Disease relevance of Ttpa

• Mutations of the alpha-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED) [1].
• We produced a model mouse of AVED by deleting the alpha-TTP gene, which showed ataxia and retinal degeneration after 1 year of age [1].

High impact information on Ttpa

• alpha-Tocopherol transfer protein (alpha-TTP) maintains the concentration of serum alpha-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating alpha-tocopherol export from the liver [1].
• Lipid peroxidation in alpha-TTP(-/-) mice brains showed a significant increase, especially in degenerating neurons. alpha-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms [1].
• Moreover, alpha-TTP(-/-) mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress [1].
• Because the brain alpha-TTP functions in maintaining alpha-tocopherol levels in the brain, alpha-tocopherol was completely depleted in the alpha-TTP(-/-) mouse brain, and the neurological phenotype of alpha-TTP(-/-) mice is much more severe than that of wild-type mice when maintained on an alpha-tocopherol-deficient diet [1].
• Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the alpha-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta [2].

Biological context of Ttpa

• Ttpa(-/-) mice are a genetic model of vitamin E deficiency and should be valuable for studying other diseases in which oxidative stress is thought to play a role [2].
• The activation of cell proliferation pathways in Ttpa(-/-) livers was indicated by the induction of genes that encode growth factor-binding proteins, mitogen-activated protein kinase kinase 3, and apoptosis inhibitor 6 [3].
• We previously generated alpha-tocopherol transfer protein knockout (Ttpa(-/-)) mice, in which lipid peroxidation in the brain was significantly increased by complete depletion of alpha-tocopherol (alpha-Toc) [4].
• In alpha-TTP(+/+) animals, alpha-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days postcoitum) [5].
• The use of excess alpha-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by alpha-TTP(-/-) females prevented placental failure and allowed full-term pregnancies [5].

Anatomical context of Ttpa

• This may predispose Ttpa(-/-) cortex to increased formation of synuclein-alpha aggregates and Lewy body, often associated with oxidant stress [3].
• Cortex of Ttpa(-/-) mice revealed repression of genes encoding synaptic proteins, protein kinase C family members, and myelin proteins [3].
• When Ttpa(-/-)-fertilized eggs were transferred into Ttpa+/+ (wild-type) recipients, plasma alpha-tocopherol concentrations in the Ttpa-/- fetuses were below the detection limit but the fetuses grew normally [6].
• Increased basal oxidative stress in Ttpa(-/-) mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate [7].
• Alpha-tocopherol transfer protein is important for the normal development of placental labyrinthine trophoblasts in mice [5].

Associations of Ttpa with chemical compounds

• In the Ttpa(-/-) mice, low total alpha-tocopherol concentrations were found in plasma (5.4%) and most other tissues (2-20%), but liver concentrations were 39% of those of Ttpa(+/+) mice [8].
• Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of alpha-T and neurological dysfunctions described in patients with mutated Ttpa [3].
• Lipopolysaccharide (LPS) injected intraperitoneally induced increases in lung and liver HO-1 and iNOS, as well as plasma NO(x) in Ttpa(+/+) mice [7].
• The intraperitoneal administration of MPTP to mice induced a decrease in the striatal levels of dopamine (DA) 3 days after the administration in both alpha-TTP((+/-)) and wild-type mice; these mice were fed an alphaT-deficient diet for 3 weeks before the MPTP administration [9].

Other interactions of Ttpa

• We therefore analyzed the embryonic expression of apoB, MTP, and alpha-tocopherol transfer protein (alpha-TTP), which have been associated with the assembly and secretion of apoB-containing lipoproteins in the adult liver, at different developmental time points [10].
• Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development and that in addition to the hepatic alpha-TTP, which governs plasma alpha-tocopherol level, the uterine alpha-TTP may also play an important role in supplying this vitamin [5].

Analytical, diagnostic and therapeutic context of Ttpa

• By immunohistochemistry, alpha-TTP could be localized in the secretory columnar epithelial cells of the pregnant uterus on Days 4.5 and 6.5 postcoitum as well as in the glandular epithelial cells and the inner decidual reaction zone surrounding the implantation site [11].

References