Genomic and functional analysis of the sodium-dependent vitamin C transporter SLC23A1–SVCT1

Eck, Peter; Erichsen, Hans Christian; Taylor, James G.; Corpe, Christopher; Chanock, Stephen J.; Levine, Mark

doi:10.1007/s12263-007-0040-7

Cited by 12 publications

(10 citation statements)

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“…Functional studies in the Xenopus laevis oocyte expression system did not show significant differences in transport function between the proteins reflecting the variant genotypes of SVCT1 [43] . Additional in vitro studies examining the functional consequences of SVCT1 and SVCT2 genetic polymorphisms are needed.…”

Section: Discussionmentioning

confidence: 84%

Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid

Cahill

El-Sohemy²

2009

Lifestyle Genomics

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Background/Aims: Vitamin C transporter proteins SVCT1 and SVCT2 are required for the absorption and transport of vitamin C in humans. This study aims to determine whether common SVCT genotypes modify the association between dietary vitamin C and serum ascorbic acid. Methods: Non-smoking men and women (n = 1,046) aged 20–29 were participants of the Toronto Nutrigenomics and Health Study. Overnight fasting blood samples were collected to determine serum ascorbic acid concentrations by HPLC and to genotype for two SVCT1 (rs4257763 and rs6596473) and two SVCT2 (rs6139591 and rs2681116) polymorphisms. Results: No diet-gene interactions were observed for the vitamin C transporter polymorphisms, however, the average (mean ± SE) serum ascorbic acid concentrations differed between rs4257763 genotypes (GG: 24.4 ± 1.3, GA: 26.8 ± 1.1, AA: 29.7 ± 1.4 µmol/l; p = 0.002). For this polymorphism, the correlation between dietary vitamin C and serum ascorbic acid was only significant in subjects with a G allele. The SVCT2 polymorphisms also appeared to modify the strength of the diet-serum correlation. Conclusions: Our findings demonstrate that genetic variation in SVCT1 can influence serum ascorbic acid concentrations and that SVCT1 and SVCT2 genotypes modify the strength of the correlation between dietary vitamin C and serum ascorbic acid.

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Section: Discussionmentioning

confidence: 84%

Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid

Cahill

El-Sohemy²

2009

Lifestyle Genomics

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“…SLC23A1 was expressed in human kidney and localized to proximal convoluted and straight tubule segments, based on high-resolution mapping of gene expression patterns ( Figure 5A). Although preliminary experiments suggested that SNPs did not affect SLC23A1 activity (36), activity was quantitated in more detail here. Using cRNA-injected Xenopus laevis oocytes, SLC23A1 transported ascorbate robustly, whereas an SLC23A1 knockout construct and sham injections lacked activity.…”

Section: Figurementioning

confidence: 99%

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

et al. 2010

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Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1 -/-mice. Compared with wild-type mice, Slc23a1 -/-mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1 -/-dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1 -/-pups born to Slc23a1 -/-dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1 -/-mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice.

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“…Genomic and functional analyses of the SVCT1 initially showed 22 single nucleotide polymorphisms in Caucasians and African‐Americans, but no significant differences in transporter function when expressed in Xenopus oocytes (Eck et al ., 2007). Subsequent studies revealed that several human polymorphic variants expressed in oocytes did in fact have substantial decreases in ascorbate transport (Corpe et al ., 2010).…”

Section: Biochemistry and Genetics Of The Svctsmentioning

confidence: 99%

The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C

May

2011

British J Pharmacology

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The ascorbate transporters SVCT1 and SVCT2 are crucial for maintaining intracellular ascorbate concentrations in most cell types. Although the two transporter isoforms are highly homologous, they have different physiologic functions. The SVCT1 is located primarily in epithelial cells and has its greatest effect in reabsorbing ascorbate in the renal tubules. The SVCT2 is located in most non-epithelial tissues, with the highest expression in brain and neuroendocrine tissues. These transporters are hydrophobic membrane proteins that have a high affinity and are highly selective for ascorbate. Their ability to concentrate ascorbate inside cells is driven by the sodium gradient across the plasma membrane as generated by Na+/K+ ATPase. They can concentrate ascorbate 20 to 60-fold over plasma ascorbate concentrations. Ascorbate transport on these proteins is regulated at the transcriptional, translational and post-translational levels. Available studies show that transporter function is acutely regulated by protein kinases A and C, whereas transporter expression is increased by low intracellular ascorbate and associated oxidative stress. The knockout of the SVCT2 in mice is lethal on day 1 of life, and almost half of SVCT1 knockout mice do not survive to weaning. These findings confirm the importance both of cellular ascorbate and of the two transport proteins as key to maintaining intracellular ascorbate. LINKED ARTICLESThis article is part of a themed section on Transporters. To view the other articles in this section visit http://dx

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Genomic and functional analysis of the sodium-dependent vitamin C transporter SLC23A1–SVCT1

Cited by 12 publications

References 4 publications

Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid

Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C

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