Integration of temporal single cell cellular stress response activity with logic-ODE modeling reveals activation of ATF4-CHOP axis as a critical predictor of drug-induced liver injury

  1. Wijaya, Lukas Surya
  2. Trairatphisan, Panuwat ORCID logo
  3. Gabor, Attila
  4. Niemeijer, Marije ORCID logo
  5. Keet, Jason
  6. Alcalà Morera, Ariadna
  7. Snijders, Kirsten E.
  8. Wink, Steven
  9. Yang, Huan ORCID logo
  10. Schildknecht, Stefan ORCID logo
  11. Stevens, James L.
  12. Bouwman, Peter ORCID logo
  13. Kamp, Hennicke ORCID logo
  14. Hengstler, Jan ORCID logo
  15. Beltman, Joost ORCID logo
  16. Leist, Marcel ORCID logo
  17. Le Dévédec, Sylvia
  18. Saez-Rodriguez, Julio
  19. van de Water, Bob

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WeightNameValue
1000 Titel
  • Integration of temporal single cell cellular stress response activity with logic-ODE modeling reveals activation of ATF4-CHOP axis as a critical predictor of drug-induced liver injury
1000 Autor/in
  1. Wijaya, Lukas Surya |
  2. Trairatphisan, Panuwat |
  3. Gabor, Attila |
  4. Niemeijer, Marije |
  5. Keet, Jason |
  6. Alcalà Morera, Ariadna |
  7. Snijders, Kirsten E. |
  8. Wink, Steven |
  9. Yang, Huan |
  10. Schildknecht, Stefan |
  11. Stevens, James L. |
  12. Bouwman, Peter |
  13. Kamp, Hennicke |
  14. Hengstler, Jan |
  15. Beltman, Joost |
  16. Leist, Marcel |
  17. Le Dévédec, Sylvia |
  18. Saez-Rodriguez, Julio |
  19. van de Water, Bob |
1000 Erscheinungsjahr 2021
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-05-04
1000 Erschienen in
1000 Quellenangabe
  • 190:114591
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.bcp.2021.114591 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Drug-induced liver injury (DILI) is the most prevalent adversity encountered in drug development and clinical settings leading to urgent needs to understand the underlying mechanisms. In this study, we have systematically investigated the dynamics of the activation of cellular stress response pathways and cell death outcomes upon exposure of a panel of liver toxicants using live cell imaging of fluorescent reporter cell lines. We established a comprehensive temporal dynamic response profile of a large set of BAC-GFP HepG2 cell lines representing the following components of stress signaling: i) unfolded protein response (UPR) [ATF4, XBP1, BIP and CHOP]; ii) oxidative stress [NRF2, SRXN1, HMOX1]; iii) DNA damage [P53, P21, BTG2, MDM2]; and iv) NF-κB pathway [A20, ICAM1]. We quantified the single cell GFP expression as a surrogate for endogenous protein expression using live cell imaging over > 60 h upon exposure to 14 DILI compounds at multiple concentrations. Using logic-based ordinary differential equation (Logic-ODE), we modelled the dynamic profiles of the different stress responses and extracted specific descriptors potentially predicting the progressive outcomes. We identified the activation of ATF4-CHOP axis of the UPR as the key pathway showing the highest correlation with cell death upon DILI compound perturbation. Knocking down main components of the UPR provided partial protection from compound-induced cytotoxicity, indicating a complex interplay among UPR components as well as other stress pathways. Our results suggest that a systematic analysis of the temporal dynamics of ATF4-CHOP axis activation can support the identification of DILI risk for new candidate drugs.
1000 Sacherschließung
lokal Drug-induced liver injury (DILI)
lokal Stress response pathway
lokal Logic-ODE
lokal GFP-reporter
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/V2lqYXlhLCBMdWthcyBTdXJ5YQ==|https://orcid.org/0000-0001-9015-5855|https://frl.publisso.de/adhoc/uri/R2Fib3IsIEF0dGlsYQ==|https://orcid.org/0000-0003-0045-2317|https://frl.publisso.de/adhoc/uri/S2VldCwgSmFzb24=|https://frl.publisso.de/adhoc/uri/QWxjYWzDoCBNb3JlcmEsIEFyaWFkbmE=|https://frl.publisso.de/adhoc/uri/U25pamRlcnMsIEtpcnN0ZW4gRS4=|https://frl.publisso.de/adhoc/uri/V2luaywgU3RldmVu|https://orcid.org/0000-0002-3471-8235|https://orcid.org/0000-0001-9824-4991|https://frl.publisso.de/adhoc/uri/U3RldmVucywgSmFtZXMgTC4=|https://orcid.org/0000-0002-9252-5896|https://orcid.org/0000-0002-1316-8756|https://orcid.org/0000-0002-1427-5246|https://orcid.org/0000-0001-9215-3087|https://orcid.org/0000-0002-3778-8693|https://frl.publisso.de/adhoc/uri/TGUgRMOpdsOpZGVjLCBTeWx2aWE=|https://frl.publisso.de/adhoc/uri/U2Flei1Sb2RyaWd1ZXosIEp1bGlv|https://frl.publisso.de/adhoc/uri/dmFuIGRlIFdhdGVyLCBCb2I=
1000 Label
1000 Förderer
  1. Innovative Medicines Initiative |
  2. Horizon 2020 Framework Programme |
1000 Fördernummer
  1. 116030
  2. 681002
1000 Förderprogramm
  1. 2 Joint TransQST project
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Innovative Medicines Initiative |
    1000 Förderprogramm 2 Joint TransQST project
    1000 Fördernummer 116030
  2. 1000 joinedFunding-child
    1000 Förderer Horizon 2020 Framework Programme |
    1000 Förderprogramm -
    1000 Fördernummer 681002
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6429635.rdf
1000 Erstellt am 2021-09-30T13:40:04.756+0200
1000 Erstellt von 254
1000 beschreibt frl:6429635
1000 Bearbeitet von 317
1000 Zuletzt bearbeitet 2021-10-18T13:09:53.085+0200
1000 Objekt bearb. Mon Oct 18 12:32:07 CEST 2021
1000 Vgl. frl:6429635
1000 Oai Id
  1. oai:frl.publisso.de:frl:6429635 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

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