Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Mol Med Rep. 2013 Oct;8(4):1023-8. doi: 10.3892/mmr.2013.1618. Epub 2013 Aug 7.
It is currently thought that the transforming growth factor-β (TGF-β)/Smad signaling pathway acts as a central pathway leading to liver fibrosis, and that the aberrant Wnt/β-catenin signaling pathway also plays a vital role in the development of liver fibrosis. There is evidence that the histidine triad nucleotide-binding protein 1 (Hint1) was capable of inhibiting these two pathways. However, little data regarding the effects of Hint1 on liver fibrosis exists. Thus, we sought to investigate whether the recombinant human Hint1 protein (rhHint1) was capable of attenuating liver fibrosis induced by carbon tetrachloride (CCl4) in rats and the possible underlying mechanism(s) of action. In the present study, purified rhHint1 was obtained using genetic engineering technology. Liver fibrosis was induced in male Sprague-Dawley (SD) rats by the subcutaneous injection of CCl4. The rats were randomly divided into the normal control, the liver fibrosis model and the rhHint1 (doses, 50 and 100 µg/kg)‑treated groups. Following four weeks of treatment, the rhHint1-treated rats exhibited significantly reduced liver fibrosis upon histopathological analysis and lower levels of hydroxyproline. Furthermore, rhHint1 inhibited the expression of α-smooth muscle actin (α-SMA) in the liver tissues. Additionally, rhHint1 lowered the gene expression levels of TGF-β1/Smad3 and β-catenin/cyclin D1, whereas it increased the gene expression levels of Smad7. In conclusion, the results of this study indicated that rhHint1 is capable of attenuating CCl4-induced liver fibrosis by simultaneously targeting multiple pathogenic pathways, which may be developed as a new treatment for liver fibrosis.
目前认为转化生长因子-β（TGF-β）/Smad 信号通路作为导致肝纤维化的中心通路起作用，并且异常的 Wnt/β-连环蛋白信号通路在肝纤维化的发展中也起着至关重要的作用。有证据表明组氨酸三核苷酸结合蛋白 1（Hint1）能够抑制这两条通路。然而，关于 Hint1 对肝纤维化影响的数据很少。因此，我们试图研究重组人 Hint1 蛋白（rhHint1）是否能够减轻四氯化碳（CCl4）诱导的大鼠肝纤维化，以及其可能的作用机制。在本研究中，使用基因工程技术获得纯化的 rhHint1。通过皮下注射 CCl4 诱导雄性 Sprague-Dawley（SD）大鼠肝纤维化。将大鼠随机分为正常对照组、肝纤维化模型组和 rhHint1（剂量为 50 和 100μg/kg）治疗组。治疗 4 周后，rhHint1 治疗组的大鼠在组织病理学分析中表现出明显减轻的肝纤维化，羟脯氨酸水平降低。此外，rhHint1 抑制了肝组织中α-平滑肌肌动蛋白（α-SMA）的表达。此外，rhHint1 降低了 TGF-β1/Smad3 和 β-连环蛋白/细胞周期蛋白 D1 的基因表达水平，而增加了 Smad7 的基因表达水平。总之，这项研究的结果表明，rhHint1 能够通过同时针对多个致病途径来减轻 CCl4 诱导的肝纤维化，这可能成为肝纤维化的一种新的治疗方法。
