Wu Nan, Meng Fanyin, Invernizzi Pietro, Bernuzzi Francesca, Venter Julie, Standeford Holly, Onori Paolo, Marzioni Marco, Alvaro Domenico, Franchitto Antonio, Gaudio Eugenio, Glaser Shannon, Alpini Gianfranco
Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Research, Central Texas Veterans Health Care System, Temple, TX.
Hepatology. 2016 Sep;64(3):865-79. doi: 10.1002/hep.28622. Epub 2016 Jun 11.
The secretin/secretin receptor (SR) axis is up-regulated by proliferating cholangiocytes during cholestasis. Secretin stimulates biliary proliferation by down-regulation of let-7a and subsequent up-regulation of the growth-promoting factor, nerve growth factor (NGF). It is not known whether the secretin/SR axis plays a role in subepithelial fibrosis observed during cholestasis. Our aim was to determine the role of the secretin/SR axis in activation of biliary fibrosis in animal models and human primary sclerosing cholangitis (PSC). Studies were performed in wild-type (WT) mice with bile duct ligation (BDL), BDL SR(-/-) mice, or Mdr2(-/-) mouse models of cholestatic liver injury. In selected studies, the SR antagonist (Sec 5-27) was used to block the secretin/SR axis. Biliary proliferation and fibrosis were evaluated as well as secretion of secretin (by cholangiocytes and S cells), expression of markers of fibrosis, transforming growth factor-β1 (TGF-β1), transforming growth factor-β1 receptor (TGF-β1R), let-7a, and downstream expression of NGF. Correlative studies were performed in human control and PSC liver tissue biopsies, serum, and bile. SR antagonist reduced biliary proliferation and hepatic fibrosis in BDL WT and Mdr2(-/-) mice. There was decreased expression of let-7a in BDL and Mdr2(-/-) cholangiocytes that was associated with increased NGF expression. Inhibition of let-7a accelerated liver fibrosis was attributed to cholestasis. There was increased expression of TGF-β1 and TGF-β1R. Significantly higher expression of secretin, SR, and TGF-β1 was observed in PSC patient liver samples compared to healthy controls. In addition, there was higher expression of fibrosis genes and remarkably decreased expression of let-7a and increased expression of NGF compared to the control.
The secretin/SR axis plays a key role in regulating the biliary contribution to cholestasis-induced hepatic fibrosis. (Hepatology 2016;64:865-879).
在胆汁淤积期间，促胰液素/促胰液素受体（SR）轴会被增殖的胆管细胞上调。促胰液素通过下调let-7a并随后上调生长促进因子神经生长因子（NGF）来刺激胆管增殖。目前尚不清楚促胰液素/SR轴在胆汁淤积期间观察到的上皮下纤维化中是否起作用。我们的目的是确定促胰液素/SR轴在动物模型和人类原发性硬化性胆管炎（PSC）中胆管纤维化激活中的作用。在野生型（WT）小鼠胆管结扎（BDL）、BDL SR(-/-)小鼠或Mdr2(-/-)胆汁淤积性肝损伤小鼠模型中进行了研究。在选定的研究中，使用SR拮抗剂（Sec 5-27）阻断促胰液素/SR轴。评估了胆管增殖和纤维化以及促胰液素的分泌（由胆管细胞和S细胞分泌）、纤维化标志物、转化生长因子-β1（TGF-β1）、转化生长因子-β1受体（TGF-β1R）、let-7a的表达以及NGF的下游表达。在人类对照和PSC肝组织活检、血清和胆汁中进行了相关性研究。SR拮抗剂可降低BDL WT和Mdr2(-/-)小鼠的胆管增殖和肝纤维化。BDL和Mdr2(-/-)胆管细胞中let-7a表达降低，这与NGF表达增加有关。let-7a抑制加速肝纤维化归因于胆汁淤积。TGF-β1和TGF-β1R表达增加。与健康对照相比，PSC患者肝脏样本中促胰液素、SR和TGF-β1的表达明显更高。此外，与对照相比，纤维化基因表达更高，let-7a表达显著降低，NGF表达增加。
促胰液素/SR轴在调节胆汁淤积诱导的肝纤维化中胆管的作用方面起关键作用。（《肝脏病学》2016年；64:865-879）
