Tauroursodeoxycholic Acid Affects PPARγ and TLR4 in Steatotic Liver Transplantation

Authors

  • M. B. Jiménez-Castro,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
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  • M. Elias-Miro,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
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  • M. Mendes-Braz,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
    2. Departamento de Patologia e Medicina Legal, Faculdade de Medicina, Universidade de Sao Paulo, Sau Paulo, Brazil
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  • A. Lemoine,

    1. APHP, Biochimie et Oncogénétique Moléculaire, Inserm U1004/Université Paris 11, Institut du Foie, Hopital Paul Brousse, Villejuif, France
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  • A. Rimola,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
    2. Liver Unit, Hospital Clínic, Barcelona, Spain
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  • J. Rodés,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
    2. Liver Unit, Hospital Clínic, Barcelona, Spain
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  • A. Casillas-Ramírez,

    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
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    • Both authors contributed equally to this work.

  • C. Peralta

    Corresponding author
    1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBPAS), Barcelona, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
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    • Both authors contributed equally to this work.


Carmen Peralta, cperalta@clinic.ub.es

Abstract

Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-γ (PPARγ) and damage. When PPARγ was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARγ, and the PPARγ antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNβ (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARγ antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARγ and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.

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