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Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans

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dc.contributor.author Wojtal, Kacper A.
dc.contributor.author Cee, Alexandra
dc.contributor.author Lang, Silvia
dc.contributor.author Götze, Oliver
dc.contributor.author Frühauf, Heiko
dc.contributor.author Geier, Andreas
dc.contributor.author Pastor-Anglada, Marcal
dc.contributor.author Torres-Torronteras, Javier
dc.contributor.author Martí, Ramon
dc.contributor.author Fried, Michael
dc.contributor.author Lutz, Thomas A.
dc.contributor.author Maggiorini, Marco
dc.contributor.author Gassmann, Max
dc.contributor.author Rogler, Gerhard
dc.contributor.author Vavricka, Stephan R.
dc.date.accessioned 2022-01-04T20:29:53Z
dc.date.available 2022-01-04T20:29:53Z
dc.date.issued 2014
dc.identifier.uri https://hdl.handle.net/20.500.12866/10364
dc.description.abstract Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals (n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans. en_US
dc.language.iso eng
dc.publisher American Physiological Society
dc.relation.ispartofseries American Journal of Physiology - Gastrointestinal and Liver Physiology
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject genetics en_US
dc.subject metabolism en_US
dc.subject Humans en_US
dc.subject blood en_US
dc.subject Time Factors en_US
dc.subject altitude en_US
dc.subject acclimatization en_US
dc.subject autacoid en_US
dc.subject Biological Markers en_US
dc.subject carrier protein en_US
dc.subject Cell Line en_US
dc.subject Cytokines en_US
dc.subject down regulation en_US
dc.subject duodenum en_US
dc.subject Hypoxia en_US
dc.subject Inflammation Mediators en_US
dc.subject Intestinal Absorption en_US
dc.subject Intestinal Mucosa en_US
dc.subject Membrane Transport Proteins en_US
dc.subject oxygen en_US
dc.subject pathophysiology en_US
dc.subject RNA, Messenger en_US
dc.subject Signal Transduction en_US
dc.subject Solute carrier en_US
dc.subject Up-Regulation en_US
dc.title Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1152/ajpgi.00353.2013
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.01.08
dc.relation.issn 1522-1547


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