TGR5 protects against cholestatic liver disease via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway

Haojun Yang; Fengyong Luo; Yi Wei; Yuwen Jiao; Jun Qian; Shuai Chen; Yu Gong; Liming Tang

doi:10.21037/atm-21-2631

TGR5 protects against cholestatic liver disease via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway

Ann Transl Med. 2021 Jul;9(14):1158. doi: 10.21037/atm-21-2631.

Authors

Haojun Yang¹, Fengyong Luo², Yi Wei¹, Yuwen Jiao¹, Jun Qian¹, Shuai Chen¹, Yu Gong¹, Liming Tang¹

Affiliations

¹ Gastrointestinal Surgery Department, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China.
² School of Graduate, Dalian Medical University, Dalian, China.

Abstract

Background: Characterized by the presence of inflammation, fibrosis, and bile duct proliferation, cholestatic liver disease (CLD) affects people of all age groups. Takeda G-protein-coupled receptor (TGR5) has been implicated in the suppression of inflammation via toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB). Kupffer cells and their M1 polarization play important roles in inflammation and cholestatic liver injury via production of pro-inflammatory cytokines. Nevertheless, the function of TGR5 signaling in CLD is largely unknown.

Methods: We conducted liver tissue experiments, animal experiments, serum marker testing, liver histology analysis, Kupffer cell experiments, RNA extraction and Real-time PCR, western blotting, evaluation of ROS production by flow cytometry and statistical differences were analyzed by student t-test using GraphPad Prism.

Results: We found that serum bile acid (BA) and TGR5 levels were elevated in patients with cholestasis cirrhosis. Knockout of TGR5 in animals significantly increased bile duct ligation (BDL)-caused liver injury through increasing oxidative stress, promoting M1-predominant polarization of Kupffer cells, and elevating the serum levels of inflammatory cytokines. In contrast, TGR5 activation inhibited ROS production, secretion of pro-inflammatory cytokines, and M1-predominant polarization of Kupffer cells. Moreover, results showed that TGR5 exerted its effects via suppressing NF-κB signaling and activating nuclear factor 2 (Nrf2)/HO-1 signaling. Finally, the effect of TGR5 on cholestatic liver damage was also confirmed in vivo.

Conclusions: TGR5 activation protected against BDL-induced CLD by both suppressing inflammation via inhibiting the NF-κB pathway and reducing ROS production via activation of Nrf2/HO-1 signaling. These findings show the importance of TGR5 in CLD and provide new insight into therapeutic strategies for CLD.

Keywords: Cholestatic liver disease (CLD); TGR5; inflammation; inflammatory cytokines; reactive oxygen species.