A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. (5th September 2014)

• Record Type: Journal Article
• Authors: Park, Ki Cheong; Park, Ji Hyun; Jeon, Jeong Yong; Kim, Sang Yong; Kim, Jung Min; Lim, Chang Yong; Lee, Tae Hyung; Kim, Hyung Kwan; Lee, Hyun Gyu; Kim, Sung Min; Kwon, Ho Jeong; Suh, Jin Suck; Kim, Seung Won; Choi, Seung Hoon
• Is Part Of: British journal of pharmacology. Volume 171:Number 21(2014:Nov.)
• Page Start: 4820
• Page End: 4830
• Publication Date: 2014-09-05
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12590
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12590-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>Activation of hepatic stellate cells (HSCs) is a crucial step in the pathogenesis of hepatic fibrosis. Histone deacetylase (HDAC) is an attractive target in liver fibrosis because it plays a key role in gene expression and cell differentiation. We have developed a HDAC inhibitor, N‐hydroxy‐7‐(2‐naphthylthio)heptanomide (HNHA), and investigated the anti‐fibrotic activity of HNHA <italic>in vitro</italic> and <italic>in vivo</italic>.</p> </sec> <sec id="bph12590-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>We investigated the anti‐fibrotic effect of HNHA on mouse and human HSC activation <italic>in vitro</italic> and in the liver of bile duct‐ligated (BDL) rats <italic>in vivo</italic> using cell proliferation assays, cell cycle analysis, biochemical assay, immunohistochemistry and Western blots. Liver pathology was assessed with histochemical techniques.</p> </sec> <sec id="bph12590-sec-0003" sec-type="section"> <title>Key Results</title> <p>HNHA inhibited proliferation and arrested the cell cycle via p21 induction in HSCs. In addition, HNHA induced apoptosis of HSCs, which was correlated with reduced COX‐2 expression, NF‐κB activation and cell death signals. HNHA restored liver function and decreased the accumulation of extracellular matrix in the liver via suppression of HSC activation in BDL rats <italic>in vivo</italic>. HNHA administration also increased survival in BDL rats.</p> </sec> <sec id="bph12590-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>HNHA improved liver function, suppressed liver fibrosis and increased survival of BDL rats, accompanied by reduction of cell growth, activation and survival of HSCs. These findings show that HNHA may be a potent anti‐fibrosis agent against hepatic fibrosis because of its multi‐targeted inhibition of HSC activity <italic>in vivo</italic> and <italic>in vitro</italic>.</p> </sec> </abstract>