Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou, China.
Yonsei Med J. 2021 May;62(5):453-460. doi: 10.3349/ymj.2021.62.5.453.
Multiple pathways are involved in inducing liver fibrosis, which can damage the integrity of liver. Among them, miR-125b has been found to exert an activating action on hepatic stellate cells. Endoplasmic reticulum stress and autophagy lead to liver disorders. Here, we evaluated the therapeutic influence of miR-125b on the endoplasmic reticulum function in injured livers submitted to bile duct ligation.
For inducing injury, bile duct ligation was done on miR-125b transgenic rats (miR-125b-Tg) in wild type rats. The rat T-6 cells received transfection of miR-125b mimic and Tunicamycin. Protein expressions were observed by western blot analysis.
Compared to wild type rats, liver-injured rats showed significant impairment of liver function as assessed by the total bilirubin levels. The miR-125b-Tg rats showed decrease in activity of aspartate transaminase and alanine transaminase. Liver tissues of miR-125b-Tg rats showed weaker fibrotic matrix formation. Upregulation of miR-125b decreased the bile duct ligation-mediated hepatic disturbances for the expressions of endoplasmic reticulum kinase, inositol-requiring kinase 1alpha, sXBP1, CHOP, LC3, p62, ULK, and caspase-3/-8/-9. T-6 cells transfected with miR-125b mimic and treated with Tunicamycin caused decrease in levels of cleaved caspase-3, sXBP1, CHOP, and LC3. The miR-125b signaling showed protective effect on the liver tissues subjected to injury and fibrosis histopathology.
This study demonstrates a novel insight into the miR125b-mediated stabilization of endoplasmic reticulum integrity, which slows the progression of injury-induced hepatic deterioration.
多种途径参与诱导肝纤维化，可破坏肝脏完整性。其中，miR-125b 已被发现对肝星状细胞具有激活作用。内质网应激和自噬导致肝脏紊乱。在这里，我们评估了 miR-125b 对胆管结扎损伤肝脏内质网功能的治疗影响。
为了诱导损伤，在野生型大鼠中对 miR-125b 转基因大鼠（miR-125b-Tg）进行胆管结扎。大鼠 T-6 细胞接受 miR-125b 模拟物和衣霉素的转染。通过 Western blot 分析观察蛋白表达。
与野生型大鼠相比，肝功能受损的肝损伤大鼠总胆红素水平明显受损。miR-125b-Tg 大鼠的天冬氨酸转氨酶和丙氨酸转氨酶活性降低。miR-125b-Tg 大鼠的肝组织显示出较弱的纤维基质形成。miR-125b 的上调降低了胆管结扎介导的肝内紊乱，内质网激酶、肌醇需要激酶 1alpha、sXBP1、CHOP、LC3、p62、ULK 和 caspase-3/-8/-9 的表达。用 miR-125b 模拟物转染的 T-6 细胞并用衣霉素处理导致裂解的 caspase-3、sXBP1、CHOP 和 LC3 水平降低。miR-125b 信号对损伤和纤维化组织病理学的肝组织具有保护作用。
本研究证明了 miR125b 介导的内质网完整性稳定的新见解，这减缓了损伤诱导的肝恶化的进展。
