Localization of α-tocopherol transfer protein in rat brain

Hosomi, Akihiro; Goto, Kaoru; Kondo, Hisatake; Iwatsubo, Takeshi; Yokota, Takanori; Ogawa, Masako; Arita, Makoto; Aoki, Junken; Arai, Hiroyuki; Inoue, Keizō

doi:10.1016/s0304-3940(98)00785-x

Cited by 106 publications

(69 citation statements)

References 17 publications

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“…Experimental data do not support this prediction. A previous study (Hosomi et al, 1998) indicated higher expression of α-TTP mRNA in the cerebellum compared to that in the cortex suggesting an inverse relationship between α-TTP mRNA expression and α-T concentrations. We also note that Yokota et al, 2001 detected very low levels of α-TTP in brain regions compared to that in liver (Yokota et al, 2001); however α-T concentration in the two organs are very similar, further suggesting a lack of causal relationship between α-TTP expression and whole tissue α-T concentrations.…”

Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 86%

“…Previous studies have reported such discrete cellular localization of α-TTP. For example, the occurrence of α-TTP has been reported in rat cerebellar Bergman glia (Hosomi et al, 1998) and in Purkinje cells of AVED patients, in selected cells of patients with oxidative stress related to neurodegeneration (Copp et al, 1999) and in trophoblast, fetal capillaries, endothelium and amnion epithelium of human term placenta (Muller-Schmehl et al, 2004). However, the presence of a few α-TTP expressing cells in a tissue may not account for bulk α-T determined in whole tissue homogenates.…”

Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 99%

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Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

et al. 2008

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Ataxia with vitamin E deficiency is caused by mutations in α-tocopherol transfer protein (α-TTP) gene and it can be experimentally generated in mice by α-TTP gene inactivation (α-TTP-KO). This study compared α-tocopherol (α-T) concentrations of five brain regions and of four peripheral organs from 5 months old, male and female, wild-type (WT) and α-TTP-KO mice. All brain regions of female WT mice contained significantly higher α-T than those from WT males. α-T concentration in the cerebellum was significantly lower than that in other brain regions of WT mice. These sex and regional differences in brain α-T concentrations do not appear to be determined by α-TTP expression which was undetectable in all brain regions. All the brain regions of α-TTP-KO mice were severely depleted in α-T. The concentration of another endogenous antioxidant, total glutathione, was unaffected by gender but was decreased slightly but significantly in most brain regions of α-TTP-KO mice. The results show that both gender and the hepatic α-TTP, but not brain α-TTP gene expression are important in determining α-T concentrations within the brain. Interestingly, functional abnormality (ataxia) develops only very late in α-TTP-KO mice in spite of the severe α-tocopherol deficiency in brain starting at an early age.

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Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 86%

Section: Tissue α-T Concentrations Are Not Directly Correlated With αmentioning

confidence: 99%

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

et al. 2008

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“…As α-TTP is also abundantly expressed in the placenta, the importance of α-TOH in preventing fetus resorption is evident [98] . Furthermore, α-TTP is also expressed in several other tissues [76] , such as rat brain, spleen, lung and kidney [99] , the pregnant mouse uterus [100] , retina [101] and central nervous system [21] , suggesting an ubiquitous role for α-TTP in intra-organ trafficking [102] . Hosomi et al [103] estimated the relative affinities of α-TTP to the different vitamin E forms and stereoisomers starting from RRR-α-TOH set to 100%: β-TOH (38%), α-T3 (12%), SRR-α-TOH (11%), γ-TOH and trolox (9%) followed by δ-TOH, α-TOH acetate and α-TOH quinone with 2%.…”

Section: Intracellular Binding Proteins α -Tocopherol Transfer Proteinmentioning

confidence: 99%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

183

138

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Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e. , when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their sidechain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a REVIEW

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“…Further homeostatic control is provided by the fact that TTP's stability in cells is modulated by ubiquitination which, in turn, is regulated by ␣-tocopherol (61). Finally, TTP is also expressed in the brain (25,62) and the placenta (28,39,63). It is likely that in these locations, TTP provides an additional layer of regulation that maintains local ␣-tocopherol sufficiency in the most sensitive tissues, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…TTP is expressed at high levels in parenchymal cells of the liver (23,24), but low level expression has been described also in the cerebellum (25) and the placenta (26 -28). In vitro, TTP displays selective high affinity binding to ␣-tocopherol and facilitation of ␣-tocopherol transfer between lipid vesicles (29 -31).…”

mentioning

confidence: 99%

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

Chung¹,

Ghelfi

Atkinson

et al. 2016

Journal of Biological Chemistry

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␣-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, ␣-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic ␣-tocopherol transfer protein (TTP) preferentially selects dietary ␣-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of ␣-tocopherol. The mechanisms by which TTP facilitates ␣-tocopherol trafficking in hepatocytes are poorly understood. We found that the intracellular localization of TTP in hepatocytes is dynamic and responds to the presence of ␣-tocopherol. In the absence of the vitamin, TTP is localized to perinuclear vesicles that harbor CD71, transferrin, and Rab8, markers of the recycling endosomes. Upon treatment with ␣-tocopherol, TTP-and ␣-tocopherol-containing vesicles translocate to the plasma membrane, prior to secretion of the vitamin to the exterior of the cells. The change in TTP localization is specific to ␣-tocopherol and is time-and dose-dependent. The aberrant intracellular localization patterns of lipid binding-defective TTP mutants highlight the importance of protein-lipid interaction in the transport of ␣-tocopherol. These findings provide the basis for a proposed mechanistic model that describes TTP-facilitated trafficking of ␣-tocopherol through hepatocytes.Vitamin E is a plant-derived lipid that was discovered as a dietary component vital for female fertility in rodents (1) and for neuronal health in humans (2). Eight vitamin E forms are synthesized by plants, differing in the degree of methylation of the chromanol ring and the saturation of the isoprenoid side chain (3). Of the eight naturally occurring forms of vitamin E, ␣-tocopherol exhibits the most potent biological activity in preventing deficiency-induced reproductive failure in rodents (4, 5). ␣-Tocopherol's efficacy in scavenging free radicals (i.e. functioning as an antioxidant) is thought to underlie its critical roles in health (6 -8), but additional redox-independent actions have been recently proposed (9).The major regulator of vitamin E status is the ␣-tocopherol transfer protein (TTP), 2 and mutations in the TTPA gene cause heritable vitamin E deficiency. In humans, mutations in the TTPA gene cause systemic vitamin E deficiency accompanied by neurological compromise, primarily spinocerebellar ataxia (10 -17). Patients afflicted with this disorder (ataxia with vitamin E deficiency; OMIM 277460) present with debilitating neurodegeneration, the severity of which depends on the specific mutation's effect on TTP's biochemical activity (18,19). Lifelong vitamin E supplementation can delay or reverse disease progression, especially when patients are treated in earlier stages (20,21). Disruption of the TtpA gene in mice recapitulated the human ataxia with vitamin E deficiency disorder (22).TTP is expressed at high levels in parenchymal cells of the liver (23, 24), but low level expression has b...

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Localization of α-tocopherol transfer protein in rat brain

Cited by 106 publications

References 17 publications

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

Mice lacking α-tocopherol transfer protein gene have severe α-tocopherol deficiency in multiple regions of the central nervous system

Complexity of vitamin E metabolism

Vitamin E and Phosphoinositides Regulate the Intracellular Localization of the Hepatic α-Tocopherol Transfer Protein

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