Wu Nan, Meng Fanyin, Zhou Tianhao, Han Yuyan, Kennedy Lindsey, Venter Julie, Francis Heather, DeMorrow Sharon, Onori Paolo, Invernizzi Pietro, Bernuzzi Francesca, Mancinelli Romina, Gaudio Eugenio, Franchitto Antonio, Glaser Shannon, Alpini Gianfranco
Division of Gastroenterology, Department of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA.
Digestive Research Center, Baylor Scott & White Health, Temple, Texas, USA.
FASEB J. 2017 Oct;31(10):4305-4324. doi: 10.1096/fj.201700097R. Epub 2017 Jun 20.
Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2-knockout (Mdr2) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2 mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2 mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine -acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells , we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2 mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2 mice and patients with PSC compared with controls and decreased in Mdr2 mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2 ablates biliary proliferation, liver fibrosis, and angiogenesis. , overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.
褪黑素疗法或长时间处于完全黑暗环境可减轻胆管结扎（BDL）大鼠的胆管增生和肝纤维化；然而，关于原发性硬化性胆管炎（PSC）的相关情况尚无信息。因此，我们旨在确定长时间黑暗疗法或褪黑素给药对PSC多药耐药基因2敲除（Mdr2）小鼠模型肝纤维化的治疗效果。对暴露于黑暗环境或接受褪黑素治疗的野生型和Mdr2小鼠，以及男性PSC患者和健康对照者，评估其褪黑素水平、胆管质量、肝纤维化、血管生成和miR-200b表达。在评估胆管质量、肝纤维化和血管生成之前，还对Mdr2小鼠用miR-200b抑制剂或对照进行处理。在胆管细胞和肝星状细胞中过表达芳基烷基胺-N-乙酰转移酶（AANAT；调节褪黑素合成的酶）或抑制miR-200b后，我们评估了血管生成和纤维化基因表达。暴露于黑暗环境或给予褪黑素后，Mdr2小鼠血清褪黑素水平升高，胆管质量受到抑制，同时肝纤维化和血管生成减少。微小RNA聚合酶链反应分析表明，与对照组相比，Mdr2小鼠和PSC患者中miR-200b表达增加，而接受黑暗暴露或褪黑素治疗的Mdr2小鼠中miR-200b表达降低。在Mdr2小鼠中抑制miR-200b可消除胆管增殖、肝纤维化和血管生成。此外，在胆管细胞和肝星状细胞中过表达AANAT或抑制miR-200b可降低miR-200b、血管生成和纤维化基因的表达。黑暗疗法或靶向褪黑素/miR-200b轴可能在包括PSC在内的胆管疾病的胆管损伤和肝纤维化管理中具有重要意义。——吴，N.，孟，F.，周，T.，韩，Y.，肯尼迪，L.，文特尔，J.，弗朗西斯，H.，德莫罗，S.，奥诺里，P.，因韦尔尼齐，P.，贝尔努齐，F.，曼奇内利，R.，加迪奥，E.，弗兰基托，A.，格拉泽，S.，阿尔皮尼，G. 长时间黑暗通过下调miR-200b减轻原发性硬化性胆管炎小鼠模型中的肝纤维化
