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      A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis.

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          Abstract

          Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.

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          Author and article information

          Journal
          Toxicol Sci
          Toxicological sciences : an official journal of the Society of Toxicology
          Oxford University Press (OUP)
          1096-0929
          1096-0929
          September 01 2020
          : 177
          : 1
          Affiliations
          [1 ] State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University.
          [2 ] State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing 210093, P.R. China.
          Article
          5862026
          10.1093/toxsci/kfaa097
          32579217
          4894ae14-70f1-491e-b200-a726e99a603f
          © The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
          History

          H19,Sox9,apoptosis,hepatocyte,liver fibrosis
          H19, Sox9, apoptosis, hepatocyte, liver fibrosis

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