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ABSTRACT: Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) plays a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-β(25-35) (Aβ(25-35)) peptide, a nontransgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain Aβ(1-42) levels, and a lower expression of the synaptic function marker synaptophysin, as compared to wild-type mice. This PLTP-deficient phenotype was associated with increased memory impairment one week after Aβ(25-35) peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented Aβ(25-35)-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies.Neuropsychopharmacology accepted article preview online, 3 December 2012; doi:10.1038/npp.2012.247.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2012; · 6.99 Impact Factor
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David Masson,
Valérie Deckert,
Thomas Gautier,
Alexis Klein, Catherine Desrumaux,
Céline Viglietta,
Jean-Paul Pais de Barros,
Naig Le Guern,
Jacques Grober,
Jérôme Labbé,
Franck Ménétrier,
Pierre-Jean Ripoll,
Mathieu Leroux-Coyau,
Geneviève Jolivet,
Louis-Marie Houdebine,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity.
In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-α gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates.
Human PLTP expression in HuPLTPTg rabbit worsens atherosclerosis as a result of increased levels of atherogenic apoB-containing lipoproteins but not of alterations in their antioxidative protection or in cholesterol content of plasma HDL.
Arteriosclerosis Thrombosis and Vascular Biology 01/2011; 31(4):766-74. · 6.37 Impact Factor
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Catherine Desrumaux,
Valérie Deckert,
Stéphanie Lemaire-Ewing,
Claude Mossiat,
Anne Athias,
David Vandroux,
Laure Dumont,
Serge Monier,
Jean-Paul Pais de Barros,
Alexis Klein,
Emmanuel De Maistre,
Denis Blache,
Alain Beley,
Christine Marie,
Philippe Garnier,
Laurent Lagrost
[show abstract]
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ABSTRACT: Earlier in vitro studies suggested a putative role for the plasma phospholipid transfer protein (PLTP) in the modulation of blood coagulation. The effect of PLTP expression on blood coagulation under both basal and oxidative stress conditions was compared here in wild-type and PLTP-deficient (PLTP-/-) mice.
Under basal conditions, PLTP deficiency was associated with an extended tail bleeding time despite a significant depletion of vascular α-tocopherol content and an impairment of endothelial function. When acute oxidative stress was generated in vivo in the brain vasculature, the steady state levels of oxidized lipid derivatives, the extent of blood vessel occlusion, and the volume of ischemic lesions were more severe in wild-type than in PLTP-/- mice.
In addition to its recognized hyperlipidemic, proinflammatory, and proatherogenic properties, PLTP increases blood coagulation and worsens the extent of ischemic lesions in response to acute oxidative stress. Thus, PLTP arises here as a cardiovascular risk factor for the late thrombotic events occurring in the acute phase of atherosclerosis.
Arteriosclerosis Thrombosis and Vascular Biology 12/2010; 30(12):2452-7. · 6.37 Impact Factor
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Thomas Gautier,
Catherine Paul,
Valérie Deckert, Catherine Desrumaux,
Alexis Klein,
Jérôme Labbé,
Naig Le Guern,
Anne Athias,
Serge Monier,
Arlette Hammann,
Ali Bettaieb,
Jean-François Jeannin,
Laurent Lagrost
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ABSTRACT: Hexaacyl lipopolysaccharide (LPS) aggregates in aqueous media, but its partially deacylated lipid A moiety forms monomers with weaker toxicity. Because plasma phospholipid transfer protein (PLTP) transfers hexaacyl LPS, its impact on metabolism and biological activity of triacyl lipid A in mice was addressed. Triacyl lipid A bound readily to plasma high-density lipoproteins (HDLs) when active PLTP was expressed [HDL-associated lipid A after 4.5 h: 59.1+/-16.0% of total in wild-type (WT) vs. 32.5+/-10.3% in PLTP-deficient mice, P<0.05]. In the opposite to hexaacyl LPS, plasma residence time of lipid A was extended by PLTP, and proinflammatory cytokines were produced in higher amounts in WT than PLTP(-/-) mice (remaining lipid A after 8 h: 53+/-12 vs. 35+/-7%, and IL6 concentration after 4.5 h: 45.5+/-5.9 vs. 14.6+/-7.8 ng/ml, respectively; P<0.05 in all cases). After 1 wk, onset of B16-induced melanoma was observed in only 30% of lipid A-treated WT mice, whereas >80% of the untreated WT, untreated PLTP-deficient, or lipid A-treated PLTP-deficient animals bore tumors (P<0.05 in all cases). It is concluded that PLTP is essential in mediating the association of triacyl lipid A with lipoproteins, leading to extension of its residence time and to magnification of its proinflammatory and anticancer properties.
The FASEB Journal 04/2010; 24(9):3544-54. · 5.71 Impact Factor
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ABSTRACT: Vitamin E is composed of closely related compounds, including tocopherols and tocotrienols. Studies of the last decade provide strong support for a specific role of alpha-tocopherol in cell signalling and the regulation of gene expression. It produces significant effects on inflammation, cell proliferation and apoptosis that are not shared by other vitamin E isomers with similar antioxidant properties. The different behaviours of vitamin E isomers might relate, at least in part, to the specific effects they exert at the plasma membrane. alpha-Tocopherol is not randomly distributed throughout the phospholipid bilayer of biological membranes, and as compared with other isomers, it shows a propensity to associate with lipid rafts. Distinct aspects of vitamin E transport and metabolism is discussed with emphasis on the interaction between alpha-tocopherol and lipid rafts and the consequences of these interactions on cell metabolism.
Molecular Nutrition & Food Research 02/2010; 54(5):631-40. · 4.30 Impact Factor
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ABSTRACT: Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall
when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin
E, but the molecular mechanism involved is unclear. In this study, unlike γ-tocopherol, the α-tocopherol vitamin E form was
found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, α-tocopherol needed to
be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together
or after 7-ketocholesterol, respectively. Both pre- and co-treatment of the cells with α-tocopherol resulted in the redistribution
of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of α-tocopherol
associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell
death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB
was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by α-tocopherol, but not
γ-tocopherol pretreatment.
Journal of Biological Chemistry 06/2009; 284(23):15826-15834. · 4.77 Impact Factor
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[show abstract]
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ABSTRACT: Cholesterol oxides, in particular 7-ketocholesterol, are proatherogenic compounds that induce cell death in the vascular wall when localized in lipid raft domains of the cell membrane. Deleterious effects of 7-ketocholesterol can be prevented by vitamin E, but the molecular mechanism involved is unclear. In this study, unlike gamma-tocopherol, the alpha-tocopherol vitamin E form was found to prevent 7-ketocholesterol-mediated apoptosis of A7R5 smooth muscle cells. To be operative, alpha-tocopherol needed to be added to the cells before 7-ketocholesterol, and its anti-apoptotic effect was reduced and even suppressed when added together or after 7-ketocholesterol, respectively. Both pre- and co-treatment of the cells with alpha-tocopherol resulted in the redistribution of 7-ketocholesterol out of the sphingolipid/cholesterol-enriched (lipid raft) domains. In turn, fewer amounts of alpha-tocopherol associated with lipid rafts on 7-ketocholesterol-pretreated cells compared with untreated cells, with no prevention of cell death in this case. In further support of the implication of lipid raft domains, the dephosphorylation/inactivation of Akt-PKB was involved in the 7-ketocholesterol-induced apoptosis. Akt-PKB dephosphorylation was prevented by alpha-tocopherol, but not gamma-tocopherol pretreatment.
Journal of Biological Chemistry 05/2009; 284(23):15826-34. · 4.77 Impact Factor
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Stéphanie Lemaire-Ewing,
Arnaud Berthier,
Marie Royer,
Emmanuelle Logette,
Laurent Corcos,
André Bouchot,
Serge Monier,
Céline Prunet,
Magalie Raveneau,
Cédric Rébé, Catherine Desrumaux,
Gérard Lizard,
Dominique Néel
[show abstract]
[hide abstract]
ABSTRACT: Oxysterols found in oxidized low-density lipoproteins are probably involved in the appearance of atheroma; some are cytotoxic and some able to induce cytokine secretion. An oxysterol-induced interleukin-8 (IL-8) secretion in human monocytes/macrophages has been previously noticed, but the mechanisms remained unclear. In this paper, we investigated the signaling pathways leading to the induction of IL-8 secretion in monocytic THP-1 cells treated with 7β-hydroxycholesterol, a cytototoxic oxysterol, or with 25-hydroxycholesterol, an oxysterol non-cytotoxic toward this cell line. The oxysterol-induced IL-8 secretion appears to be a calcium-dependent phenomenon as shown by the use of calcium channel blockers, which strongly decreased IL-8 secretion and IL-8 messenger RNA (mRNA) levels. Fluo-3 staining used in flow cytometry and video microscopy revealed an oxysterol-induced Ca2+ influx, varying according to the oxysterol studied, leading to the activation of the MEK/ERK1/2 pathway as demonstrated by Western blot analysis. ERK activation led to an increase of c-fos mRNA and/or an activation of c-fos. Luciferase reporter gene assay using constructs of the human IL-8 gene promoter and Transam assay revealed the involvement of the AP-1 transcription factor in oxysterol-dependent IL-8 secretion. These results demonstrate that oxysterol-induced IL-8 secretion is a calcium-dependent phenomenon involving the MEK/ERK1/2 pathway leading to the activation of IL-8 gene via AP-1 (c-fos).
Cell Biology and Toxicology 03/2009; 25(2):127-139. · 2.51 Impact Factor
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Thomas Gautier,
Alexis Klein,
Valérie Deckert, Catherine Desrumaux,
Nicolas Ogier,
Anne-Laure Sberna,
Catherine Paul,
Naig Le Guern,
Anne Athias,
Thomas Montange,
Serge Monier,
Françoise Piard,
Xian-Cheng Jiang,
David Masson,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Lipopolysaccharides (LPS) are components of Gram-negative bacteria. The cellular response from the host to LPS is mediated through stepwise interactions involving the lipopolysaccharide-binding protein (LBP), CD14, and MD-2, which produces the rearrangement of TLR4. In addition to LBP, the lipid transfer/lipopolysaccharide-binding protein gene family includes the phospholipid transfer protein (PLTP). Here we show that the intravascular redistribution of LPS from the plasma lipoprotein-free fraction toward circulating lipoproteins is delayed in PLTP-deficient mice. In agreement with earlier in vitro studies, which predicted the neutralization of the endotoxic properties of LPS when associated with lipoproteins, significant increases in the plasma concentration of proinflammatory cytokines were found in PLTP-deficient as compared with wild type mice. Similar inflammatory damage occurred in tissues from wild type and PLTP-deficient mice 24 h after one single intraperitoneal injection of LPS but with a more severe accumulation of red blood cells in glomeruli of LPS-injected PLTP-deficient mice. Complementary ex vivo experiments on isolated splenocytes from wild type and PLTP-deficient mice further supported the ability of cell-derived PLTP to prevent LPS-mediated inflammation and cytotoxicity when combined with lipoprotein acceptors. Finally, PLTP deficiency in mice led to a significant increase in LPS-induced mortality. It is concluded that increasing circulating levels of PLTP may constitute a new and promising strategy in preventing endotoxic shock.
Journal of Biological Chemistry 08/2008; 283(27):18702-10. · 4.77 Impact Factor
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Stéphanie Lemaire-Ewing,
Arnaud Berthier,
Marie Charlotte Royer,
Emmanuelle Logette,
Laurent Corcos,
André Bouchot,
Serge Monier,
Céline Prunet,
Magalie Raveneau,
Cédric Rébé, Catherine Desrumaux,
Gérard Lizard,
Dominique Néel
[show abstract]
[hide abstract]
ABSTRACT: Oxysterols found in oxidized low-density lipoproteins are probably involved in the appearance of atheroma; some are cytotoxic and some able to induce cytokine secretion. An oxysterol-induced interleukin-8 (IL-8) secretion in human monocytes/macrophages has been previously noticed, but the mechanisms remained unclear. In this paper, we investigated the signaling pathways leading to the induction of IL-8 secretion in monocytic THP-1 cells treated with 7beta-hydroxycholesterol, a cytototoxic oxysterol, or with 25-hydroxycholesterol, an oxysterol non-cytotoxic toward this cell line. The oxysterol-induced IL-8 secretion appears to be a calcium-dependent phenomenon as shown by the use of calcium channel blockers, which strongly decreased IL-8 secretion and IL-8 messenger RNA (mRNA) levels. Fluo-3 staining used in flow cytometry and video microscopy revealed an oxysterol-induced Ca(2+) influx, varying according to the oxysterol studied, leading to the activation of the MEK/ERK1/2 pathway as demonstrated by Western blot analysis. ERK activation led to an increase of c-fos mRNA and/or an activation of c-fos. Luciferase reporter gene assay using constructs of the human IL-8 gene promoter and Transam assay revealed the involvement of the AP-1 transcription factor in oxysterol-dependent IL-8 secretion. These results demonstrate that oxysterol-induced IL-8 secretion is a calcium-dependent phenomenon involving the MEK/ERK1/2 pathway leading to the activation of IL-8 gene via AP-1 (c-fos).
Cell Biology and Toxicology 04/2008; 25(2):127-39. · 2.51 Impact Factor
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[show abstract]
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ABSTRACT: Phospholipid transfer protein (PLTP) is a multifunctional, extracellular lipid transport protein that plays a major role in lipoprotein metabolism and atherosclerosis. Recent in vivo studies suggested that unlike systemic PLTP, macrophage-derived PLTP would be antiatherogenic. The present study aimed at characterizing the atheroprotective properties of macrophage-derived PLTP.
Peritoneal macrophages were isolated from PLTP-deficient and wild-type mice and their biochemical characteristics were compared. It is shown that macrophages isolated from PLTP-deficient mice have increased basal cholesterol content and accumulate more cholesterol in the presence of LDL compared with wild-type cells. Cholesterol parameters in macrophages of PLTP-deficient mice were normalized by dietary alpha-tocopherol supplementation.
The antiatherogenic properties of macrophage-derived PLTP are related at least in part to its ability to reduce cholesterol accumulation in macrophages through changes in the alpha-tocopherol content and oxidative status of the cells.
Arteriosclerosis Thrombosis and Vascular Biology 12/2007; 27(11):2407-12. · 6.37 Impact Factor
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Marianne Zeller,
David Masson,
Michel Farnier,
Luc Lorgis,
Valérie Deckert,
Jean-Paul Pais de Barros, Catherine Desrumaux,
Pierre Sicard,
Jacques Grober,
Denis Blache,
Philippe Gambert,
Luc Rochette,
Yves Cottin,
Laurent Lagrost
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ABSTRACT: Our aim was to characterize cholesteryl ester transfer protein (CETP) activity in the early phase of acute myocardial infarction (MI).
Cholesteryl ester transfer protein catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) donors to apolipoprotein B-containing lipoprotein acceptors.
The CETP concentration, lipid profiles, and the rate of cholesteryl ester transfer (CET) from a tracer dose of radiolabeled HDL toward endogenous lipoproteins were determined within 24 h after symptom onset.
Among 347 patients with first MI, CETP concentration, triglycerides, and non-HDL-cholesterol increased across tertiles of the CET rate, whereas HDL-cholesterol, HDL, and LDL sizes decreased gradually. Among lipoprotein donors and acceptors, the best predictors of the CET rate were HDL2b and non-HDL-cholesterol, respectively. Mean age at first MI was 8.5 years lower in the patients from the highest CET tertile than in those in the lowest CET tertile. Diagonal stratification according to both non-HDL-cholesterol and HDL2b tertiles revealed that patients in the highest CET group were 18 years younger than patients in the lowest CET group. Parameters of the high CETP mass/high non-HDL-cholesterol/low HDL2b triad were independently associated with the CET rate.
In patients with acute MI, high CET rates are characterized by the presence of the high CETP mass/high non-HDL-cholesterol/low HDL2b triad. The association of high CET rates with young age at first MI lends support to a significant contribution of CETP to the accelerated progression of disease among asymptomatic patients.
Journal of the American College of Cardiology 12/2007; 50(20):1948-55. · 14.16 Impact Factor
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Alexis Klein,
Valérie Deckert,
Martina Schneider,
Fabienne Dutrillaux,
Arlette Hammann,
Anne Athias,
Naig Le Guern,
Jean-Paul Pais de Barros, Catherine Desrumaux,
David Masson,
Xian-Cheng Jiang,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to assess the effect of alpha-tocopherol, the main vitamin E isomer on phosphatidylserine (PS) exposure at the surface of circulating erythrocytes, and to determine consequences on erythrocyte properties.
In vitro alpha-tocopherol enrichment of isolated erythrocytes significantly decreased PS externalization as assessed by lower Annexin V-fluorescein isothiocyanate labeling. Plasma phospholipid transfer protein (PLTP) transfers vitamin E, and both alpha- and gamma-tocopherol accumulated in circulating erythrocytes from PLTP-deficient homozygous (PLTP-/-) mice as compared with wild-type mice. In agreement with in vitro studies, vitamin E-enriched erythrocytes from PLTP-/- mice displayed fewer externalized PS molecules than wild-type controls (-64%, P<0.05). The perturbation of phospholipid membrane asymmetry from PLTP-/- erythrocytes was accompanied by impairment of their procoagulant properties, with a 20% increase in clotting time as compared with wild-type controls (P<0.05). Less pronounced, however still significant, changes were observed in alpha-tocopherol content, procoagulant properties, and PS externalization in erythrocytes of PLTP-deficient heterozygotes. Finally, whole blood coagulation and circulating level of D-dimer, which reflects increased thrombus formation in vivo, were significantly decreased in PLTP-/- mice compared with wild-type mice.
Vitamin E modifies PS externalization in circulating erythrocytes, thus modulating in vivo their PS-dependent procoagulant properties.
Arteriosclerosis Thrombosis and Vascular Biology 10/2006; 26(9):2160-7. · 6.37 Impact Factor
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Véronique Drouineaud,
Laurent Lagrost,
Alexis Klein, Catherine Desrumaux,
Naig Le Guern,
Anne Athias,
Franck Ménétrier,
Philippe Moiroux,
Paul Sagot,
Clément Jimenez,
David Masson,
Valérie Deckert
[show abstract]
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ABSTRACT: Vitamin E was discovered for its implication in reproductive biology, and its transport in mammalian plasma and brain was shown to be governed by plasma phospholipid transfer protein (PLTP). We show that PLTP deficiency is associated with hypofertility of mouse males but not mouse females, and it accounts for a significant decrease in total number of pups produced over a 2-month breeding period of PLTP knocked out mice (-32%, P<0.03). PLTP is highly expressed in epididymis of mouse males, and alpha-tocopherol, the main vitamin E isomer in vivo, was significantly less abundant in cauda and caput epididymis of PLTP-deficient mice as compared with wild-type counterparts (caput: -26%, P<0.05; cauda: -21%, P<0.05). Mature spermatozoa from PLTP-deficient epididymis were shown to retain an abnormal alpha-tocopherol content. PLTP deficiency tended to reduce sperm motility as shown by a 24% reduction in spermatozoa with progressive motility (P<0.02), with no change in other sperm parameters as compared with wild-type males. Finally, in vitro fertilization rates of wild-type oocytes with spermatozoa from PLTP-deficient males were markedly reduced as compared with those measured with spermatozoa from wild-type males (-60%, P<0.05). It is concluded that PLTP is a new, key factor that determines sperm motility and male fertility.
The FASEB Journal 05/2006; 20(6):794-6. · 5.71 Impact Factor
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Catherine Desrumaux,
Pierre-Yves Risold,
Henri Schroeder,
Valérie Deckert,
David Masson,
Anne Athias,
Hélène Laplanche,
Naig Le Guern,
Denis Blache,
Xian-Cheng Jiang,
Alan R Tall,
Didier Desor,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Vitamin E supplementation constitutes a promising strategy in the prevention of neurodegenerative diseases. Here, we show that a phospholipid transfer protein (PLTP) is widely expressed in the brain where it appears to function as a transfer factor for alpha-tocopherol, the main isomer of vitamin E. PLTP deficiency results in significant depletion of brain alpha-tocopherol in both homozygous (-30.1%, P<0.0002) and heterozygous (-18.0%, P<0.05) PLTP knocked-out mice. Alpha-tocopherol depletion in PLTP-deficient homozygotes is associated with the elevation of lipofuscin (+25% and +450% increases in cortex and substantia nigra, respectively), cholesterol oxides (+54.5%, P<0.05), and cellular peroxides (+32.3%, P<0.01) in the brain. Complete PLTP deficiency in homozygotes is accompanied by increased anxiety as shown by fewer entries (8.3% vs. 44.4% in controls, P<0.01) and less time spent (1.7% vs. 41.3% in controls, P<0.05) in the open arms of an elevated plus-maze, in the absence of locomotor deterioration. Thus, the vitamin E transfer activity of PLTP appears to be a key process in preventing oxidative damage in the brain, and PLTP-deficient mice could be a new model of the contribution of oxidative brain injury in the etiology of neurodegenerative diseases.
The FASEB Journal 03/2005; 19(2):296-7. · 5.71 Impact Factor
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Martina Schneider,
Bruno Vergès,
Alexis Klein,
Elizabeth R Miller,
Valérie Deckert, Catherine Desrumaux,
David Masson,
Philippe Gambert,
Jean-Marcel Brun,
Jamila Fruchart-Najib,
Denis Blache,
Joseph L Witztum,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Mouse studies indicated that plasma phospholipid transfer protein (PLTP) determines the plasma distribution of vitamin E, a potent lipophilic antioxidant. Vitamin E distribution, antioxidant status, and titer of anti-oxidized LDLs (oxLDL) autoantibodies were evaluated in plasma from control subjects (n = 31) and type 2 diabetic patients (n = 31) with elevated plasma PLTP concentration. Unlike diabetic and control HDLs, which displayed similar vitamin E contents, diabetic VLDLs and diabetic LDLs contained fewer vitamin E molecules than normal counterparts. Plasma PLTP concentration in diabetic plasmas correlated negatively with vitamin E in VLDL+LDL, but positively with vitamin E in HDL, with an even stronger correlation with the VLDL+LDL-to-HDL vitamin E ratio. Circulating levels of oxLDL were significantly higher in diabetic plasmas than in control plasmas. Whereas the titer of IgG autoantibodies to modified LDL did not differ significantly between diabetic patients and control subjects, diabetic plasmas showed significantly lower levels of potentially protective IgM autoantibodies. The present observations support a pathophysiological role of PLTP in decreasing the vitamin E content of apolipoprotein B-containing lipoproteins, but not of HDL in plasma of type 2 diabetic patients, contributing to a greater potential for LDL oxidation.
Diabetes 11/2004; 53(10):2633-9. · 8.29 Impact Factor
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David Masson,
Bart Staels,
Thomas Gautier, Catherine Desrumaux,
Anne Athias,
Naig Le Guern,
Martina Schneider,
Zoulika Zak,
Laure Dumont,
Valérie Deckert,
Alan Tall,
Xian-Cheng Jiang,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice. In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion.
The Journal of Lipid Research 04/2004; 45(3):543-50. · 5.56 Impact Factor
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ABSTRACT: Red wine polyphenolic compounds (RWPCs) have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study was to determine further the mechanism by which RWPCs can prevent the formation of vasoactive compounds in oxidized LDL. RWPCs were obtained from the Cabernet-Sauvignon grape variety. Human LDL was oxidized in the presence of CuSO(4) (ox-LDL). Vascular reactivity studies were conducted on rabbit aortic rings. RWPCs significantly reduced the formation of 7 beta-hydroxycholesterol and 7-ketocholesterol and in a lower extent the emergence of lysophosphatidylcholine in ox-LDL. The ability of RWPCs to prevent cholesterol oxide formation was directly dependent on the LDL alpha-tocopherol content. Once the LDL alpha-tocopherol has been consumed, RWPCs were no longer effective, indicating that RWPCs act by sparing endogenous alpha-tocopherol. As a consequence of the preservation of the endogenous alpha-tocopherol content of LDL, RWPCs could prevent the inhibition of the acetylcholine-mediated endothelium-dependent relaxation of rabbit aorta which was linked to a direct effect on NO release. Independently of a treatment with ox-LDL, RWPC exerted a concentration-dependent and persistent inhibitory effect on the norepinephrine-induced contraction of rabbit aorta. In conclusion, RWPCs can preserve a normal vascular reactivity by acting at different stages of the cascade that leads to lipid oxidation, endothelium dysfunction and vasospasm.
Atherosclerosis 12/2002; 165(1):41-50. · 3.79 Impact Factor
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Xian-Cheng Jiang,
Alan R Tall,
Shucun Qin,
Min Lin,
Martina Schneider,
Florent Lalanne,
Valéerie Deckert, Catherine Desrumaux,
Anne Athias,
Joseph L Witztum,
Laurent Lagrost
[show abstract]
[hide abstract]
ABSTRACT: Vitamin E is a lipophilic anti-oxidant that can prevent the oxidative damage of atherogenic lipoproteins. However, human trials with vitamin E have been disappointing, perhaps related to ineffective levels of vitamin E in atherogenic apoB-containing lipoproteins. Phospholipid transfer protein (PLTP) promotes vitamin E removal from atherogenic lipoproteins in vitro, and PLTP deficiency has recently been recognized as an anti-atherogenic state. To determine whether PLTP regulates lipoprotein vitamin E content in vivo, we measured alpha-tocopherol content and oxidation parameters of lipoproteins from PLTP-deficient mice in wild type, apoE-deficient, low density lipoprotein (LDL) receptor-deficient, or apoB/cholesteryl ester transfer protein transgenic backgrounds. In all four backgrounds, the vitamin E content of very low density lipoprotein (VLDL) and/or LDL was significantly increased in PLTP-deficient mice, compared with controls with normal plasma PLTP activity. Moreover, PLTP deficiency produced a dramatic delay in generation of conjugated dienes in oxidized apoB-containing lipoproteins as well as markedly lower titers of plasma IgG autoantibodies to oxidized LDL. The addition of purified PLTP to deficient plasma lowered the vitamin E content of VLDL plus LDL and normalized the generation of conjugated dienes. The data show that PLTP regulates the bioavailability of vitamin E in atherogenic lipoproteins and suggest a novel strategy for achieving more effective concentrations of anti-oxidants in lipoproteins, independent of dietary supplementation.
Journal of Biological Chemistry 09/2002; 277(35):31850-6. · 4.77 Impact Factor
