Department of Cell Biology, School of Medicine, Taizhou University, Taizhou, PR China; Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
Department of Cell Biology, Jinzhou Medical University, Jinzhou, PR China.
Free Radic Biol Med. 2021 Jun;169:158-168. doi: 10.1016/j.freeradbiomed.2021.04.019. Epub 2021 Apr 16.
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.
临床研究表明，维生素 D 受体 (VDR) 在原发性胆汁性肝硬化患者肝脏中的表达减少。然而，激活的 VDR 如何影响胆汁淤积性肝损伤的机制尚不清楚。
在胆管结扎 (BDL) 前 3 天和手术后 5 或 28 天，通过腹腔注射 VDR 激动剂帕立骨化醇或载体对小鼠进行处理。通过 H&E 染色分析肝形态和坏死区域。通过商业试剂盒分析血清生化指标以评估肝损伤。通过 Western blot 分析确定帕立骨化醇对胆汁淤积性肝损伤的作用机制。
帕立骨化醇改善了 BDL 诱导的小鼠肝损伤。帕立骨化醇增加了 BEC 的增殖，以促进胆管的修复。帕立骨化醇还降低了 BDL 诱导的小鼠氧化应激水平。机制分析表明，帕立骨化醇减少了 SA-β-gal 阳性细胞的数量，并下调了与减少氧化应激相关的 p53、p21 和 p16 蛋白的表达。此外，帕立骨化醇通过减少 DNA 损伤和促进 DNA 修复来发挥抑制细胞衰老的作用。有趣的是，我们发现帕立骨化醇可防止 BDL 小鼠和 t-BHP 诱导的 BEC 模型中氧化应激诱导的 Sirt1 表达下调。此外，帕立骨化醇通过 Sirt1 依赖的途径抑制细胞衰老。抗氧化剂 ALCAR 和 Sirt1 抑制剂 EX-527 证实了这些结果。
帕立骨化醇通过促进受损胆管的修复和减少氧化应激诱导的胆管细胞衰老来缓解胆汁淤积性肝损伤，其作用机制是通过调节 Sirt1 通路实现的。
