Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

  1. Ghallab, Ahmed ORCID logo
  2. Hassan, Reham
  3. Hofmann, Ute
  4. Friebel, Adrian
  5. Hobloss, Zaynab
  6. Brackhagen, Lisa
  7. Begher-Tibbe, Brigitte
  8. Myllys, Maiju ORCID logo
  9. Reinders, Joerg ORCID logo
  10. Overbeck, Nina
  11. Sezgin, Selahaddin
  12. Zühlke, Sebastian
  13. Seddek, Abdel-latif
  14. murad, walaa ORCID logo
  15. Brecklinghaus, Tim ORCID logo
  16. Kappenberg, Franziska ORCID logo
  17. Rahnenführer, Jörg ORCID logo
  18. González, Daniela
  19. Goldring, Christopher
  20. Copple, Ian M.
  21. Marchan, Rosemarie ORCID logo
  22. Longerich, Thomas
  23. Vucur, Mihael
  24. Luedde, Tom ORCID logo
  25. Urban, Stephan ORCID logo
  26. Canbay, Ali
  27. Schreiter, Thomas
  28. Yu, Wenhui ORCID logo
  29. Akakpo , Jephte yao ORCID logo
  30. Olyaee, Mojtaba
  31. Curry, Steven C.
  32. Sowa, Jan-Peter
  33. Jaeschke, Hartmut ORCID logo
  34. Hoehme, Stefan ORCID logo
  35. Hengstler, Jan ORCID logo

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WeightNameValue
1000 Titel
  • Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity
1000 Autor/in
  1. Ghallab, Ahmed |
  2. Hassan, Reham |
  3. Hofmann, Ute |
  4. Friebel, Adrian |
  5. Hobloss, Zaynab |
  6. Brackhagen, Lisa |
  7. Begher-Tibbe, Brigitte |
  8. Myllys, Maiju |
  9. Reinders, Joerg |
  10. Overbeck, Nina |
  11. Sezgin, Selahaddin |
  12. Zühlke, Sebastian |
  13. Seddek, Abdel-latif |
  14. murad, walaa |
  15. Brecklinghaus, Tim |
  16. Kappenberg, Franziska |
  17. Rahnenführer, Jörg |
  18. González, Daniela |
  19. Goldring, Christopher |
  20. Copple, Ian M. |
  21. Marchan, Rosemarie |
  22. Longerich, Thomas |
  23. Vucur, Mihael |
  24. Luedde, Tom |
  25. Urban, Stephan |
  26. Canbay, Ali |
  27. Schreiter, Thomas |
  28. Yu, Wenhui |
  29. Akakpo , Jephte yao |
  30. Olyaee, Mojtaba |
  31. Curry, Steven C. |
  32. Sowa, Jan-Peter |
  33. Jaeschke, Hartmut |
  34. Hoehme, Stefan |
  35. Hengstler, Jan |
1000 Erscheinungsjahr 2022
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2022-07-01
1000 Erschienen in
1000 Quellenangabe
  • 77(1):71-83
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2022
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.jhep.2022.01.020 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9209783/ |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S0168827822000629?via%3Dihub#appsec1 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.
1000 Sacherschließung
lokal APAP
lokal tight junctions
lokal intravital imaging
lokal acute liver failure
lokal blood-bile barrier
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-0695-3403|https://frl.publisso.de/adhoc/uri/SGFzc2FuLCBSZWhhbQ==|https://frl.publisso.de/adhoc/uri/SG9mbWFubiwgVXRl|https://frl.publisso.de/adhoc/uri/RnJpZWJlbCwgQWRyaWFu|https://frl.publisso.de/adhoc/uri/SG9ibG9zcywgWmF5bmFi|https://frl.publisso.de/adhoc/uri/QnJhY2toYWdlbiwgTGlzYQ==|https://frl.publisso.de/adhoc/uri/QmVnaGVyLVRpYmJlLCBCcmlnaXR0ZQ==|https://orcid.org/0000-0001-9117-4572|https://orcid.org/0000-0003-1025-7849|https://frl.publisso.de/adhoc/uri/T3ZlcmJlY2ssIE5pbmE=|https://frl.publisso.de/adhoc/uri/U2V6Z2luLCBTZWxhaGFkZGlu|https://frl.publisso.de/adhoc/uri/WsO8aGxrZSwgU2ViYXN0aWFu|https://frl.publisso.de/adhoc/uri/U2VkZGVrLCBBYmRlbC1sYXRpZg==|https://orcid.org/0000-0002-7891-0376|https://orcid.org/0000-0001-6650-9166|https://orcid.org/0000-0001-8066-5333|https://orcid.org/0000-0002-8947-440X|https://frl.publisso.de/adhoc/uri/R29uesOhbGV6LCBEYW5pZWxh|https://frl.publisso.de/adhoc/uri/R29sZHJpbmcsIENocmlzdG9waGVy|https://frl.publisso.de/adhoc/uri/Q29wcGxlLCBJYW4gTS4=|https://orcid.org/0000-0003-4414-1633|https://frl.publisso.de/adhoc/uri/TG9uZ2VyaWNoLCBUaG9tYXM=|https://frl.publisso.de/adhoc/uri/VnVjdXIsIE1paGFlbA==|https://orcid.org/0000-0002-6288-8821|https://orcid.org/0000-0003-1560-8038|https://frl.publisso.de/adhoc/uri/Q2FuYmF5LCBBbGk=|https://frl.publisso.de/adhoc/uri/U2NocmVpdGVyLCBUaG9tYXM=|https://orcid.org/0000-0003-1545-2803|https://orcid.org/0000-0001-5324-1164|https://frl.publisso.de/adhoc/uri/T2x5YWVlLCBNb2p0YWJh|https://frl.publisso.de/adhoc/uri/Q3VycnksIFN0ZXZlbiBDLg==|https://frl.publisso.de/adhoc/uri/U293YSwgSmFuLVBldGVy|https://orcid.org/0000-0002-8695-6980|https://orcid.org/0000-0002-9716-9587|https://orcid.org/0000-0002-1427-5246
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. European Research Council |
1000 Fördernummer
  1. 457840828, LU 1360/3-2; SFB CRC 138; 267/13-3
  2. 771083
1000 Förderprogramm
  1. ERC Consolidator Grant PhaseControl
  2. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm ERC Consolidator Grant PhaseControl
    1000 Fördernummer 457840828, LU 1360/3-2; SFB CRC 138; 267/13-3
  2. 1000 joinedFunding-child
    1000 Förderer European Research Council |
    1000 Förderprogramm -
    1000 Fördernummer 771083
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6434815.rdf
1000 Erstellt am 2022-09-07T10:08:43.085+0200
1000 Erstellt von 254
1000 beschreibt frl:6434815
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet 2022-12-24T12:23:02.962+0100
1000 Objekt bearb. Sat Dec 24 12:23:02 CET 2022
1000 Vgl. frl:6434815
1000 Oai Id
  1. oai:frl.publisso.de:frl:6434815 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
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