MicroRNA-125b-5p mimic inhibits acute liver failure.

Dakai Yang,Qinggong Yuan,Jan-Henning Klusmann,Asha Balakrishnan,Heike Bantel,Michael P Manns,Tobias Cantz,Amar Deep Sharma,Michael Ott

doi:10.1038/ncomms11916

Abstract

The lack of broad-spectrum anti-acute liver failure (ALF) therapeutic agents contributes to ALF-related mortality. MicroRNAs (miRNAs) are suggested to be potent serum biomarkers for ALF, but their functional and therapeutic relevance in ALF are unclear. Here we show an unbiased approach, using two complementary miRNA screens, to identify miRNAs that can attenuate ALF. We identify miR-125b-5p as a regulator of cell death that attenuates paracetamol-induced and FAS-induced toxicity in mouse and human hepatocytes. Importantly, administration of miR-125b-5p mimic in mouse liver prevents injury and improves survival in models of ALF. Functional studies show that miR-125b-5p ameliorates ALF by directly regulating kelch-like ECH-associated protein 1, in turn elevating expression of nuclear factor-E2-related factor 2, a known regulator in ALF. Collectively, our findings establish miR-125b-5p as an important regulator of paracetamol-induced and FAS-induced cell death. Thus, miR-125b-5p mimic may serve as a broad-spectrum therapeutic attenuator of cell death during ALF.

Highlights

The lack of broad-spectrum anti-acute liver failure (ALF) therapeutic agents contributes to ALF-related mortality
We undertook an unbiased screening approach to identify miRNAs that are capable of inhibiting cell death during ALF
We examined whether inhibition of those seven miRNAs reverses the protective effect against APAP

Summary

Introduction

The lack of broad-spectrum anti-acute liver failure (ALF) therapeutic agents contributes to ALF-related mortality. We identify miR-125b-5p as a regulator of cell death that attenuates paracetamol-induced and FAS-induced toxicity in mouse and human hepatocytes. MiR-125b-5p mimic may serve as a broad-spectrum therapeutic attenuator of cell death during ALF. Circulating miRNAs in plasma may even be better biomarkers than classical parameters, such as alanine transaminase (ALT) and aspartate transaminase (AST), as miRNAs precede the injury, whereas ALT and AST follow the injury[9] In contrast to their use as biomarkers, miRNAs are only beginning to be explored as therapeutic agents[12,13]. Identification of miRNAs as broad-spectrum antiALF agents, which are capable of attenuating cell death, would have the potential to reduce the mortality rate

Methods

Results

Conclusion