Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by SORT1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts, and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in wild-type and Sort1-/- mice, with or without augmentation of Il-6 or Lif. Mice with BEC sortilin deficiency (HgfapcreSort1fl/fl) and controls were subjected to BDL and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) induced cholestatic injury. Sort1-/- mice displayed reduced BEC proliferation and expression of BEC reactive markers. Administration of Lif or Il-6 restored BEC proliferation in Sort1-/- mice, without affecting BEC reactive or inflammatory markers. Sort1-/- mice also displayed impaired morphogenesis, which was corrected by Lif treatment. Similarly, HgfapcreSort1fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum Il-6 and Lif were comparable, yet liver pStat3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. HgfapcreSortfl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promotes ductular reaction and morphogenesis during cholestatic injury. Moreover, BEC sortilin is pivotal for the development of fibrosis.
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