Intestinal Dehydroascorbic Acid (DHA) Transport Mediated by the Facilitative Sugar Transporters, GLUT2 and GLUT8

Corpe, Christopher; Eck, Peter; Wang, Jin; Al-Hasani, Hadi; Levine, Mark

doi:10.1074/jbc.m112.436790

Cited by 120 publications

(125 citation statements)

References 33 publications

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“…They encode for intestinal membrane transporters of antioxidants, and it was hypothesized that genetically determined dysregulation of dietary antioxidants, prominently vitamin C, may contribute to IBD (9,19,20).…”

Section: Introductionmentioning

confidence: 99%

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Shaghaghi

Zhouyao

et al. 2017

The American Journal of Clinical Nutrition

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Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD. Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD. Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene. Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1. 95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively). Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.Am J Clin Nutr 2017;106:1508-13.

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Section: Introductionmentioning

confidence: 99%

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

Shaghaghi

Zhouyao

et al. 2017

The American Journal of Clinical Nutrition

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“…Notably, Vc is unstable in aqueous solution and spontaneously oxidizes to its biologically inactive form, dehydroascorbate (DHA) (1), also producing ascorbate radical as an intermediate product. Cells can take up DHA using a different type of low-affinity transporters: the glucose transporters GLUT1, GLUT2, GLUT3, GLUT4, GLUT8, and GLUT10 (3,4). Among these GLUT isoforms, only GLUT1 has a ubiquitous distribution (5,6).…”

Section: Vcmentioning

confidence: 99%

The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity

Tian

Wang

et al. 2014

Journal of Biological Chemistry

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Background:There is renewed interest in the possibility of using Vc as an anticancer agent. Results: Activation of HIF triggers a Warburg effect that renders cancer cells more sensitive to Vc-induced toxicity. Conclusion: These results provide a link between the metabolic state and the susceptibility to Vc. Significance: Our work helps to understand the preferential toxicity of Vc toward cancer cells.

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“…In order to understand the concept of vitamin C recycling, it is necessary to remember that vitamin C is found in two forms: (1) a reduced form, AA, that enters the cells specifically through SVCT transporters and (2) an oxidized form, DHA, that enters the cells through the facilitative glucose transporters, GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8 [29][30][31]. These two forms of vitamin C represent two different molecules with independent functions and characteristics, although they are interconvertible by means of oxidation-reduction reactions [32].…”

Section: General Aspectsmentioning

confidence: 99%

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

Ferrada¹,

Salazar²,

Santander³

2017

Vitamin C

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Vitamin C is the major antioxidant molecule in the central nervous system (CNS), reaching concentrations of 10 mM in neurons and 400 μM in the cerebrospinal fluid (CSF). Uptake of vitamin C by brain cells is performed through the co-transporter of ascorbic acid and sodium isoform 2, SVCT2, which is expressed in cells from the choroid plexus, neurons, oligodendrocytes, and ependymal cells. SVCT2 expression has also been described in cells at the neurogenic niche, specifically in proliferative type C cells. In this chapter, we will describe recently published studies of SVCT2 expression during brain development and define its polarization in cells from the radial glia (neuronal precursors within the CNS) and vitamin C-mediated effects in regulating genes associated with the maintenance of CNS stem cell pluripotency. We will discuss the differential biological effect that vitamin C generates in neurons versus astrocytes and how the oxidized form of vitamin C, dehydroascorbic acid (DHA), produced by neurons in conditions of oxidative stress must leave this cell to be incorporated by astrocytes. In this context, we will discuss recent literature, which shows that DHA regulates glycolytic metabolism in neurons. In parallel, we will analyze vitamin C recycling by astrocytes, which reduce DHA into ascorbic acid (AA), increasing the antioxidant potential of the brain. Data discussed in this chapter will provide an updated view of SVCT2 distribution in the brain and will also describe how vitamin C recycling participates in normal or pathological brain function.

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Intestinal Dehydroascorbic Acid (DHA) Transport Mediated by the Facilitative Sugar Transporters, GLUT2 and GLUT8

Cited by 120 publications

References 33 publications

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease

The Hypoxia-inducible Factor Renders Cancer Cells More Sensitive to Vitamin C-induced Toxicity

Vitamin C Transporter (SVCT2) Distribution in Developing and Adult Brains

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