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dc.contributor.authorMohapatra, Soumya R
dc.contributor.authorSadik, Ahmed
dc.contributor.authorSharma, Suraj
dc.contributor.authorPoschet, Gernot
dc.contributor.authorGegner, Hagen M
dc.contributor.authorLanz, Tobias V
dc.contributor.authorLucarelli, Philippe
dc.contributor.authorKlingmüller, Ursula
dc.contributor.authorPlatten, Michael
dc.contributor.authorHeiland, Ines
dc.contributor.authorOpitz, Christiane A.
dc.date.accessioned2021-08-11T08:03:04Z
dc.date.available2021-08-11T08:03:04Z
dc.date.issued2021-02-19
dc.description.abstractThe liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.en_US
dc.identifier.citationMohapatra SR, Sadik A, Sharma S, Poschet G, Gegner, Lanz, Lucarelli P, Klingmüller, Platten M, Heiland I, Opitz CA. Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production. Frontiers in Immunology. 2021;12en_US
dc.identifier.cristinIDFRIDAID 1903951
dc.identifier.doi10.3389/fimmu.2021.590532
dc.identifier.issn1664-3224
dc.identifier.urihttps://hdl.handle.net/10037/21985
dc.language.isoengen_US
dc.publisherFrontiers Mediaen_US
dc.relation.journalFrontiers in Immunology
dc.relation.projectIDEU: 754688en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/MESI-STRAT/754688/Norway/Systems Medicine of Metabolic-Signaling Networks: A New Concept for Breast Cancer Patient Stratification//en_US
dc.relation.urihttps://doi.org/10.3389/fimmu.2021.590532
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2021 The Author(s)en_US
dc.subjectVDP::Mathematics and natural science: 400::Zoology and botany: 480en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Zoologiske og botaniske fag: 480en_US
dc.titleHypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Productionen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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