Brain Vitamin E Deficiency During Development Is Associated With Increased Glutamate Levels and Anxiety in Adult Mice

Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin E levels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin E supplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP−/−) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) “early supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP−/− mice born from vitamin E-supplemented parents; and (ii) “late supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP−/− mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy

Plasma phospholipid transfer protein (PLTP): review of an emerging cardiometabolic risk factor

International audiencePlasma phospholipid transfer protein (PLTP) is a lipid transfer glycoprotein that binds to and transfers a number of amphipathic compounds. In earlier studies, the attention of the scientific community focused on the positive role of PLTP in high-density lipoprotein (HDL) metabolism. However, this potentially antiatherogenic role of PLTP has been challenged recently by another picture: PLTP arose as a pro-atherogenic factor through its ability to increase the production of apolipoprotein B-containing lipoproteins, to decrease their antioxidative protection and to trigger inflammation. In humans, PLTP has mostly been studied in patients with cardiometabolic disorders. Both PLTP and related cholesteryl ester transfer protein (CETP) are secreted proteins, and adipose tissue is an important contributor to the systemic pools of these two proteins. Coincidently, high levels of PLTP and CETP have been found in the plasma of obese patients. PLTP activity and mass have been reported to be abnormally elevated in type 2 diabetes mellitus (T2DM) and insulin-resistant states, and this elevation is frequently associated with hypertriglyceridemia and obesity. This review article presents the state of knowledge on the implication of PLTP in lipoprotein metabolism, on its atherogenic potential, and the complexity of its implication in obesity, insulin resistance and T2DM

Structure and function of the plasma phospholipid transfer protein

International audienceRecent cloning and sequencing of plasma phospholipid transfer protein complementary DNA revealed that phospholipid transfer protein belongs to the lipid transfer/lipopolysaccharide binding protein family that includes the cholesteryl ester transfer protein, the bactericidal permeability increasing protein and the lipopolysaccharide-binding protein. In addition to structural similarities, members of the lipid transfer/lipopolysaccharide-binding protein family might share some common functional properties, and recent studies demonstrated that phospholipid transfer protein can act in several distinct metabolic processes. In particular, the molecular transfer of phospholipids, unesterified cholesterol, alpha-tocopherol and lipopolysaccharides by phospholipid transfer protein suggests that it might be involved both in lipoprotein metabolism and in antimicrobial defence, resulting in a growing interest in this protein

Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility

International audienceCholesteryl ester and phospholipid transfer activities were determined in plasmas from 14 vertebrates, and lipid transfer values were analyzed in the light of the known atherogenesis susceptibility of studied species. Whereas cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities among vertebrate species were only measured in lipoprotein-deficient fractions in previous studies, both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays were used in the present work. In agreement with previous studies, a few species (chicken, man, rabbit and trout) displayed substantial CETP activity, whereas CETP activity was not detectable in other species (cow, dog, horse, mouse, pig, and rat). Additional species that were not studied before, i.e. cat, goat, and sheep, were shown to be deficient in plasma cholesteryl ester transfer activity, while duck was shown to constitute a new member of the high activity group. Unlike CETP activity, PLTP activity was detected in plasmas from all studied species, most of them being assayed here for the first time (cat, chicken, cow, duck, goat, horse, sheep, and trout). While dog, trout, mouse, and pig displayed the highest phospholipid transfer activity levels, the remarkable preservation of facilitated phospholipid transfers in plasma from all vertebrates might indicate an essential role of PLTP in vivo. Interestingly, animals with well-documented atherogenesis susceptibility (chicken, pig, rabbit, and man) displayed significantly higher mean CETP activity, but lower mean PLTP activity than known 'resistant' animals (cat, dog, mouse, and rat). In conclusion, the present study revealed marked differences in plasma lipid transfer activities between vertebrate species, and interspecies comparisons indicated that both CETP and PLTP may constitute two determinants of the atherogenicity of the plasma lipoprotein profile

Influence of the electrostatic charge of lipoprotein particles on the activity of the human plasma phospholipid transfer protein

The aim of the present study was to determine the effect of the electrostatic charge of lipoproteins on the phospholipid transfer activity of the plasma phospholipid transfer protein (PLTP). Progressive decreases in the PLTP-mediated phospholipid transfer rates were observed when the surface potential of isolated high density lipoproteins (HDL) was either reduced from -11.7 mV down to -15.7 mV by succinylation of apolipoprotein lysyl residues, or increased from -11.6 mV up to -10.9 mV by replacing apolipoprotein (apo) A-I by apoA-II. When succinylated low density lipoprotein (LDL) series with surface potentials ranging between -4.3 mV and -14.3 mV were used, successive increase and decrease in phospholipid transfer rates were observed along the electronegativity scale. When various plasma HDL subfractions with surface potentials ranging from -10.5 mV to -12.5 mV were separated by anion exchange chromatography, PLTP-mediated phospholipid transfer activity increased progressively with HDL electronegativity until maximal lipid transfer rates were reached for a mean HDL surface potential of -11.6 mV. As the electronegativity of plasma HDL subfractions kept increasing beyond the optimal value, a progressive decrease in PLTP activity was observed. Striking parallelism between cholesteryl ester transfer protein (CETP) and PLTP transfer activity curves obtained with each HDL series were noted, and the optimal HDL surface potential values were remarkably similar, approximating -11.6 mV in all the experiments. With isolated plasma LDL subfractions with surface potentials ranging from -3.5 mV to -5.0 mV, a linear rise in PLTP activity was observed. In conclusion, data of the present study indicate that, like CETP, the activity of PLTP is influenced by electrostatic interactions with lipoproteins

Prevention of LDL a-tocopherol consumption, cholesterol oxidation, and vascular endothelium dysfunction by polyphenolic compounds from red wine

International audienceRed 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 7bhydroxycholesterol 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 a-tocopherol content. Once the LDL atocopherol has been consumed, RWPCs were no longer effective, indicating that RWPCs act by sparing endogenous a-tocopherol. As a consequence of the preservation of the endogenous a-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

Plasma phospholipid transfer protein prevents vascular endothelium dysfunction by delivering α-tocopherol to endothelial cells

International audienceα-tocopherol, the most potent antioxidant form of vitamin E, is mainly bound to lipoproteins in plasma and its incorporation into the vascular wall can prevent the endothelium dysfunction at an early stage of atherogenesis. In the present study, the plasma phospholipid transfer protein (PLTP) was shown to promote the net mass transfer of α-tocopherol from high density lipoproteins (HDL) and α-tocopherol-albumin complexes toward α-tocopherol-depleted, oxidized low density lipoproteins (LDL). The facilitated transfer reaction of α-tocopherol could be blocked by specific anti-PLTP antibodies. These observations indicate that PLTP may restore the antioxidant potential of plasma LDL at an early stage of the oxidation cascade that subsequently leads to cellular damages. In addition, the present study demonstrated that the PLTP-mediated net mass transfer of α-tocopherol can constitute a new mechanism for the incorporation of α-tocopherol into the vascular wall in addition to the previously recognized LDL receptor and lipoprotein lipase pathways. In ex vivo studies on rabbit aortic segments, the impairment of the endothelium-dependent arterial relaxation induced by oxidized LDL was found to be counteracted by a pretreatment with purified PLTP and α-tocopherol-albumin complexes, and both the maximal response and the sensitivity to acetylcholine were significantly improved. We conclude that PLTP, by supplying oxidized LDL and endothelial cells with α-tocopherol through a net mass transfer reaction may play at least two distinct beneficial roles in preventing endothelium damage, i.e., the antioxidant protection of LDL and the preservation of a normal relaxing function of vascular endothelial cells

Cholesterol Accumulation Is Increased in Macrophages of Phospholipid Transfer Protein-Deficient Mice

International audienceObjective-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. Methods and Results-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 ␣-tocopherol supplementation. Conclusions-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

Phospholipid transfer protein is present in human atherosclerotic lesions and is expressed by macrophages and foam cells

International audiencePhospholipid transfer protein (PLTP) in plasma promotes phospholipid transfer from triglyceride-rich lipoproteins to HDL and plays a major role in HDL remodeling. Recent in vivo observations also support a key role for PLTP in cholesterol metabolism. Our immunohistochemical analysis of human carotid endarterectomy samples identified immunoreactive PLTP in areas that colocalized with CD68-positive macrophages, suggesting that PLTP could be produced locally by intimal macrophages. Using RT-PCR, Western blot analysis with a monoclonal anti-PLTP antibody, and a PLTP activity assay, we observed PLTP mRNA and protein expression in human macrophages. In adherent peripheral blood human macrophages, this PLTP expression was increased by culture with granulocyte macrophage colony-stimulating factor. Incubation of macrophages with acetylated-LDL induced an increase in PLTP mRNA and protein expression that paralleled cholesterol loading. PLTP expression was observed in elicited mouse peritoneal macrophages and in cultured Raw264.7 cells as well. Thus, this study demonstrates that PLTP is expressed by macrophages, is regulated by cholesterol loading, and is present in atherosclerotic lesions.-Desrumaux, C