Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments

Abstract

Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.

Keywords: GPBAR1 (TGR5); bile acids; biliary fibrosis; cholangiocytes; cholestasis; farnesoid X receptor; microbiota; primary sclerosing cholangitis.

Figure 1

Risk factors involved in development of PSC. PSC: primary sclerosing cholangitis; SSC: secondary sclerosing cholangitis; CCA/PSC: cholangiocarcinoma in PSC.

Figure 2

Role of cholangiocytes in PSC pathogenesis. DAMP: damage-associated molecular patterns. TGF, transforming growth factor beta. CCL2, chemokine (C-C motif) ligand 2.

Figure 3

FXR- and GPBAR1-activated pathways in hepatic (A), intestinal (B), and immune cells (C). Pathway induction is indicated by green arrows; pathway inhibition by black dotted lines. Abbreviations: AE2: Anion Exchange protein 2; ASBT/IBAP: Apical Sodium–Bile Acid Transporter/Ileal Bile Acid Transporter; BSEP: Bile Salt Export Pump; cAMP: cyclic Adenosine Monophosphate; CCL2: C-C Motif Chemokine Ligand 2; CFTR: Cystic Fibrosis Transmembrane Regulator; Cl-: Chloride Ion; CYP7A1: Cholesterol-7-alpha-hydroxylase; FAPBP6 (I-BABP): Fatty Acid Binding Protein 6 (Ileal-Bile Acid Binding Protein); FGF19: Fibroblast Growth Factor 19; FGFR4: Fibroblast Growth Factor Receptor 4; FXR: farnesoid X receptor; GLP-1: Glucagon-like Peptide 1; GPBAR1 (TGR5): G Protein-Coupled Bile Acid Receptor (Takeda G protein-coupled Receptor 5); HCO3-: Bicarbonate Ion; IL-1 β: Interleukin 1 beta; IL-10: Interleukin 10; MDR2: multidrug resistance protein 2; MRP3: Multidrug Resistance-associated Protein 3; MRP4: multidrug resistance-associated Protein 4; NF-κB: Nuclear Factor kappa B; NLRP3: NOD-, LRR- and Pyrin domain-containing protein 3; OATPs: Organic Anion-Transporting Polypeptides; OSTα/β: Organic Solute Transporter alpha/beta.

Figure 4

Evolving approaches to PSC.