The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling |
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| Institution: | 1. 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;2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China;3. Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China;4. School of Traditional Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan 650500, China;5. Infectious Diseases Department and Hepatic Diseases Department, The First People''s Hospital of Yunnan Province, Kunming, Yunnan 650034, China;6. Infectious Diseases Department and Hepatic Diseases Department, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan 650034, China;7. School of Laboratory Animal & Shandong Laboratory Animal Center, Science and Technology Innovation Center,Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250021, China;8. Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Liaoning Provence Key Lab of Genome Engineered Animal Models Dalian Medical University, Dalian, Liaoning 116044, China;1. State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China;2. Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai 200040, China;1. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China;2. University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049, China;3. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China;4. Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK;5. CAS Center of Excellence for Animal Evolution and Genetics, Kunming, Yunnan 650223, China |
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| Abstract: | 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. |
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| Keywords: | Chronic liver diseases Liver fibrosis TGF-β SIRT6 Smad3 |
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