Both authors contributed equally to this work.
Tauroursodeoxycholic Acid Affects PPARγ and TLR4 in Steatotic Liver Transplantation
Article first published online: 20 SEP 2012
© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 12, Issue 12, pages 3257–3271, December 2012
How to Cite
Jiménez-Castro, M. B., Elias-Miro, M., Mendes-Braz, M., Lemoine, A., Rimola, A., Rodés, J., Casillas-Ramírez, A. and Peralta, C. (2012), Tauroursodeoxycholic Acid Affects PPARγ and TLR4 in Steatotic Liver Transplantation. American Journal of Transplantation, 12: 3257–3271. doi: 10.1111/j.1600-6143.2012.04261.x
- Issue published online: 30 NOV 2012
- Article first published online: 20 SEP 2012
- Received 31 May 2012, revised 13 July 2012 and accepted for publication 30 July 2012
- ER tress;
- steatotic liver grafts;
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.