Abstract
Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21 −/− mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21 −/− mice, via relieved repression of CDK2AP1. Further, miR-21 −/− mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
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Acknowledgements
The authors thank Prof. Eric Olson, Southwestern Medical Center, University of Texas, for kindly providing miR-21 −/− mice, as well as Dr. Vishva Dixit, Molecular Oncology Department, Genentech, Inc. (San Fransisco, CA, USA) and Dr. Miguel Soares, Instituto Gulbenkian de Ciência (Oeiras, Portugal) for kindly providing Rip3 −/− mice. We also thank Dolores Bonaparte, Rodent Facility, Instituto de Medicina Molecular for the training in BDL, and Elisa Alves from Clinical Analyses Core Laboratory, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal for routine clinical analyses. Finally, we thank all members of the laboratory for insightful discussions. The study was supported in part by Fundação para a Ciência e a Tecnologia through grants PTDC/BIM-MEC/0895/2014 and UID/DTP/04138/2013, and fellowships SFRH/BD/91119/2012 (MBA), SFRH/BD/88212/2012 (PMR), and SFRH/BD/104160/201 (ALS).
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Afonso, M.B., Rodrigues, P.M., Simão, A.L. et al. miRNA-21 ablation protects against liver injury and necroptosis in cholestasis. Cell Death Differ 25, 857–872 (2018). https://doi.org/10.1038/s41418-017-0019-x
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DOI: https://doi.org/10.1038/s41418-017-0019-x
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