shown to promote macrophage RCT in vivo. 6 Human apoA-I is a 243-residue protein made up of repeating amphipathic ␣-helices, 7 and it contains 2 domains, an N-terminal ␣-helix bundle spanning residues 1 to 189 and a separately folded C-terminal domain that spans the remainder of the molecule. 8 -10 The more hydrophobic C-terminal domain has high lipid affinity compared with the helix bundle domain. 11 Mouse apoA-I, which has 65% amino acid identity with human apoA-I, adopts a similar 2-domain structure. 12 However, compared with the human protein, the N-terminal domain of mouse apoA-I is relatively unstable and has high lipid affinity, whereas the C-terminal domain is more polar and has poor lipid affinity. 12 The differences in tertiary structure domain characteristics between human and mouse apoA-I present the opportunity to understand how the properties of these domains influence the functionality of apoA-I in the RCT pathway. To investigate this que...

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“…The few existing studies regarding the relationship between plasma PLTP activity and cardiovascular disease in humans show contradictory findings. Whereas Schlitt et al (27) identified PLTP activity as an independent predictive value for coronary artery disease, others found variable relationships between PLTP activity and peripheral artery disease (26,28).…”

Section: Discussionmentioning

confidence: 99%

Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

Samyn

Moerland

Gent

et al. 2008

Journal of Lipid Research

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Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL. Overexpressing human PLTP in mice increases the susceptibility to atherosclerosis. In human plasma, highactive and low-active forms of PLTP exist. To elucidate the contribution of phospholipid transfer activity to changes in lipoprotein metabolism and atherogenesis, we developed mice expressing mutant PLTP, still able to associate with HDL but lacking phospholipid transfer activity. In mice heterozygous for the LDL receptor, effects of the mutant and normal human PLTP transgene (mutPLTP tg and PLTP tg, respectively) were compared. In PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. In contrast, in mutPLTP tg mice, lipid levels were not different from controls. Furthermore, hepatic VLDL-TG secretion was stimulated in PLTP tg mice, but not in mutPLTP tg mice. When mice were fed a cholesterol-enriched diet, atherosclerotic lesion size in PLTP tg mice was increased more than 2-fold compared with control mice, whereas in mutPLTP tg mice, there was no change. Our findings demonstrate that PLTP transfer activity is essential for the development of atherosclerosis in PLTP transgenic mice, identifying PLTP activity as a possible target to prevent atherogenesis, independent of plasma PLTP concentration.-Samyn, H., M. Moerland, T. van Gent, R. van Haperen, J. Metso, F. Grosveld, M. Jauhiainen, A. van Tol, and R. de Crom. Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study. Phospholipid transfer protein (PLTP) is a multifunctional protein secreted by various cell types into the plasma, where it associates with HDL particles. Plasma PLTP has a central role in cholesterol and lipoprotein metabolism. It mediates the transfer of phospholipids between lipoprotein particles (1, 2). In addition, PLTP in vitro is able to transfer other lipophilic substances such as diacylglycerol (3), cholesterol (4), lipopolysaccharide (5, 6), and a-tocopherol (7), an important anti-oxidant. Furthermore, plasma PLTP has been identified as an HDL conversion factor. It remodels HDL to generate large particles and small lipid-poor preb-HDL (8-10). In vitro, HDL conversion depends on phospholipid transfer activity of PLTP (11).Studies using genetically modified mouse models have provided more insight into the (patho-) physiological role of PLTP in lipoprotein metabolism and the development of atherosclerosis. PLTP-deficient mice have markedly reduced HDL levels (12). These mice are more resistant to atherosclerosis development; this is partly attributable to diminished secretion and lower levels of apolipoprotein B (apoB)-containing lipoproteins and to the increase in bioavailability of vitamin E in these particles (13,14). When overexpressing human PLTP in mice, elevation of plasma PLTP activity levels results in a dose-dependent decrease ...

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Net mass transfer of plasma cholesteryl esters and lipid transfer proteins in normolipidemic patients with peripheral vascular disease

Cited by 20 publications

References 40 publications

Lecithin: cholesterol acyltransferase – from biochemistry to role in cardiovascular disease

Lecithin: cholesterol acyltransferase – from biochemistry to role in cardiovascular disease

Influence of Apolipoprotein A-I Domain Structure on Macrophage Reverse Cholesterol Transport in Mice

Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

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