A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells

Ki Cheong Park, Ji Hyun Park, Jeong Yong Jeon, Sang Yong Kim, Jung Min Kim, Chang Yong Lim, Tae Hyung Lee, Hyung Kwan Kim, Hyun Gyu Lee, Sung Min Kim, Ho Jeong Kwon, Jin Suck Suh, Seung Won Kim, Seung Hoon Choi

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Abstract

BACKGROUND AND PURPOSE: 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 in vitro and in vivo.

EXPERIMENTAL APPROACH: We investigated the anti-fibrotic effect of HNHA on mouse and human HSC activation in vitro and in the liver of bile duct-ligated (BDL) rats in vivo using cell proliferation assays, cell cycle analysis, biochemical assay, immunohistochemistry and Western blots. Liver pathology was assessed with histochemical techniques.

KEY RESULTS: 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-B 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 in vivo. HNHA administration also increased survival in BDL rats.

CONCLUSIONS AND IMPLICATIONS: 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 in vivo and in vitro.

Original languageEnglish
Pages (from-to)4820-4830
Number of pages11
JournalBritish Journal of Pharmacology
Volume171
Issue number21
DOIs
Publication statusPublished - 2014 Nov

All Science Journal Classification (ASJC) codes

  • Pharmacology

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    Park, K. C., Park, J. H., Jeon, J. Y., Kim, S. Y., Kim, J. M., Lim, C. Y., Lee, T. H., Kim, H. K., Lee, H. G., Kim, S. M., Kwon, H. J., Suh, J. S., Kim, S. W., & Choi, S. H. (2014). A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. British Journal of Pharmacology, 171(21), 4820-4830. https://doi.org/10.1111/bph.12590