| Autor: |
Xiaoyan Lu, Lingqi Yu, Jie Zheng, Anyao Li, Junying Li, He Lou, Wentao Zhang, Hui Guo, Yuzhen Wang, Xuemei Li, Yue Gao, Xiaohui Fan, Jürgen Borlak |
| Rok vydání: |
2023 |
| DOI: |
10.21203/rs.3.rs-2920061/v1 |
| Popis: |
Background Adaptive response to drug-induced liver injury (arDILI) reflects the critical role of restorative tissue repair, and understanding the endogenous mechanism may discover innovative strategies to manage DILI. Methods To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Its target gene was validated by dual luciferase reporter and siRNA assays. The biological function of miR-106b-5p was determined using agomir and antagomir treatment. Single-cell RNA-sequencing was conducted to identify the key hepatocytes under miR-106b-5p treatment. Knockout mice were used to enable mechanistic insights into arDILI. DILI patient samples were collected to confirm clinical significance. Results miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR-106b-5p. Single-cell RNA-sequencing of toosendanin-injured mice revealed a cluster of Vim+ hepatocytes; however, declined following miR-106b-5p-agomir co-treatment. Strikingly, liver-specific and/or whole-body Vim knockout protected mice from both TILI and acetaminophen poisoning. Serum miR-106b-5p expression levels correlated with the severity of DILI. Liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, inflammatory cell infiltrates and Kupffer cells, therefore demonstrating translational significance. Conclusion We report novel mechanisms of arDILI whereby miR-106b-5p safeguards restorative tissue repair by targeting vimentin. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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