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

被引：127

作者：

Afonso, Marta B. ^{[1
]}

Rodrigues, Pedro M. ^{[1
]}

Simao, Andre L. ^{[1
]}

Gaspar, Maria M. ^{[1
]}

Carvalho, Tania ^{[2
]}

Borralho, Paula ^{[3
,4
,5
]}

Banales, Jesus M. ^{[6
]}

Castro, Rui E. ^{[1
]}

Rodrigues, Cecilia M. P. ^{[1
]}

机构：

[1] Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, Lisbon, Portugal

[2] Inst Med Mol, Histol & Comparat Pathol Lab, Lisbon, Portugal

[3] Escola Super Tecnol Saude Lisboa ESTEsL, Lisbon, Portugal

[4] Univ Lisbon, Inst Anat Patol, Lisbon, Portugal

[5] Hosp Cuf Descobertas, Lisbon, Portugal

[6] Univ Basque Country UPV EHU, CIBERehd, Ikerbasque, Donostia Univ Hosp,Biodonostia Res Inst,Dept Live, San Sebastian, Spain

来源：

CELL DEATH AND DIFFERENTIATION | 2018年 / 25卷 / 05期

关键词：

CELL-DEATH; BILE-ACIDS; KINASE; 3; ACTIVATION; NECROSIS; RECEPTOR; MLKL; MICRORNA-21; EXPRESSION; FIBROSIS;

D O I：

10.1038/s41418-017-0019-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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, miR21(-/-) 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 miR21(-/-) 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 miR21 should arise as a promising approach to treat cholestasis.

引用

页码：857 / 872

页数：16

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