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

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

doi:10.7717/peerj.1362

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

PeerJ. 2015 Nov 3:3:e1362. doi: 10.7717/peerj.1362. eCollection 2015.

Authors

Wenwen Wang¹, Min Yan², Qiuhong Ji³, Jinbiao Lu², Yuhua Ji⁴, Juling Ji²

Affiliations

¹ Department of Pathology, Medical School of Nantong University , Nantong , China ; Department of Pathology, Traditional Chinese Medicine Hospital of Jiangyin City , Jiangyin , China.
² Department of Pathology, Medical School of Nantong University , Nantong , China.
³ Neurology Department, Affiliated Hospital of Nantong University , Nantong , China.
⁴ Key Laboratory of Neuroregeneration, Nantong University , Nantong , China.

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.

Keywords: Hepatic stellate cell; High mobility group box 1; Histone deacetylase inhibitor; Liver fibrosis; Nuclear factor kappa B1; Suberoylanilide hydroxamic acid.

Grants and funding

This research is supported by grants from the Natural Science Foundation of China (NSFC), No 81141048 and 81572871 to JJL, No 81272027 to JYH and No 81201016 to JQH; Jiangsu Overseas Research & Training Program for University Prominent Young & Middle-aged Teachers and Presidents from Jiangsu Provincial Department of Education to JJL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.