Deficiency of G-protein-coupled bile acid receptor Gpbar1 (TGR5) enhances chemically induced liver carcinogenesis

Abstract

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. We recently reported that TGR5 activation inhibits nuclear factor κB (NF-κB)-mediated inflammation. Here we show that TGR5 deficiency enhances chemically-induced liver carcinogenesis, and that TGR5 is a negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling. Mice lacking TGR5 were much more susceptible to diethylnitrosamine (DEN)-induced acute liver injury and liver carcinogenesis than wild-type (WT) mice. Consistent with the increasing incidence of liver cancer in TGR5−/− mice, hepatocyte death, compensatory proliferation, and gene expression of certain inflammatory cytokines and matrix metalloproteinases were more sensitive to DEN induction in the absence of TGR5 signaling. In vitro, TGR5 activation greatly inhibited proliferation and migration of human liver cancer cells. We then found that TGR5 activation strongly suppressed STAT3 signaling in vitro and in vivo. Furthermore, we revealed that TGR5 antagonizes STAT3 pathway through suppressing STAT3 phosphorylation, its transcription activity and DNA binding activity, which suggests that TGR5 antagonizes liver tumorigenesis at least in part by inhibiting STAT3 signaling. Conclusion These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.

Bile acid dysregulation, gut dysbiosis, and gastrointestinal cancer

“…72 Loss of TGR5 in mice also increased susceptibility to diethylnitrosamine-induced acute liver injury and cancer due to increased hepatocyte death, compensatory proliferation, and expression of inflammatory cytokines. 73 Moreover, TGR5 KO mice displayed abnormal hydrophobic BA composition, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response, and delayed regeneration compared to WT mice post partial hepatectomy. 74 Treatment of non-alcoholic fatty liver disease (NAFLD) mice with dual FXR/TGR5 agonist decreased intrahepatic inflammation and improved histological features.…”

TGR5 activation suppressed S1P/S1P2 signaling and resisted high glucose-induced fibrosis in glomerular mesangial cells

“…We conducted TGR5 overexpression under normal and high glucose levels and found that, without exogenous stimulation, overexpression of TGR5 decreased FN, ICAM-1, and TGF-β1 protein contents (Figs.3B-3E). TGR5 showed receptor activity without ligand binding, which could be related to TGR5 constitutive activity [13,28].…”

Primary biliary cholangitis: new treatments for an old disease

“…Animal studies show that activation of this receptor inhibits inflammatory processes55–57 and minimises associated liver injury. It may also have a protective role in carcinogenesis of the liver 58. Fibroblast growth factor 19 (FGF19) has also been discovered as a therapeutic target for patients with PBC.…”