Disruption of TFGβ-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand. (May 2018)

• Record Type: Journal Article
• Authors: Carino, Adriana; Biagioli, Michele; Marchianò, Silvia; Scarpelli, Paolo; Zampella, Angela; Limongelli, Vittorio; Fiorucci, Stefano
• Is Part Of: Pharmacological research. Volume 131(2018)
• Page Start: 17
• Page End: 31
• Publication Date: 2018-05
• Subjects: CDCA chenodeoxycholic acid -- CA cholic acid -- DCA deoxycholic acid -- LCA litocholic acid -- BAs bile acids -- BARS bile acid activated receptors -- GPBAR1 G protein coupled bile acid receptor -- TGR5 Takeda G protein receptor 5 -- FXR farnesoid x-receptor -- PXR pregnane x-receptor -- LXRs liver x-receptors -- AMPK AMP activated protein kinase -- RXR retinoid x-receptor -- Cyp7a1 Cholesterol 7 alpha hydroxylase -- Cyp7b1 25-hydroxycholesterol 7 alpha-hydroxylase -- Cyp8b1 12-alpha hydroxylase -- Cyp27b1 1-alpha-hydroxylase -- NTCP Na+ -taurocholate cotrasporting polypeptide -- OSTα/β organic solute transporter alpha/beta -- BSEP bile salt export pump -- SHP small heterodimer partner -- NASH non-alcoholic steatohepatitis -- ECM extracellular matrix -- HSCs hepatic stellate cells -- SMAD small mother against decapentaplegic -- CCl4 carbon tetrachloride -- AST aspartate aminotransferase -- CRE cAMP response element -- ChIP chromatin immunoprecipitation -- LBD ligand binding domain -- CSE cystathionine gamma-lyase -- Col1α1 alpha-1 type 1 collagen -- αSMA alpha smooth muscle actin -- MRP4 multidrug resistance protein 4 -- Cav1 caveolin 1 -- ET1 endothelin1 -- MCP1 monocyte chemoattractantprotein-1 -- CCR2 chemokine receptor type 2 -- Cd38 cluster of differentiation 38 -- Fpr2 N-formyl peptide receptor 2 -- Gpr18 G protein-coupled receptor 18 -- c-myc myc proto-oncogene protein -- PBC primary biliary cholangitis; Nuclear receptors -- Liver fibrosis -- Hepatic stellate cells -- FXR-SHP axis -- TGFβ Signaling; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.02.033
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation . While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist. Methods: Liver Fibrosis was induced in mice by carbon tetrachloride (CCl4 ). Main results: In transactivation assay BAR704 activated FXR with and EC50 of 967 nM while exerted no agonistic activity on other receptors including GPBAR1. In naïve mice, BAR704 modulated the expression of FXR target genes in the liver of wild type mice but not in FXR −/− mice. In cirrhotic mice, administration of BAR704, 15 mg/kg for 9 weeks, spared the liver biosynthetic activity (bilirubin and albumin plasma levels), reduced liver fibrosis score (Sirius red staining), expression of pro-fibrogenetic (Colα1α, TGFβ and αSMA) and inflammatory genes (IL-1β, TNFα) and portal pressure. From mechanistic stand point, we have found that exposure of LX2 cells, a human HSCs line, to BAR704 increased the transcription of the short heterodimer partner (SHP) and induced the binding of this nuclear receptor to SMAD3, thus abrogating the binding of phosho-SMAD3 to the TGFβ promoter. Conclusions and applications: BAR704 is a selective FXR agonist that reduces liver fibrosis by interfering with the TGFβ-SMAD3 pathway in HSCs. Selective FXR agonists may represent an attractive strategy for the treatment of liver fibrosis.