Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1.

Wenwen Wang,Yuhua Ji,Juling Ji,Min Yan,Jinbiao Lu,Qiuhong Ji

doi:10.7717/peerj.1362

Abstract

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I and α-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

Highlights

Liver fibrosis is a chronic wound-healing response caused by a variety of injuries such as viral infection, autoimmune and metabolic disease as well as drug or alcoholic induced disease (Pellicoro et al, 2014)
In searching for safe and efficient anti-fibrotic drugs, we found that suberoylanilide hydroxamic acid (SAHA), an analog of trichostatin A (TSA), prominently suppressed human hepatic stellate cells (HSCs) activation
By real-time reverse transcription-PCR (RT-PCR), we found that LX2 cells cultured in the medium containing 2.5 μM SAHA for 24 h showed a decreased mRNA transcription of α-smooth muscle actin (α-SMA) and collagen I (Fig. 1A)

Summary

Introduction

Liver fibrosis is a chronic wound-healing response caused by a variety of injuries such as viral infection, autoimmune and metabolic disease as well as drug or alcoholic induced disease (Pellicoro et al, 2014). The underlying mechanisms of liver fibrosis has been extensively studied, we are still in great need of safe and efficient anti-fibrotic drugs (Schuppan & Kim, 2013). It has been well acknowledged that activation of hepatic stellate cells (HSCs) upon liver injury is the central event that leads to liver fibrosis (Puche, Saiman & Friedman, 2013). Activated HSCs transdifferentiated form vitamin A-storing perisinusoidal cells to proliferative and fibrogenic myofibroblasts, start to express alpha smooth muscle actin (α-SMA), produce more extracellular matrix (ECM) and cause extensive ECM deposition. Exploring drugs targeting HSCs activation is a promising anti-fibrotic strategy

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Conclusion