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

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.

• Authors: Haojun Yang, Fengyong Luo, Yi Wei, Yuwen Jiao, Jun Qian, Shuai Chen, Yu Gong, Liming Tang
• Journal: Annals of translational medicine (Ann Transl Med) Vol. 9 Issue 14 Pg. 1158 (Jul 2021) ISSN: 2305-5839 [Print] China
• PMID: 34430599 (Publication Type: Journal Article)
• Copyright: 2021 Annals of Translational Medicine. All rights reserved.