{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T22:57:01Z","timestamp":1776466621340,"version":"3.51.2"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T00:00:00Z","timestamp":1613260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK107474"],"award-info":[{"award-number":["DK107474"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The process of obtaining ascorbic acid (AA) via intestinal absorption and blood circulation is carrier-mediated utilizing the AA transporters SVCT1 and SVCT2, which are expressed in the intestine and brain (SVCT2 in abundance). AA concentration is decreased in Alzheimer\u2019s disease (AD), but information regarding the status of intestinal AA uptake in the AD is still lacking. We aimed here to understand how AA homeostasis is modulated in a transgenic mouse model (5xFAD) of AD. AA levels in serum from 5xFAD mice were markedly lower than controls. Expression of oxidative stress response genes (glutathione peroxidase 1 (GPX1) and superoxide dismutase 1 (SOD1)) were significantly increased in AD mice jejunum, and this increase was mitigated by AA supplementation. Uptake of AA in the jejunum was upregulated. This increased AA transport was caused by a marked increase in SVCT1 and SVCT2 protein, mRNA, and heterogeneous nuclear RNA (hnRNA) expression. A significant increase in the expression of HNF1\u03b1 and specific protein 1 (Sp1), which drive SLC23A1 and SLC23A2 promoter activity, respectively, was observed. Expression of hSVCT interacting proteins GRHPR and CLSTN3 were also increased. SVCT2 protein and mRNA expression in the hippocampus of 5xFAD mice was not altered. Together, these investigations reveal adaptive up-regulation of intestinal AA uptake in the 5xFAD mouse model.<\/jats:p>","DOI":"10.3390\/nu13020617","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T08:53:56Z","timestamp":1613292836000},"page":"617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Upregulation of Vitamin C Transporter Functional Expression in 5xFAD Mouse Intestine"],"prefix":"10.3390","volume":"13","author":[{"given":"Trevor","family":"Teafatiller","sequence":"first","affiliation":[{"name":"Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher W.","family":"Heskett","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anshu","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan S.","family":"Marchant","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet E.","family":"Baulch","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Munjal M.","family":"Acharya","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veedamali S.","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1093\/ajcn\/69.6.1086","article-title":"Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans","volume":"69","author":"Carr","year":"1999","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_2","unstructured":"Packer, L., and Fuchs, J. (1997). Vitamin C in Health and Disease, Marcel Dekker Inc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3233\/JAD-2012-111853","article-title":"A Critical Review of Vitamin C for the Prevention of Age-Related Cognitive Decline and Alzheimer\u2019s Disease","volume":"29","author":"Harrison","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1021\/cn500308h","article-title":"Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP\/PSEN1 and Normally Aging Mice","volume":"6","author":"Dixit","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0006-8993(81)90056-1","article-title":"Regional distribution of ascorbate in human brain","volume":"212","author":"Mefford","year":"1981","journal-title":"Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Monacelli, F., Acquarone, F.M.E., Giannotti, C., Borghi, R., and Nencioni, A. (2017). Vitamin C, Aging and Alzheimer\u2019s Disease. Nutr., 9.","DOI":"10.3390\/nu9070670"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3233\/JAD-2011-101971","article-title":"Vitamin C Restores Behavioral Deficits and Amyloid-\u03b2 Oligomerization without Affecting Plaque Formation in a Mouse Model of Alzheimer\u2019s Disease","volume":"26","author":"Murakami","year":"2011","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_8","first-page":"99","article-title":"Lowered plasma vitamin C, but not vitamin E, concentrations in dementia patients","volume":"8","author":"Rabinowitz","year":"2004","journal-title":"J. Nutr. Health Aging"},{"key":"ref_9","first-page":"85","article-title":"Vitamin C Transport and Its Role in the Central Nervous System","volume":"56","author":"May","year":"2011","journal-title":"Cholest. Bind. Cholest. Transp. Proteins"},{"key":"ref_10","first-page":"382","article-title":"Intestinal ascorbic acid transport following diets of high or low ascorbic acid content","volume":"48","author":"Rose","year":"1978","journal-title":"Int. J. Vitam. Nutr. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.mam.2012.12.002","article-title":"The sodium-dependent ascorbic acid transporter family SLC23","volume":"34","author":"Suzuki","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_12","first-page":"G340","article-title":"Molecular mechanism(s) involved in differential expression of vitamin C transporters along the intestinal tract","volume":"312","author":"Subramanian","year":"2017","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1172\/JCI39191","article-title":"Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice","volume":"120","author":"Corpe","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/0502-514","article-title":"Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival","volume":"8","author":"Sotiriou","year":"2002","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0166-2236(99)01543-X","article-title":"Ascorbate regulation and its neuroprotective role in the brain","volume":"23","author":"Rice","year":"2000","journal-title":"Trends Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer\u2019s Disease Mutations: Potential Factors in Amyloid Plaque Formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1007\/s11481-020-09908-9","article-title":"Immune and Inflammatory Determinants Underlying Alzheimer\u2019s Disease Pathology","volume":"15","author":"Baulch","year":"2020","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.bbamem.2017.10.010","article-title":"Inhibition of intestinal ascorbic acid uptake by lipopolysaccharide is mediated via transcriptional mechanisms","volume":"1860","author":"Subramanian","year":"2018","journal-title":"Biochim. et Biophys. Acta Biomembr."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Heskett, C.W., Teafatiller, T., Hennessey, C., Gareau, M.G., Marchant, J.S., Said, H.M., and Subramanian, V.S. (2020). Enteropathogenic Escherichia coli Infection Inhibits Intestinal Ascorbic Acid Uptake via Dysregulation of Its Transporter Expression. Dig. Dis. Sci., 1\u201311.","DOI":"10.1007\/s10620-020-06389-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fnmol.2016.00042","article-title":"Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction","volume":"9","author":"Acharya","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1080\/10284150290029205","article-title":"Serum Levels of Antioxidant Vitamins and Lipid Peroxidation in Multiple Sclerosis","volume":"5","author":"Besler","year":"2002","journal-title":"Nutr. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.4110\/in.2012.12.1.18","article-title":"The Analysis of Vitamin C Concentration in Organs ofGulo-\/-Mice Upon Vitamin C Withdrawal","volume":"12","author":"Kim","year":"2012","journal-title":"Immune Netw."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.brainres.2010.06.037","article-title":"Low ascorbic acid and increased oxidative stress in gulo(\u2212\/\u2212) mice during development","volume":"1349","author":"Harrison","year":"2010","journal-title":"Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1017\/S0007114507787457","article-title":"Vitamin C deficiency in weanling guinea pigs: Differential expression of oxidative stress and DNA repair in liver and brain","volume":"98","author":"Lykkesfeldt","year":"2007","journal-title":"Br. J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.redox.2014.01.009","article-title":"Prenatal vitamin C deficiency results in differential levels of oxidative stress during late gestation in foetal guinea pig brains","volume":"2","author":"Paidi","year":"2014","journal-title":"Redox Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1242\/dmm.018218","article-title":"Triptolide treatment reduces Alzheimer\u2019s disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD","volume":"7","author":"Wang","year":"2014","journal-title":"Dis. Model. Mech."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1083","DOI":"10.1038\/cddis.2014.26","article-title":"High-dose of vitamin C supplementation reduces amyloid plaque burden and ameliorates pathological changes in the brain of 5XFAD mice","volume":"5","author":"Kook","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev.ph.51.030189.001013","article-title":"Specific Regulation of Intestinal Nutrient Transporters by their Dietary Substrates","volume":"51","author":"Ferraris","year":"1989","journal-title":"Annu. Rev. Physiol."},{"key":"ref_29","first-page":"G443","article-title":"Adaptive regulation of sugar and amino acid transport by vertebrate intestine","volume":"245","author":"Karasov","year":"1983","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_30","first-page":"G275","article-title":"Molecular mechanisms involved in the adaptive regulation of human intestinal biotin uptake: A study of the hSMVT system","volume":"292","author":"Reidling","year":"2007","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_31","first-page":"G1127","article-title":"Adaptive regulation of intestinal thiamin uptake: Molecular mechanism using wild-type and transgenic mice carrying hTHTR-1 and -2 promoters","volume":"288","author":"Reidling","year":"2005","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jcp.10324","article-title":"Folate uptake in the human intestine: Promoter activity and effect of folate deficiency","volume":"196","author":"Subramanian","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Subramanian, V.S., Ghosal, A., Kapadia, R., Nabokina, S.M., and Said, H.M. (2015). Molecular Mechanisms Mediating the Adaptive Regulation of Intestinal Riboflavin Uptake Process. PLOS ONE, 10.","DOI":"10.1371\/journal.pone.0131698"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C663","DOI":"10.1152\/ajpcell.00396.2008","article-title":"Membrane targeting and intracellular trafficking of the human sodium-dependent multivitamin transporter in polarized epithelial cells","volume":"296","author":"Subramanian","year":"2009","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"470","DOI":"10.2144\/19962003470","article-title":"Quantitative RT-PCR on CYP1A1 Heterogeneous Nuclear RNA: A Surrogate for the In Vitro Transcription Run-On Assay","volume":"20","author":"Elferink","year":"1996","journal-title":"Biotech."},{"key":"ref_36","first-page":"G1217","article-title":"Mechanisms and regulation of vitamin C uptake: Studies of the hSVCT systems in human liver epithelial cells","volume":"295","author":"Reidling","year":"2008","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jnutbio.2010.03.001","article-title":"Promoter analysis of the human ascorbic acid transporters SVCT1 and 2: Mechanisms of adaptive regulation in liver epithelial cells","volume":"22","author":"Reidling","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.bbaexp.2005.11.002","article-title":"Functional analysis of two regulatory regions of the human Na+-dependent vitamin C transporter 2, SLC23A2, in human vascular smooth muscle cells","volume":"1732","author":"Rubin","year":"2005","journal-title":"Biochim. Biophys. Acta Gene Struct. Expr."},{"key":"ref_39","first-page":"G1079","article-title":"Glyoxalate reductase\/hydroxypyruvate reductase interacts with the sodium-dependent vitamin C transporter-1 to regulate cellular vitamin C homeostasis","volume":"304","author":"Subramanian","year":"2013","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/joa.12769","article-title":"Vitamin transporters in mice brain with aging","volume":"232","author":"Marcos","year":"2018","journal-title":"J. Anat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/S0197-4580(03)00031-9","article-title":"Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer\u2019s disease","volume":"24","author":"Rinaldi","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/(SICI)1099-1166(1998110)13:11<749::AID-GPS860>3.0.CO;2-T","article-title":"Low plasma vitamin C in Alzheimer patients despite an adequate diet","volume":"13","author":"Vellas","year":"1998","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"L868","DOI":"10.1152\/ajplung.1999.277.5.L868","article-title":"Expression of type II Na-Picotransporter in alveolar type II cells","volume":"277","author":"Traebert","year":"1999","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pbb.2009.06.006","article-title":"Vitamin C reduces spatial learning deficits in middle-aged and very old APP\/PSEN1 transgenic and wild-type mice","volume":"93","author":"Harrison","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1177\/1533317512473193","article-title":"The Possible Role of Antioxidant Vitamin C in Alzheimer\u2019s Disease Treatment and Prevention","volume":"28","author":"Heo","year":"2013","journal-title":"Am. J. Alzheimer\u2019s Dis. Other Dementiasr"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0891-5849(99)00247-6","article-title":"Increased lipoprotein oxidation in alzheimer\u2019s disease","volume":"28","author":"Schippling","year":"2000","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Tveden-Nyborg, P., Vogt, L., Schjoldager, J.G., Jeannet, N., Hasselholt, S., Paidi, M.D., Christen, S., and Lykkesfeldt, J. (2012). Maternal Vitamin C Deficiency during Pregnancy Persistently Impairs Hippocampal Neurogenesis in Offspring of Guinea Pigs. PLOS ONE, 7.","DOI":"10.1371\/journal.pone.0048488"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.brainres.2010.05.090","article-title":"Vitamin C distribution and retention in the mouse brain","volume":"1348","author":"Harrison","year":"2010","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0304-3940(82)90147-1","article-title":"Detailed mapping of ascorbate distribution in rat brain","volume":"28","author":"Milby","year":"1982","journal-title":"Neurosci. Lett."},{"key":"ref_50","first-page":"70","article-title":"A family of mammalian Na+-dependent L-ascorbic acid transporters","volume":"399","author":"Tsukaguchi","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/jnr.20751","article-title":"Immunohistochemical study of the distribution of sodium-dependent vitamin C transporters in adult rat brain","volume":"83","author":"Mun","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/jnr.21204","article-title":"Ascorbate transport by primary cultured neurons and its role in neuronal function and protection against excitotoxicity","volume":"85","author":"Qiu","year":"2007","journal-title":"J. Neurosci. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/2\/617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:24:10Z","timestamp":1760160250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/2\/617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,14]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["nu13020617"],"URL":"https:\/\/doi.org\/10.3390\/nu13020617","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,14]]}}}