Human α‐tocopherol transfer protein: Gene structure and mutations in familial vitamin E deficiency

Hentati, Afif; Deng, Han Xiang; Hung, Wu Yen; Nayer, Muhammad; Ahmed, Mohammed; He, Xiaoxuan; Tim, Richard W.; Stumpf, David A.; Siddique, Teepu

doi:10.1002/ana.410390305

Cited by 95 publications

(66 citation statements)

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“…Ttpa Ϫ/Ϫ mice at 18 months of age had no obvious signs of neurological disease. In contrast, humans with ␣-TTP gene defects develop ataxia with vitamin E deficiency by the first decade of life (16)(17)(18). This discrepancy may reflect species differences in the susceptibility of the nervous system to vitamin E deficiency (31).…”

Section: Resultsmentioning

confidence: 99%

“…Although the mechanism is unknown (15), ␣-TTP is believed to selectively transfer ␣-tocopherol from lipoproteins taken up by hepatocytes via the endocytic pathway to newly secreted lipoproteins, which facilitate its delivery to peripheral tissues (12). Humans with ␣-TTP gene defects have extremely low plasma ␣-tocopherol concentrations and develop severe neurodegenerative disease unless they are treated with high doses of vitamin E (16)(17)(18).…”

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confidence: 99%

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Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Terasawa

Ladha

Leonard

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

224

156

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Although lipid peroxidation in the subendothelial space has been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remains uncertain. Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the ␣-tocopherol transfer protein gene (Ttpa) increased the severity of atherosclerotic lesions in the proximal aorta. The increase was associated with increased levels of isoprostanes, a marker of lipid peroxidation, in aortic tissue. These results show that vitamin E deficiency promotes atherosclerosis in a susceptible setting and support the hypothesis that lipid peroxidation contributes to lesion development. 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.antioxidants O xidative modification of lipoproteins (e.g., low-density lipoproteins) has been hypothesized to play a key role in the pathogenesis of atherosclerosis (1, 2). Because vitamin E is the most potent lipid-soluble antioxidant normally found on lipoproteins in the plasma, there is strong interest in the relationship between vitamin E levels and the development of atherosclerosis. In animal models and human clinical trials, studies of the effects of vitamin E supplementation on atherosclerosis have yielded conf licting results (3-8), and little is known about the effects of vitamin E deficiency on atherosclerosis development (9).The major form of vitamin E in human plasma and tissues is ␣-tocopherol (10). ␣-Tocopherol enrichment of plasma and tissues is mediated by the ␣-tocopherol transfer protein (␣-TTP), a cytosolic lipid-transfer protein expressed in the liver (11)(12)(13)(14). Although the mechanism is unknown (15), ␣-TTP is believed to selectively transfer ␣-tocopherol from lipoproteins taken up by hepatocytes via the endocytic pathway to newly secreted lipoproteins, which facilitate its delivery to peripheral tissues (12). Humans with ␣-TTP gene defects have extremely low plasma ␣-tocopherol concentrations and develop severe neurodegenerative disease unless they are treated with high doses of vitamin E (16-18).To investigate the relationship between vitamin E deficiency and atherosclerosis, we used gene targeting to disrupt the mouse ␣-TTP gene (Ttpa) and generate a genetic model of vitamin E deficiency. We then crossed the ␣-TTP-deficient mice (Ttpa Ϫ/Ϫ ) mice with apolipoprotein (apo) E knockout (Apoe Ϫ/Ϫ ) mice (19), which spontaneously develop atherosclerosis on a chow diet (20,21). This enabled us to generate Apoe Ϫ/Ϫ mice with different Ttpa genotypes (ϩ͞ϩ, ϩ͞Ϫ, and Ϫ͞Ϫ) to test the hypothesis that ␣-TTP and vitamin E deficiency increase atherosclerosis in a susceptible setting. Materials and MethodsGeneration of ␣-TTP Knockout Mice. A 14-kb 129͞Sv genomic clone containing the Ttpa gene was isolated and subcloned into pBSSKII. A sequence replacement vector was constructed by PCR amplifica...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Terasawa

Ladha

Leonard

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

224

156

View full text Add to dashboard Cite

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“…2B). The TTP(R192H) mutant, however, is associated with a mild late-onset form of heritable vitamin E deficiency in humans (48), and the protein's biochemical activities in vitro are very similar to those of the wild-type protein (18). We found that the intracellular localization of the protein and its response to ␣-tocopherol treatment are indistinguishable from the wild-type protein (Fig.…”

Section: Resultsmentioning

confidence: 72%

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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“…Ben Hamida et al 6 localizaram o gen da deficiência de vitamina no cromossomo 8q em duas famílias com consangüinidade. A estrutura do gen TTP1 (tocopherol transporting protein 1) e outras mutações associadas à deficiência familial de vitamina E foram posteriormente descritas 37 .…”

Section: Ataxia De Friedreichunclassified

Ataxias cerebelares hereditárias: do martelo ao gen

Arruda

Teive²

1997

Arq. Neuro-Psiquiatr.

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RESUMO -As heredoataxias constituem grupo complexo de doenças neurodegenerativas hereditárias, para o qual várias formas de classificação clínica e patológica foram propostas com sucesso variável. O desenvolvimento das técnicas de biologia molecular trouxe informações importantes que têm permitido caracterizar geneticamente as ataxias cerebelares hereditárias. O reconhecimento das doenças causadas por expansões de trinucleotídeos abre novo capítulo para a pesquisa sobre outros mecanismos de doenças, como na ataxia de Friedreich e nas várias formas de ataxia cerebelar autossômica dominante(SCAl a SCA7), das quais a doença de MachadoJoseph / SCA3 parece ser a mais comum no nosso meio. A deficiência familial de vitamina E (cromossomo 8q) leva a quadro semelhante ao da ataxia de Friedreich (cromossomo 9p), mas responde à reposição oral de tocoferol. Formas familiais de ataxia periódica com (cromossomo 12p) ou sem (cromossomo 19p) mioquimia foram caracterizadas, a primeira resultado de mutações dos gens de canais de potássio. Os portadores do gen da ataxiateleangiectasia (cromossomo 1 lq) representam 1-3% da população e são suscetíveis aos efeitos oncogênicos da radiação iônica. Sem olvidar da importância da avaliação clínica neurológica, a avaliação genética laboratorial passa a ser valiosa ferramenta para o diagnóstico e aconselhamento genético, além do melhor entendimento da patogênese dessas doenças. PALAVRAS-CHAVE: ataxia cerebelar, doenças cerebelares, trinucleotídeos, genética. Hereditary cerebellar ataxias from neurological hammer to geneticsABSTRACT -The hereditary ataxias comprise a complex group of neurological disorders involving the cerebellum and its connections. Several classifications based on clinical and/or pathological data have been only partially successful. Recent progress in molecular genetics has identified the genic loci of hereditary ataxias and has allowed a more precise diagnosis of distinct genetic diseases. Trinucleotide repeat expansions has been recognized as a mechanism of disease in some autosomal dominant spinocerebellar ataxias (ADCA) (SCA1 to SCA7), including Machado-Joseph disease / SCA3, probably the most common form of ADCA in South Brazil, and Friedreich ataxia (GAA expansion -chromosome 9p). Familial alpha-tocopherol deficiency (chromosome 8q) may have a Friedreich ataxia phenotype and responds to the oral supplementaion with vitamin E. Familial episodic ataxias with (EA1 -chromosome 12p) and without (chromosome 19p -EA2) myokimia were identified, the first one caused by point mutations in the gene encoding the KCNA1 potassium voltage-gated channel. The gene responsible for ataxia-teleangiectasia (chromosome 1 lq) was found to encode a putative DNA binding protein kinase (ATM), related to the cell cycle control. One to 3% of the population are heterozygotic ATM gen carry and pose a higher risk of cancer when exposed to ionizing radiation. Molecular biology has provided us with useful tools to diagnosis and genetic counseling and, hopefully, will provide us with a better under...

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Human α‐tocopherol transfer protein: Gene structure and mutations in familial vitamin E deficiency

Cited by 95 publications

References 11 publications

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

Increased atherosclerosis in hyperlipidemic mice deficient in α-tocopherol transfer protein and vitamin E

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

Ataxias cerebelares hereditárias: do martelo ao gen

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