title: Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1.
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.
authors.affiliation: Department of Pathology, Medical School of Nantong University , Nantong , China ; Department of Pathology, Traditional Chinese Medicine Hospital of Jiangyin City , Jiangyin , China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Medical School of Nantong University , Nantong , China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Neurology Department, Affiliated Hospital of Nantong University , Nantong , China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Pathology, Medical School of Nantong University , Nantong , China.
authors.forename: Jinbiao
authors.initials: J
authors.lastname: Lu
authors.affiliation: Key Laboratory of Neuroregeneration, Nantong University , Nantong , China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pathology, Medical School of Nantong University , Nantong , China.
authors.forename: Juling
authors.initials: J
authors.lastname: Ji
keywords: Hepatic stellate cell; High mobility group box 1; Histone deacetylase inhibitor; Liver fibrosis; Nuclear factor kappa B1; Suberoylanilide hydroxamic acid