Paricalcitol inhibits oxidative stress-induced cell senescence of the bile duct epithelium dependent on modulating Sirt1 pathway in cholestatic mice

Clinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear. Mice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis. Paricalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-β-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527. Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway. A model illustrating how paricalcitol protects the liver from BDL-induced liver injury. BDL not only directly induced the damage of bile duct, but also increased levels of oxidative stress and down-regulated the Sirt1 expression leading to cell senescence of bile duct. Meanwhile, cell senescence eventually accelerated bile duct damage. Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 expression. [Display omitted] •Paricalcitol ameliorates liver damage through inhibits oxidative stress by BDL induced in mice.•Paricalcitol promotes the repair of the damaged bile duct.•Paricalcitol prevented the downregulation