Long Non-coding RNA NEAT1 Alleviates Acute-on-Chronic Liver Failure Through Blocking TRAF6 Mediated Inflammatory Response

Yumin Xu,Hui Wang,Ronggui Hu,Wei Cai,Xiaogang Xiang,Zike Sheng,Zhujun Cao,Rongtao Lai,Qing Xie,Yuhan Liu,Ziqiang Li,Yezhou Ding

doi:10.3389/fphys.2019.01503

Abstract

BackgroundLong non-coding RNAs (lncRNAs) have recently been tightly linked to plenty of human diseases. However, knowledge of acute-on-chronic liver failure (ACLF) related lncRNAs remains insufficient. In this work, we studied the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in the pathogenesis of ACLF.MethodsACLF model was established by challenging D-galactosamine (D-GalN)/ lipopolysaccharide (LPS) i.p. in rats with cirrhosis. The serum levels of IL-1, IL-6, and HMGB1 were determined using ELISA. Quantitative real time-PCR and western blot were performed to evaluate RNA and protein levels of inflammatory response. RNA immunoprecipitation assay was performed to confirm protein that interacts with NEAT1.FindingsOver-expression of NEAT1 could interact with TRAF6 and decrease its ubiquitination level, and significantly reduced the expression levels of IL-6, IL-22. Importantly, in ACLF rat model, NEAT1 over-expression reduced several cytokines expression and alleviated the pathological status in contrast to the control group. Additionally, NEAT1 was increased and positively correlated with IL-22 and IL-6 levels in PBMCs from the ACLF patients.InterpretationNEAT1 can suppress inflammatory response through blockade of TRAF6 ubiquitination in ACLF rat model, suggesting that lncRNA NEAT1 might play protective roles in the pathogenesis of ACLF and provide promising novel target for pharmacological intervention.

Highlights

Liver failure is a common syndrome of severe liver diseases, which causes serious damage to life and health of people
The expression level of nuclear enriched abundant transcript 1 (NEAT1) in HepG2 cells increased in time and dosage dependent manner after LPS treatment (Figure 1A), which peaked at 6 h at 1000 ng/ml (Figure 1B)
We found signal transducer and activator of transcription 1 (STAT1) could potentially bind to promoter of NEAT1 by in silico bioinformatic analysis

Summary

Introduction

Liver failure is a common syndrome of severe liver diseases, which causes serious damage to life and health of people. Acute-on-chronic liver failure (ACLF) is a fatal clinical syndrome of acute decompensated liver function, which develops on the basis of NEAT1 Alleviates Inflammatory Response in ACLF chronic liver disease and is stimulated by various inducements in a short term (Bajaj et al, 2019). Nucleoside analog therapy can effectively inhibit HBV replication, it can not improve the 3-month survival rate of HBV-related ACLF patients (Arroyo, 2019). It is urgent to carry out in-depth research to block the progression of disease, improve the survival rate of patients, and provide new countermeasures for clinical treatment. Knowledge of acute-on-chronic liver failure (ACLF) related lncRNAs remains insufficient. We studied the role of the lncRNA nuclear enriched abundant transcript 1 (NEAT1) in the pathogenesis of ACLF

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