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MicroRNA-223 knockout mice are more susceptible to acetaminophen-induced acute liver injury and inflammation

Wednesday, September 16, 2015 — Poster Session I

3:30 p.m. – 5:00 p.m.
FAES Terrace
NIAAA
MOLBIO-9

* FARE Award Winner

Authors

  • Yong He
  • Jun Li
  • DC Feng
  • Cynth Ju
  • Bin Gao

Abstract

Background and Aims: Acetaminophen (APAP) overdose is one of leading causes of acute liver failure worldwide, which is accompanied with significant neutrophil infiltration in the liver; however, the mechanisms remain obscure. MicroRNA-223 (miR-223) was previously reported to act as a fine-tuner of the generation and function of neutrophils, and was significantly increased in liver and serum after APAP injection. The aim of this study is to investigate how miR-223 controls hepatic neutrophil infiltration and liver injury induced by APAP. Methods: Overnight-fasting wild-type (WT) and miR-223 knockout (miR-223KO)mice were injected (i.p.) with an overdose of APAP, followed by histological and biochemical evaluation of liver injury. Results: Compared with WT mice, miR-223KO mice were more susceptible to APAP-induced liver injury, as indicated by higher levels of serum alanine transaminase and liver necrosis. Furthermore, miR-223KO mice showed greater degree of neutrophil and macrophage infiltration in the liver after APAP injection. Accordingly, oxidative damage manifested by 4-Hydroxynonenal and nitrotyrosine staining was more pronounced in the APAP-treated miR-223KO mice. Interestingly, hepatic cytochrome 2E1 (Cyp2E1) level, a major enzyme that mediates the metabolism of APAP, was much higher in miR-223KO mice than in WT mice after fasting. Finally, hepatic expression of β-catenin, a transcriptional factor that could control Cyp2E1 expression, was greater in miR-223KO mice compared with WT mice. Conclusions: Deletion of miR-223 causes elevation of β-catenin and Cyp2E1 expression in the liver, and subsequently exacerbates APAP-induced hepatotoxicity. This suggests that miR-223 may be used a therapeutic target for the treatment of APAP-induced liver failure.

Category: Molecular Biology and Biochemistry