The role of bile acid-activated receptor TGR5 in inflammation and liver diseases

Abstract

Takeda G-protein-coupled receptor 5 (TGR5), a bile acid receptor, has been recognized as an important signal molecule with roles extending far beyond bile acid homeostasis. Its activation has been shown to ameliorate metabolic disorders and suppress inflammatory responses through diverse mechanisms. Expressed widely in both parenchymal and non-parenchymal cells of the liver, TGR5 plays a central role in hepatic physiology and disease. This review consolidates current evidence on the involvement of TGR5 in various liver pathologies, including metabolic dysfunction-associated steatohepatitis, cholestatic diseases, liver fibrosis, and hepatocellular carcinoma. Additionally, we summarize the regulatory functions of TGR5 in immune cells and inflammatory signaling pathways. We emphasize TGR5 as a promising therapeutic target for a range of chronic liver diseases, given its pivotal role in modulating inflammation and metabolism. Future research should focus on developing tissue-specific TGR5 agonists to enhance therapeutic efficacy and reduce systemic side effects, as well as elucidating its context-dependent dual roles in hepatocarcinogenesis to ensure safe clinical application.

Keywords: bile acids; hepatocellular carcinoma; inflammation; liver fibrosis; metabolic dysfunction-associated fatty liver disease; tgr5.

FIGURE 1

TGR5-mediated anti-inflammatory mechanisms and their implications in chronic liver disease. BAs, bile acids; cAMP, cyclic AMP; PKA, Protein kinase A; p-CREB, Phosphorylated cAMP response element-binding protein; NF-κB, nuclear factor kappa- B; IκB, inhibitor a of NF- κB; NLRP3, NOD-like receptors family pyrin domain containing three; il1b, Interleukin-1β. HSCs, Hepatic stellate cells; HCC, hepatocellular carcinoma. The figure was created in https://BioRender.com.