Article

A novel biphenyl compound IMB-S7 ameliorates hepatic fibrosis in BDL rats by suppressing Sp1-mediated integrin αv expression

Authors: Na Zhang1, Shuang-shuang Zhao1,2,3, Yi-xuan Zhang1, Yu-cheng Wang1, Rong-guang Shao1, Ju-xian Wang1, Hong-wei He1
1 NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050, China
2 The Joint Program in Infection and Immunity, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
3 Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Correspondence to: Ju-xian Wang: imbjxwang@163.com, Hong-wei He: hehwei@imb.pumc.edu.cn,
DOI: 10.1038/s41401-019-0325-6
Received: 18 July 2019
Accepted: 31 October 2019
Advance online: 13 January 2020

Abstract

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, including TGF-β1, COL1A1, and ACTA2. 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 the integrin 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.
Keywords: bifendate; IMB-S7; hepatic fibrosis; integrin αv; Sp1; TGF-β/Smad pathway; bile duct ligation; LX2 cells

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