Hypoxia routes tryptophan homeostasis towards increased tryptamine production
The 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 immunosuppress...
Gespeichert in:
| Hauptverfasser: | , , , , , , , , , , |
|---|---|
| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
19 February 2021
|
| In: |
Frontiers in immunology
Year: 2021, Jahrgang: 12, Pages: 1-13 |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2021.590532 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3389/fimmu.2021.590532 Verlag, lizenzpflichtig, Volltext: https://www.frontiersin.org/articles/10.3389/fimmu.2021.590532/full 
|
| Verfasserangaben: | Soumya R. Mohapatra, Ahmed Sadik, Suraj Sharma, Gernot Poschet, Hagen M. Gegner, Tobias V. Lanz, Philippe Lucarelli, Ursula Klingmüller, Michael Platten, Ines Heiland and Christiane A. Opitz |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 175722002X | ||
| 003 | DE-627 | ||
| 005 | 20220819195421.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 210506s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fimmu.2021.590532 |2 doi | |
| 035 | |a (DE-627)175722002X | ||
| 035 | |a (DE-599)KXP175722002X | ||
| 035 | |a (OCoLC)1341408262 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Mohapatra, Soumya Ranjan |e VerfasserIn |0 (DE-588)1181830699 |0 (DE-627)166240798X |4 aut | |
| 245 | 1 | 0 | |a Hypoxia routes tryptophan homeostasis towards increased tryptamine production |c Soumya R. Mohapatra, Ahmed Sadik, Suraj Sharma, Gernot Poschet, Hagen M. Gegner, Tobias V. Lanz, Philippe Lucarelli, Ursula Klingmüller, Michael Platten, Ines Heiland and Christiane A. Opitz |
| 264 | 1 | |c 19 February 2021 | |
| 300 | |a 13 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 06.05.2021 | ||
| 520 | |a The 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 KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in liver with possible implications for immunosuppressive AHR activation and mental distrubances. | ||
| 650 | 4 | |a AhR activity | |
| 650 | 4 | |a Hallucination | |
| 650 | 4 | |a hypoxia | |
| 650 | 4 | |a Liver | |
| 650 | 4 | |a regulation | |
| 650 | 4 | |a TDO2 | |
| 650 | 4 | |a tryptamine | |
| 650 | 4 | |a Tryptophan | |
| 700 | 1 | |a Sadik, Ahmed |d 1984- |e VerfasserIn |0 (DE-588)1207935387 |0 (DE-627)1694254747 |4 aut | |
| 700 | 1 | |a Sharma, Suraj |e VerfasserIn |0 (DE-588)1160881065 |0 (DE-627)1024273415 |0 (DE-576)506211991 |4 aut | |
| 700 | 1 | |a Poschet, Gernot |e VerfasserIn |0 (DE-588)1030300712 |0 (DE-627)735006652 |0 (DE-576)378100572 |4 aut | |
| 700 | 1 | |a Gegner, Hagen M. |e VerfasserIn |0 (DE-588)1225302676 |0 (DE-627)174486389X |4 aut | |
| 700 | 1 | |a Lanz, Tobias |d 1983- |e VerfasserIn |0 (DE-588)14387036X |0 (DE-627)655121110 |0 (DE-576)339460296 |4 aut | |
| 700 | 1 | |a Lucarelli, Philippe |e VerfasserIn |0 (DE-588)1076779948 |0 (DE-627)835324362 |0 (DE-576)445661550 |4 aut | |
| 700 | 1 | |a Klingmüller, Ursula |d 1964- |e VerfasserIn |0 (DE-588)1098573455 |0 (DE-627)857742876 |0 (DE-576)46917014X |4 aut | |
| 700 | 1 | |a Platten, Michael |d 1971- |e VerfasserIn |0 (DE-588)121627780 |0 (DE-627)081431848 |0 (DE-576)261969811 |4 aut | |
| 700 | 1 | |a Heiland, Ines |d 1976- |e VerfasserIn |0 (DE-588)129604488 |0 (DE-627)477582079 |0 (DE-576)297744887 |4 aut | |
| 700 | 1 | |a Opitz, Christiane |d 1979- |e VerfasserIn |0 (DE-588)132405121 |0 (DE-627)522675913 |0 (DE-576)299125041 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in immunology |d Lausanne : Frontiers Media, 2010 |g 12(2021), Artikel-ID 590532, Seite 1-13 |h Online-Ressource |w (DE-627)657998354 |w (DE-600)2606827-8 |w (DE-576)343624834 |x 1664-3224 |7 nnas |a Hypoxia routes tryptophan homeostasis towards increased tryptamine production |
| 773 | 1 | 8 | |g volume:12 |g year:2021 |g elocationid:590532 |g pages:1-13 |g extent:13 |a Hypoxia routes tryptophan homeostasis towards increased tryptamine production |
| 856 | 4 | 0 | |u https://doi.org/10.3389/fimmu.2021.590532 |x Verlag |x Resolving-System |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u https://www.frontiersin.org/articles/10.3389/fimmu.2021.590532/full |x Verlag |z lizenzpflichtig |3 Volltext |
| 951 | |a AR | ||
| 992 | |a 20210506 | ||
| 993 | |a Article | ||
| 994 | |a 2021 | ||
| 998 | |g 132405121 |a Opitz, Christiane |m 132405121:Opitz, Christiane |d 910000 |d 911100 |e 910000PO132405121 |e 911100PO132405121 |k 0/910000/ |k 1/910000/911100/ |p 11 |y j | ||
| 998 | |g 121627780 |a Platten, Michael |m 121627780:Platten, Michael |d 60000 |d 62700 |e 60000PP121627780 |e 62700PP121627780 |k 0/60000/ |k 1/60000/62700/ |p 9 | ||
| 998 | |g 1098573455 |a Klingmüller, Ursula |m 1098573455:Klingmüller, Ursula |d 140000 |e 140000PK1098573455 |k 0/140000/ |p 8 | ||
| 998 | |g 14387036X |a Lanz, Tobias |m 14387036X:Lanz, Tobias |d 60000 |d 62700 |e 60000PL14387036X |e 62700PL14387036X |k 0/60000/ |k 1/60000/62700/ |p 6 | ||
| 998 | |g 1225302676 |a Gegner, Hagen M. |m 1225302676:Gegner, Hagen M. |d 700000 |d 721000 |e 700000PG1225302676 |e 721000PG1225302676 |k 0/700000/ |k 1/700000/721000/ |p 5 | ||
| 998 | |g 1030300712 |a Poschet, Gernot |m 1030300712:Poschet, Gernot |d 700000 |d 721000 |e 700000PP1030300712 |e 721000PP1030300712 |k 0/700000/ |k 1/700000/721000/ |p 4 | ||
| 998 | |g 1207935387 |a Sadik, Ahmed |m 1207935387:Sadik, Ahmed |d 140000 |e 140000PS1207935387 |k 0/140000/ |p 2 | ||
| 999 | |a KXP-PPN175722002X |e 392407500X | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"recId":"175722002X","physDesc":[{"extent":"13 S."}],"title":[{"title_sort":"Hypoxia routes tryptophan homeostasis towards increased tryptamine production","title":"Hypoxia routes tryptophan homeostasis towards increased tryptamine production"}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"language":["eng"],"note":["Gesehen am 06.05.2021"],"origin":[{"dateIssuedKey":"2021","dateIssuedDisp":"19 February 2021"}],"relHost":[{"physDesc":[{"extent":"Online-Ressource"}],"recId":"657998354","disp":"Hypoxia routes tryptophan homeostasis towards increased tryptamine productionFrontiers in immunology","pubHistory":["1.2010 -"],"origin":[{"publisher":"Frontiers Media","dateIssuedKey":"2010","publisherPlace":"Lausanne","dateIssuedDisp":"2010-"}],"note":["Gesehen am 07.11.13"],"type":{"bibl":"periodical","media":"Online-Ressource"},"language":["eng"],"part":{"year":"2021","pages":"1-13","extent":"13","volume":"12","text":"12(2021), Artikel-ID 590532, Seite 1-13"},"title":[{"title":"Frontiers in immunology","title_sort":"Frontiers in immunology"}],"id":{"issn":["1664-3224"],"eki":["657998354"],"zdb":["2606827-8"]}}],"person":[{"given":"Soumya Ranjan","role":"aut","family":"Mohapatra","display":"Mohapatra, Soumya Ranjan"},{"display":"Sadik, Ahmed","given":"Ahmed","role":"aut","family":"Sadik"},{"display":"Sharma, Suraj","given":"Suraj","role":"aut","family":"Sharma"},{"role":"aut","given":"Gernot","family":"Poschet","display":"Poschet, Gernot"},{"given":"Hagen M.","role":"aut","family":"Gegner","display":"Gegner, Hagen M."},{"display":"Lanz, Tobias","family":"Lanz","role":"aut","given":"Tobias"},{"display":"Lucarelli, Philippe","given":"Philippe","role":"aut","family":"Lucarelli"},{"given":"Ursula","role":"aut","family":"Klingmüller","display":"Klingmüller, Ursula"},{"family":"Platten","given":"Michael","role":"aut","display":"Platten, Michael"},{"family":"Heiland","role":"aut","given":"Ines","display":"Heiland, Ines"},{"family":"Opitz","role":"aut","given":"Christiane","display":"Opitz, Christiane"}],"id":{"eki":["175722002X"],"doi":["10.3389/fimmu.2021.590532"]},"name":{"displayForm":["Soumya R. Mohapatra, Ahmed Sadik, Suraj Sharma, Gernot Poschet, Hagen M. Gegner, Tobias V. Lanz, Philippe Lucarelli, Ursula Klingmüller, Michael Platten, Ines Heiland and Christiane A. Opitz"]}} | ||
| SRT | |a MOHAPATRASHYPOXIAROU1920 | ||