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

被引：0

作者：

Di Giorgio, Cristina ^{[1
]}

Urbani, Ginevra ^{[1
]}

Marchiano, Silvia ^{[1
]}

Biagioli, Michele ^{[1
]}

Bordoni, Martina ^{[2
]}

Bellini, Rachele ^{[1
]}

Massa, Carmen ^{[1
]}

Lachi, Ginevra ^{[1
]}

Cari, Luigi ^{[1
]}

Morretta, Elva ^{[3
]}

Spinelli, Lucio ^{[3
]}

Monti, Maria Chiara ^{[3
]}

Sepe, Valentina ^{[3
]}

Zampella, Angela ^{[3
]}

Distrutti, Eleonora ^{[4
]}

Banales, Jesus M. ^{[5
,6
,7
]}

Lapitz, Ainhoa ^{[5
]}

Milkiewicz, Piotr ^{[8
,9
]}

Milkiewicz, Malgorzata ^{[10
]}

Fiorucci, Stefano ^{[1
]}

机构：

[1] Univ Perugia, Dept Med & Surg, Perugia, Italy

[2] BAR PHARMACEUT SRL, Reggio Emilia, Italy

[3] Univ Naples Federico II, Dept Pharm, Naples, Italy

[4] Azienda Osped Perugia, Perugia, Italy

[5] Univ Basque Country, Donostia Univ Hosp, Biogipuzkoa Hlth Res Inst, Dept Liver & Gastrointestinal Dis,UPV EHU,CIBERehd, Donostia San Sebastian, Spain

[6] Basque Fdn Sci, Ikerbasque, Bilbao, Spain

[7] Univ Navarra, Sch Sci, Dept Biochem & Genet, Pamplona, Spain

[8] Med Univ Warsaw, Dept Gen Transplant & Liver Surg, Liver & Internal Med Unit, Warsaw, Poland

[9] Pomeranian Med Univ, Translat Med Grp, Szczecin, Poland

[10] Pomeranian Med Univ, Dept Biol & Med Parasitol, Szczecin, Poland

来源：

LIVER INTERNATIONAL | 2025年 / 45卷 / 02期

关键词：

bile acids; cholangiocytes-macrophages cross-talk; GPBAR1 (TGR5); gut-liver axes; intestinal microbiota; primary sclerosing cholangitis; ACID RECEPTOR TGR5; BILE-ACID; URSODEOXYCHOLIC ACID; MICROBIOTA; DISEASE;

D O I：

10.1111/liv.16235

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background and AimsPrimary 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.MethodsSingle-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.ResultsSingle-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-kappa B-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.ConclusionsOur study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation-associated cholestasis, warranting the evaluation of BAR501 in PSC patients.

引用

页数：18