Zhu Tingting, Zhang Linqiang, Li Chengbin, Tan Xiaoqiong, Liu Jing, Fan Qijing, Zhang Zhiguo, Zhan Mingfeng, Fu Lin, Luo Jinbo, Geng Jiawei, Wu Yingjie, Zou Xiaoju, Liang Bin
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
J Genet Genomics. 2022 Apr;49(4):338-349. doi: 10.1016/j.jgg.2022.02.013. Epub 2022 Feb 28.
Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases. However, the pathogenesis of liver fibrosis still remains elusive. Here, we report that the calcium binding protein A11 (S100A11) is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics. S100A11 is also experimentally activated in liver fibrosis in mouse, rat, tree shrew, and human with liver fibrosis. While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis, the inhibition of S100A11 improves liver fibrosis. Mechanistically, S100A11 activates hepatic stellate cells (HSCs) and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-β signaling pathway. S100A11 physically interacts with SIRT6, a deacetylase of Smad2/3, which may competitively inhibit the interaction between SIRT6 and Smad2/3. The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis. Additionally, a significant elevation of S100A11 in serum is observed in clinical patients. Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis, which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.
肝纤维化是各类慢性肝病的关键转变阶段，也是一个可逆的病理过程。然而，肝纤维化的发病机制仍不清楚。在此，我们报告，在来自GSE肝纤维化和树鼩肝脏蛋白质组学的整合数据中，钙结合蛋白A11（S100A11）持续上调。在小鼠、大鼠、树鼩和肝纤维化患者的肝纤维化实验中，S100A11也被激活。体内和体外过表达S100A11会加剧肝纤维化，而抑制S100A11则可改善肝纤维化。机制上，S100A11通过调节TGF-β信号通路中Smad3的去乙酰化来激活肝星状细胞（HSC）和成纤维过程。S100A11与Smad2/3的去乙酰化酶SIRT6发生物理相互作用，这可能竞争性抑制SIRT6与Smad2/3之间的相互作用。随后Smad2/3的释放和激活促进了HSC的激活和成纤维作用。此外，临床患者血清中S100A11显著升高。我们的研究揭示S100A11是肝纤维化中一种新的促纤维化因子，它可能既是一种潜在的生物标志物，也是治疗肝纤维化及纤维化相关肝病的有前景的治疗靶点。
