Prolonged administration of a secretin receptor antagonist inhibits biliary senescence and liver fibrosis in Mdr2−/− mice

Background and Aims: Secretin (SCT) and secretin receptor (SR, only expressed on cholangiocytes within the liver) play key roles in modulating liver phenotypes. Forkhead box A2 (FoxA2) is required for normal bile duct homeostasis by preventing the excess of cholangiocyte proliferation. Short-term administration of the SR antagonist (SCT 5–27) decreased ductular reaction and liver fibrosis in bile duct ligated and Mdr2 −/− [primary sclerosing cholangitis (PSC), model] mice. We aimed to evaluate the effectiveness and risks of long-term SCT 5–27 treatment in Mdr2 −/− mice. Approach and Results: In vivo studies were performed in male wild-type and Mdr2 −/− mice treated with saline or SCT 5–27 for 3 months and human samples from late-stage PSC patients and healthy controls. Compared with controls, biliary SCT/SR expression and SCT serum levels increased in Mdr2 −/− mice and late-stage PSC patients. There was a significant increase in ductular reaction, biliary senescence, liver inflammation, angiogenesis, fibrosis, biliary expression of TGF-β1/VEGF-A axis, and biliary phosphorylation of protein kinase A and ERK1/2 in Mdr2 −/− mice. The biliary expression of miR-125b and FoxA2 decreased in Mdr2 −/− compared with wild-type mice, which was reversed by long-term SCT 5–27 treatment. In vitro , SCT 5–27 treatment of a human biliary PSC cell line decreased proliferation and senescence and SR/TGF-β1/VEGF-A axis but increased the expression of miR-125b and FoxA2. Downregulation of FoxA2 prevented SCT 5–27–induced reduction in biliary damage, whereas overexpression of FoxA2 reduced proliferation and senescence in the human PSC cell line. Conclusions: Modulating the SCT/SR axis may be critical for managing PSC.