A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin alphav expression
A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin alphav expression
复制标题
一种新型联苯化合物 IMB-S7 通过抑制 Sp1 介导的整合素 α v 表达来改善 BDL 大鼠的肝纤维化
DOI：
10.1038/s41401-019-0325-6
复制
发表时间：
2020
影响因子：
8.2
通讯作者：
He H
中科院分区：
文献类型：
--
作者：
Zhang N;Zhao S.;Zhang Y.;Wang Y;Shao R;Wang J;He H
慢性组织损伤伴纤维化导致组织结构破坏、器官功能障碍和最终器官衰竭。因此，迫切需要开发有效的抗纤维化药物。IMB-S7是一种新的联苯化合物，来源于联苯双酯（联苯二甲酸酯），在中国用于治疗慢性肝炎。在目前的研究中，我们研究了IMB-S7作为抗肝纤维化药物的潜力。在胆管结扎（BDL）大鼠模型中，口服IMB-S7（400 mg· kg-1· d-1，14 d）显著改善了BDL诱导的肝坏死、胆管增生和胶原积累。然后，我们发现IMB-S7处理显著抑制了人肝星状细胞系LX 2和小鼠原代HSC以及BDL大鼠肝脏样本中的TGF-β/Smad通路，从而抑制了大多数纤维化相关基因的转录，包括TGF-β1，COL 1A 1和ACTA 2。此外，IMB-S7处理显著抑制TGF-β处理的LX 2细胞和BDL大鼠肝脏样品中整合素αv在mRNA和蛋白水平上的表达。利用整合素αv过表达和沉默，我们证明整合素αv活性与TGF-β/Smad通路的激活正相关。基于双荧光素酶法和DNA亲和沉淀法，我们发现IMB-S7通过竞争性抑制转录因子Sp1与整合素αv（ITGAV）启动子（−173/−163 bp）的结合来灭活整合素αv。这些结果表明，IMB-S7通过Sp1-integrin αv信号通路抑制HSC活化和肝纤维化，IMB-S7有可能成为未来抗肝纤维化的候选药物。
Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg−1· d−1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-β/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, includingTGF-β1,COL1A1, andACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-β-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-β/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to theintegrin αv (ITGAV) promoter (−173/−163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.