Department of Medical Physiology, Texas A&M University, College of Medicine, United States of America; Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou, PR China.
Department of Medical Physiology, Texas A&M University, College of Medicine, United States of America.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1525-1539. doi: 10.1016/j.bbadis.2019.03.002. Epub 2019 Mar 16.
Melatonin, a neuroendocrine hormone synthesized by the pineal gland and cholangiocytes, decreases biliary hyperplasia and liver fibrosis during cholestasis-induced biliary injury via melatonin-dependent autocrine signaling through increased biliary arylalkylamine N-acetyltransferase (AANAT) expression and melatonin secretion, downregulation of miR-200b and specific circadian clock genes. Melatonin synthesis is decreased by pinealectomy (PINX) or chronic exposure to light. We evaluated the effect of PINX or prolonged light exposure on melatonin-dependent modulation of biliary damage/ductular reaction/liver fibrosis. Studies were performed in male rats with/without BDL for 1 week with 12:12 h dark/light cycles, continuous light or after 1 week of PINX. The expression of AANAT and melatonin levels in serum and cholangiocyte supernatant were increased in BDL rats, while decreased in BDL rats following PINX or continuous light exposure. BDL-induced increase in serum chemistry, ductular reaction, liver fibrosis, inflammation, angiogenesis and ROS generation were significantly enhanced by PINX or light exposure. Concomitant with enhanced liver fibrosis, we observed increased biliary senescence and enhanced clock genes and miR-200b expression in total liver and cholangiocytes. In vitro, the expression of AANAT, clock genes and miR-200b was increased in PSC human cholangiocyte cell lines (hPSCL). The proliferation and activation of HHStecs (human hepatic stellate cell lines) were increased after stimulating with BDL cholangiocyte supernatant and further enhanced when stimulated with BDL rats following PINX or continuous light exposure cholangiocyte supernatant via intracellular ROS generation. Conclusion: Melatonin plays an important role in the protection of liver against cholestasis-induced damage and ductular reaction.
褪黑素是由松果体和胆管细胞合成的神经内分泌激素，通过增加胆汁芳香族烷基胺 N-乙酰转移酶 (AANAT) 表达和褪黑素分泌、下调 miR-200b 和特定的昼夜节律基因的褪黑素依赖性自分泌信号，减少胆汁增生和肝纤维化在胆汁淤积诱导的胆管损伤期间。褪黑素合成被松果体切除术 (PINX) 或慢性暴露于光减少。我们评估了 PINX 或延长光照对褪黑素依赖性调节胆管损伤/胆管反应/肝纤维化的影响。研究在有/无 BDL 的雄性大鼠中进行了 1 周，有 12:12 小时的黑暗/光照周期，持续光照或在 PINX 后 1 周。BDL 大鼠血清和胆管细胞上清液中 AANAT 和褪黑素水平的表达增加，而 PINX 或持续光照暴露后 BDL 大鼠的表达降低。BDL 诱导的血清化学、胆管反应、肝纤维化、炎症、血管生成和 ROS 生成增加在 PINX 或光照暴露后显著增强。随着肝纤维化的增强，我们观察到总肝和胆管细胞中胆汁衰老和时钟基因以及 miR-200b 的表达增强。在体外，PSC 人胆管细胞系 (hPSCL) 中 AANAT、时钟基因和 miR-200b 的表达增加。HHStecs（人肝星状细胞系）的增殖和激活在刺激 BDL 胆管细胞上清液后增加，并且当用 PINX 或 BDL 大鼠的连续光照暴露后的胆管细胞上清液刺激时进一步增强，通过细胞内 ROS 生成。结论：褪黑素在保护肝脏免受胆汁淤积诱导的损伤和胆管反应中起重要作用。
