Liver GPBAR1 Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4-/- Mice

Liver Int. 2025 Feb;45(2):e16235. doi: 10.1111/liv.16235.

Abstract

Background and aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein-coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model.

Methods: Single-cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, Abcb4-/- mice were treated with BAR501 for 12-24 weeks.

Results: Single-cell analysis demonstrated that GPBAR1 is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of GPBAR1 increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In vitro treatment of NHCs with BAR501 reversed the acquisition of a pro-inflammatory phenotype and the downregulation of GPBAR1 expression promoted by LPS in an NF-κB-dependent manner. Treating Abcb4-/- mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis-associated gut permeability, and intestinal and systemic inflammation. Ex vivo experiments using conditioned media from BAR501-treated cholangiocytes mitigated the activation of macrophages.

Conclusions: Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation-associated cholestasis, warranting the evaluation of BAR501 in PSC patients.

Keywords: GPBAR1 (TGR5); bile acids; cholangiocytes–macrophages cross‐talk; gut–liver axes; intestinal microbiota; primary sclerosing cholangitis.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B* / genetics
  • ATP Binding Cassette Transporter, Subfamily B* / metabolism
  • ATP-Binding Cassette Sub-Family B Member 4*
  • Animals
  • Bile Acids and Salts / metabolism
  • Cholangitis, Sclerosing* / genetics
  • Cholestasis* / metabolism
  • Disease Models, Animal*
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver* / metabolism
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Knockout*
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • GPBAR1 protein, human
  • Gpbar1 protein, mouse
  • ATP-Binding Cassette Sub-Family B Member 4
  • ATP Binding Cassette Transporter, Subfamily B
  • 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
  • Bile Acids and Salts