A report on the Australian Drug Induced Liver Injury Network: AusDILIN

Background and aims: Liver fibrosis is a dynamic process characterized by the deposition of the accumulated extracellular matrix (ECM).To date, there are still no therapeutic medications approved for fibrosis or cirrhosis.Osteopontin (OPN) is a phosphoglycoprotein of ECM, and has been reported to drive ductular reaction (DR) and the formation of periportal scarring.Obeticholic acid (OCA) is approved for Primary Biliary Cholangitis (PBC), and OCA has been shown to improve the fibrosis in NASH patients evaluated in REGENERATE study.But the applications of OCA are limited due to its side effects.The main objective of this study is to investigate the impact of OCA on liver diseases.Method: The bile duct ligation model was used to evaluate the effect on fibrosis of OCA assessed by assessment of blood markers of liver injury, pathological section, western blotting, RT-PCR, immunohistochemistry and immunofluorescence stainging.OPN and Thr-OPN were detected by ELISA.The primary mouse cholangiocytes and human intrahepatic bile epithelium cells were chosen to investigate in vitro.Results: Compared to control, OCA treatment (40 mg/kg) aggravated BDL induced liver injury and liver fibrosis in mice, demonstrated by significantly increase in serum ALT, AST, ALP, TGF-β1, hepatic hydroxyproline, Masson Trichrome, H&E, and Sirius red staining as well as immunohistochemistry staining of α-SMA.The serum and liver content of OPN and its another active form, thrombin-cleaved OPN (Thr-OPN), were obviously increased in OCA-treated BDL mice.Interestingly, there was also a significant increase in the content of Thr-OPN in the liver of OCA-treated sham mice.Next we examined the downstram effects of OPN in liver disease.Immunoblots analysis