Plasma Phospholipid Transfer Protein Activity Is Decreased in Type 2 Diabetes During Treatment With Atorvastatin

Dallinga‐Thie, Geesje M.; Tol, Arie van; Hashimoto, Hiroaki; Rensen, Patrick C.N.; Sijbrands, Eric J.G.

doi:10.2337/db05-1685

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…In a recent study in patients with type 2 diabetes, atorvastatin treatment resulted in a decrease in PLTP activity and an increase in PLTP mass, leading to a substantial change in mass-adjusted activity, which was related to apoE metabolism (37). In contrast, serum PLTP activity showed no significant changes in patients with type IIb hyperlipidemia after simvastatin treatment compared with controls (38).…”

Section: Discussionmentioning

confidence: 90%

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

Schlitt

Blankenberg

Bickel

et al. 2009

Journal of Lipid Research

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Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 patients who were on statins at baseline. In KaplanMeyer analyses serum PLTP activity was not associated with the combined endpoint in all patients. However, in the subgroup of patients receiving statins at baseline, PLTP was shown to be a significant predictor of cardiovascular outcome (P 5 0.019), and this also remained stable in univariate (P 5 0.027) and multivariate cox regression analyses (P 5 0.041) including potential confounders (classical risk factors, HDL cholesterol (HDL-C), and others). We showed in our study that, under statin treatment, high plasma PLTP activity was related to fatal and nonfatal cardiovascular events in CAD patients.-Schlitt, A

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Section: Discussionmentioning

confidence: 90%

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

Schlitt

Blankenberg

Bickel

et al. 2009

Journal of Lipid Research

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“…27 Plasma PLTP activity is expressed relative to control pool plasma. We measured HDL size by 4% to 30% nondenaturing polyacrylamide gradient gel electrophoresis as previously described.…”

Section: Biochemical Analysesmentioning

confidence: 99%

Genetic Variation at the Phospholipid Transfer Protein Locus Affects Its Activity and High-Density Lipoprotein Size and Is a Novel Marker of Cardiovascular Disease Susceptibility

et al. 2010

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Background-In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk. Methods and Results-We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined nϭ384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (Pϭ3.2ϫ10 Ϫ18 ) in a third study (nϭ957) and with an increased number of HDL particles of smaller size (Pϭ3.4ϫ10 Ϫ17 ) in a fourth study (nϭ3375). In a combination of 5 cardiovascular disease case-control studies (nϭ4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; Pϭ1.2ϫ10 Ϫ3 ; odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; Pϭ1.0ϫ10 Ϫ3 ). Conclusions-A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit. (Circulation. 2010;122:470-477.)Key Words: atherosclerosis Ⅲ genetics Ⅲ lipoproteins, HDL Ⅲ PLTP protein, human C lear associations between variants in genes related to low-density lipoprotein metabolism and cardiovascular disease (CVD) risk are consistent with a causal role for low-density lipoprotein in atherosclerosis development. 1,2 Whether high-density lipoprotein (HDL) has a similar role is increasingly questioned. 3,4 Genetic association studies linking Editorial see p 452 Clinical Perspective on p 477variation in HDL-related genes to CVD risk would positively add to the body of evidence, but such associations are not well supported by recent large studies. 1,3 One candidate Received September 29, 2009; accepted May 14, 2010. 8 In humans, plasma PLTP activity has been found to be slightly increased in diabetes mellitus, obesity, and the metabolic syndrome. 9 Additionally, several studies suggest that a higher PLTP activity is associated with an increased risk of atherosclerosis, 10 -12 but another study suggests the opposite. 13 Initially, 2 small studies revealed an association between common genetic PLTP variants and HDL cholesterol levels 14 and obesity-linked parameters. 15 However, a paucity of data exists in humans on the consequences of common variants in the...

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“…In type 2 diabetes, PLTP activity was positively correlated with plasma apoE levels. 18 Of the circulating PLTP mass only a minor portion is in the active form in normolipidemic subjects. 19 It has been reported that active PLTP in plasma is associated with apoE but not with apoA-I, 20 and apoE proteoliposomes can convert inactive PLTP into active one.…”

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confidence: 99%

Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion

Liu

Hojjati

Devlin

et al. 2007

ATVB

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Objective-PLTP and apoE play important roles in lipoprotein metabolism and atherosclerosis. It is known that formation of macrophage-derived foam cells (which highly express PLTP and apoE) is the critical step in the process of atherosclerosis. We investigated the relationship between PLTP and apoE in macrophages and the atherogenic relevance in a mouse model. Methods and Results-We transplanted PLTP-deficient mouse bone marrow into apoE-deficient mice (PLTP Key Words: phospholipid transfer protein Ⅲ apoE Ⅲ bone marrow transplantation Ⅲ macrophage Ⅲ lipoprotein Ⅲ atherosclerosis P lasma PLTP is known to be an independent risk factor for coronary artery disease, 1 and is significantly increased in obesity, as well as in diabetes. 2,3 Moreover, PLTP deficiency decreases, 4 and PLTP overexpression increases, 5,6 atherosclerosis in mouse models, so that it is considered a potential target for pharmacological or gene therapy. However, research toward this goal is hampered by the fact that the mechanism of the atherogenicity of PLTP is not completely understood. This is a multifunctional protein that is expressed in a variety of tissues, with some of its effects considered proatherogenic, 7,8 and others antiatherogenic. 9 -11 ApoE is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types. 12,13 ApoE serves as a ligand for receptor-mediated uptake of lipoproteins through the LDL receptor, the LDL receptor-related protein, and heparan sulfate proteoglycans. 14 ApoE also plays a key role in intracellular lipid metabolism, influencing processes such as the assembly and secretion of lipoproteins 15,16 and cholesterol efflux to HDL. 17 The relationship between PLTP and apoE is mostly unknown. In type 2 diabetes, PLTP activity was positively correlated with plasma apoE levels. 18 Of the circulating PLTP mass only a minor portion is in the active form in normolipidemic subjects. 19 It has been reported that active PLTP in plasma is associated with apoE but not with apoA-I, 20 and apoE proteoliposomes can convert inactive PLTP into active one. 21 There is a hypothesis that transfer of active PLTP from apoE-containing lipoproteins to apoA-I-containing ones results in the conversion of active PLTP to inactive PLTP. 20 However, this is not confirmed by a recent report, indicating that active plasma PLTP is associated primarily with apoA-I but not apoE-containing lipoproteins. 22 The formation of foam cells from lipid-accumulated macrophages is a critical step in atherogenesis. Both macrophages and macrophage-derived foam cells express PLTP. 23 It has recently been shown that PLTP is highly expressed in macrophages from atherosclerotic lesions. 24,25 Macrophages synthesize and secrete apoE, which makes contribution to the apoE pool in the blood circulation and associates with plasma lipoproteins and accelerates their clearance in vivo. 26,27 Macrophage-derived apoE can also act as a cholesterol acceptor to Original

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Plasma Phospholipid Transfer Protein Activity Is Decreased in Type 2 Diabetes During Treatment With Atorvastatin

Cited by 23 publications

References 45 publications

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

Genetic Variation at the Phospholipid Transfer Protein Locus Affects Its Activity and High-Density Lipoprotein Size and Is a Novel Marker of Cardiovascular Disease Susceptibility

Macrophage Phospholipid Transfer Protein Deficiency and ApoE Secretion

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