Immunological And Fibrogenic Pathogenesis In Non-viral Liver Disease

Background: With the increase of autoantibody detection methods and standards of living, the incidence of non-viral chronic liver disease, including autoimmune liver disease(AILD) and nonalcoholic fatty liver disease(NAFLD), gradually increased, and has become the major liver disease threatening human beings.Part I: Collagen triple helix repeat-containing protein 1(Cthrc1) attenuates cholestatic liver fibrosisObjective: To study the role and mechanism of Cthrc1 participating in cholestatic liver fibrosis. Methods: Murine cholestatic liver fibrosis induced by common bile duct ligation and DDC-diet feeding, were established for the study. Adenovirus vector was used to control the expression of Cthrc1; Chromatin immunoprecipitation, PCR, Western Blot, confocal laser scanning, and co-immunoprecipitation were used for studying the function of Cthrc1 on hepatic stellate cells and its mechanism. Results: Cthrc1 was increased in patients and murine model with cholestatic liver fibrosis. Cthrc1 alleviated cholestatic liver fibrosis. Cthrc1 was induced by TGF-β1, and in turn promoting the degradation of p-Smad3 via proteasomal pathway, then inhibited fibrosis gene synthesis in hepatic stellate cells. Conclusion: Cthrc1 is involved in the pathogenesis of cholestatic liver fibrosis by inhibiting TGF-β/Smad signaling.Part II: RANKL/RANK/OPG signaling is involved in primary biliary cirrhosisObjective: To study the RANKL/RANK/OPG signaling pathway in the pathogenesis of PBC. Methods: Immunohistochemistry and confocal laser clarify the expression of RANKL/ RANK /OPG in patients with PBC. Results: RANKL/RANK/OPG signaling was activated in PBC, and was mainly expressed in immunocytes and associated with the stage of disease. Conclusion: RANKL/RANK/ OPG signaling pathway is involved in the pathogenesis of PBC by adjusting hepatic immune function.Part III: Emperipolesis and its clinical significance in autoimmune liver diseaseObjective: To study emperipolesis in autoimmune liver disease(AILD) and clarify its significance. Methods: Confocal laser and H&E staining were used to determine the frequency of emperipolesis in patients with AILD. Results: Emperipolesis into hepatocyte were common in AIH, and associated with the disease; Emperipolesis into bile duct were common in PBC, and associated with the stage of disease; CD8 + T lymphocytes were involved in emperipolesis. Conclusion: Emperipolesis is involved in the pathogenesis AILD.Part IV: Inhibition of cysteine-rich protein 61(CCN1) alleviate murine NAFLD modelObjective: To study the function and mechanism of CCN1 involved in NAFLD. Methods: ELISA, immunohistochemistry, PCR, Western Blot were used to detected the CCN1 in murine NAFLD model and patients with NAFLD. Adenoviral vector was used to enforce the expression of CCN1 in murine NAFLD model. Results: CCN1 was increased in patients with NAFLD and murine NAFLD model. CCN1 aggravated murine NAFLD model by promoting apoptosis, hepatic steatosis and inflammatory cell infiltration. Conclusion: CCN1 is involved in the pathogenesis of NAFLD, and is expected to be a new target for the treatment of NAFLD.