Tudca Ameliorates Liver Injury Via Activation of SIRT1-FXR Signaling in a Rat Hemorrhagic Shock Model.

Authors:
Silei Sun
Silei Sun
Ruijin Hospital
Bing Zhao
Bing Zhao
Jilin University
China
Mengzhi Qi
Mengzhi Qi
Nanjing DrumTower Hospital
Yi Yao
Yi Yao
University of Toronto
Canada
Lili Xu
Lili Xu
Institute of Laboratory Animal Sciences
China
Ran Ji
Ran Ji
Ilmenau University of Technology
Germany
Weiwei Chen
Weiwei Chen
College of Life Sciences
China
Jinlong Wang
Jinlong Wang
Henan Normal University
China

Shock 2019 Apr 14. Epub 2019 Apr 14.

Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Objective: To investigate the changes of bile acids in the liver during hemorrhagic shock (HS) and their potential to attenuate liver injury via activation of SIRT1 (sirtuin 1)-FXR (farnesoid X receptor) signaling.

Methods: A Sprague-Dawley (SD) rat HS model was established, while HepG2 cells were hypoxically cultured to simulate HS in vitro. Liver bile acids (BA) were profiled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). FXR expression was detected by western blot and immunohistochemistry. The mRNA levels of SIRT1 and FXR were detected by polymerase chain reaction. Protein expression of SIRT1, FoxM1, NF-κB, acetyl-NF-κB, p53, and acetyl-p53 was analyzed by western blot. Hepatocyte apoptosis and proliferation were measured by TUNEL assay and Ki-67 staining, respectively. Serum and supernatant cytokines were analyzed using ELISA assays. Liver injury was also assessed. To investigate the possible mechanisms, SIRT1 agonist (SRT1720), SIRT1 inhibitor (EX527), and FXR inhibitor (Z-guggulsterone) were used.

Results: Tauroursodeoxycholic acid (TUDCA) in the liver decreased significantly after HS. SIRT1 and FXR expression was time-dependently downregulated by HS or hypoxia condition. TUDCA upregulated SIRT1-FXR activity, which inhibited expression and acetylation of NF-κB and p53 and increased FoxM1 expression, leading to decreased inflammatory response and apoptosis and increased proliferative capacity in hepatocytes, and attenuation of liver injury. EX527 pretreatment reversed the protective effect of TUDCA. Moreover, Z-guggulsterone supplementation decreased the protective effect of TUDCA in vitro.

Conclusion: TUDCA in the liver decreased during HS. TUDCA supplementation might attenuate HS-induced liver injury by upregulating SIRT1-FXR signaling.

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Source
http://dx.doi.org/10.1097/SHK.0000000000001351DOI Listing
April 2019
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