The liver has a vital role in many metabolic and regulatory processes in the body. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens. At this time there is no definitive cure for PBC; however, ursodeoxycholic acid (UDCA) has been shown to reduce injury when administered as the first line of treatment. Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression. Currently, a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus. This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

Biliary epithelium (i.e., cholangiocytes) is a heterogeneous population of epithelial cells in the liver, which line small and large bile ducts and have individual responses and functions dependent on size and location in the biliary tract. We discuss the recent findings showing that the intrahepatic biliary tree is heterogeneous regarding (1) morphology and function, (2) hormone expression and signaling (3), response to injury, and (4) roles in liver regeneration. This review overviews the significant characteristics and differences of the small and large cholangiocytes. Briefly, it outlines the in vitro and in vivo models used in the heterogeneity evaluation. In conclusion, future studies addressing biliary heterogeneity's role in the pathogenesis of liver diseases characterized by ductular reaction may reveal novel therapeutic approaches.

Lipocalin‐2 (LCN2), also known as neutrophil gelatinase‐associated lipocalin (NGAL), is a secreted glycoprotein that has been shown to regulate cell proliferation, innate immunity, metabolism, and tumor metastasis in several cell types. LCN2 expression is elevated in hepatic tissues in experimental liver injury models and patients with alcoholic hepatitis. LCN2 has been shown to stimulate proliferation and metastasis of cholangiocarcinoma. However, the role of cholangiocyte LCN2 and LCN2 receptors (NGALR/24p3‐R) during cholestasis and primary sclerosing cholangitis (PSC) has not been evaluated. Therefore, we aimed to assess the role of LCN2 and its receptor, 24p3‐R, in acute and chronic cholestatic models. Methods LCN2 and 24p3‐R were evaluated in liver sections, total liver, and isolated cholangiocytes from wild‐type (WT; C57) normal and BDL (7 days) mice and WT (FVB/NJ) and Mdr2‐/‐ mice (model of primary sclerosing cholangitis, PSC) by immunohistochemistry and qPCR, respectively. LCN2 levels were evaluated by ELISA in cholangiocyte supernatants (6 hrs) collected from animal models and serum from BDL and Mdr2‐/‐ and WT controls and late‐stage PSC patients and healthy human controls. Serum bile acid (BA) levels were measured using a commercial BA assay kit in BDL, Mdr2‐/‐, and control mice. In vitro, both human (H69) and mouse pooled (MPC) cholangiocytes were treated with either 50 ng/ml LCN2 or 100 mM taurocholic acid (TCA) for 24 hrs after which the expression of proliferation, fibrosis, LCN2, and 24p3‐R genes was determined via qPCR. Results There were significant increases in LCN2 and 24p3‐R immunostaining in BDL mice compared to controls. By qPCR significant increases were observed for both LCN2 and 24p3‐R in total liver and isolated cholangiocytes from BDL and Mdr2‐/‐ mice compared to WT. Increased levels of LCN2 were found in serum from PSC patients and serum and supernatants from isolated cholangiocytes from BDL and Mdr2‐/‐ mice compared to control. In vitro, MPC cells treated with LCN2 had increases in fibrotic marker Col1a1, proliferation marker PCNA, and inflammatory markers IL‐1b and IL‐6. Also, significant increases were seen in fibrotic markers (aSMA, FN‐1, and TGF‐b1) and LCN2 receptor 24p3‐R in H69 cells treated with LCN2 compared to untreated cells. As expected, increased serum BA levels were observed in both BDL and Mdr2‐/‐ mice compared to controls. H69 cells treated with TCA also had significant increases in FN‐1, TGF‐b1, and the LCN2 receptor 24p3‐R, indicating that BA may regulate 24p3‐R expression. Conclusion LCN2 and 24p3‐R expression is elevated in cholestatic models and stimulates a profibrotic cholangiocyte phenotype. These findings suggest that LCN2 may play a crucial role in the pathogenesis of cholestatic liver injury.