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Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-...

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Autores principales: Subramanian, Veedamali S., Teafatiller, Trevor, Agrawal, Anshu, Kitazawa, Masashi, Marchant, Jonathan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275400/
https://www.ncbi.nlm.nih.gov/pubmed/34285658
http://dx.doi.org/10.1155/2021/4157132
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author Subramanian, Veedamali S.
Teafatiller, Trevor
Agrawal, Anshu
Kitazawa, Masashi
Marchant, Jonathan S.
author_facet Subramanian, Veedamali S.
Teafatiller, Trevor
Agrawal, Anshu
Kitazawa, Masashi
Marchant, Jonathan S.
author_sort Subramanian, Veedamali S.
collection PubMed
description Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.
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spelling pubmed-82754002021-07-19 Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake Subramanian, Veedamali S. Teafatiller, Trevor Agrawal, Anshu Kitazawa, Masashi Marchant, Jonathan S. Mediators Inflamm Research Article Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors. Hindawi 2021-07-03 /pmc/articles/PMC8275400/ /pubmed/34285658 http://dx.doi.org/10.1155/2021/4157132 Text en Copyright © 2021 Veedamali S. Subramanian et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Subramanian, Veedamali S.
Teafatiller, Trevor
Agrawal, Anshu
Kitazawa, Masashi
Marchant, Jonathan S.
Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title_full Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title_fullStr Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title_full_unstemmed Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title_short Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake
title_sort effect of lipopolysaccharide and tnfα on neuronal ascorbic acid uptake
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275400/
https://www.ncbi.nlm.nih.gov/pubmed/34285658
http://dx.doi.org/10.1155/2021/4157132
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