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.

Atheroprotective potential of macrophage-derived phospholipid transfer protein in low-density lipoprotein receptor-deficient mice is overcome by apolipoprotein AI overexpression.

OBJECTIVE: Using bone marrow transplantation, we assessed the impact of macrophage-derived phospholipid transfer protein (PLTP) on lesion development in hypercholesterolemic mice that expressed either normal levels of mouse apolipoprotein AI (apoAI) or elevated levels of only human apoAI. METHODS AND RESULTS: Bone marrow transplantations were performed in low-density lipoprotein receptor-deficient mice (LDLr-/-) that expressed either normal levels of mouse apoAI (msapoAI) or high levels of only human apoAI (msapoAI-/-, LDLr-/-, huapoAITg). Mice were lethally irradiated, reconstituted with either PLTP-expressing or PLTP-deficient bone marrow cells, and fed a high-fat diet over 16 weeks. Macrophage PLTP deficiency increased atherosclerosis in LDLr-/- mice with minimal changes in total plasma cholesterol levels. In contrast, the extent of atherosclerosis in msapoAI-/-, LDLr-/-, huapoAITg mice was not significantly different between groups that had received PLTP-/- or PLTP+/+ bone marrow. In vitro studies indicated that PLTP deficiency led to a significant decrease in alpha-tocopherol content and increased oxidative stress in bone marrow cells. CONCLUSIONS: Our observations suggest an atheroprotective role of macrophage-derived PLTP in mice with normal apoAI plasma levels. The atheroprotective properties of macrophage-derived PLTP were not observable in the presence of elevated plasma concentrations of apoAI.

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

Phospholipid 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.