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Cell Death Differ. 2018 May;25(5):857-872. doi: 10.1038/s41418-017-0019-x. Epub 2017 Dec 11.

miRNA-21 ablation protects against liver injury and necroptosis in cholestasis.

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
2
Histology and Comparative Pathology Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal.
3
Escola Superior de Tecnologia da Saúde de Lisboa (ESTEsL), Lisbon, Portugal.
4
Instituto de Anatomia Patológica, Universidade de Lisboa, Lisbon, Portugal.
5
Hospital Cuf Descobertas, Lisbon, Portugal.
6
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain.
7
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal. cmprodrigues@ff.ul.pt.

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.

PMID:
29229992
PMCID:
PMC5943330
DOI:
10.1038/s41418-017-0019-x
[Indexed for MEDLINE]
Free PMC Article

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