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, Jinsuck Suh, Seung Won Kim, Seung Hoon Choi

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 Jan 1

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Hepatic Stellate Cells
Histone Deacetylase Inhibitors
Bile Ducts
Liver Cirrhosis
Liver
Fibrosis
Cell Cycle
Histone Deacetylases
Survival
Extracellular Matrix
Cell Differentiation
Cell Death
Western Blotting
Immunohistochemistry
Cell Proliferation
Apoptosis
Pathology
Gene Expression
Growth

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Park, K. C., Park, J. H., Jeon, J. Y., Kim, S. Y., Kim, J. M., Lim, C. Y., ... 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
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, Jinsuck ; Kim, Seung Won ; Choi, Seung Hoon. / A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. In: British Journal of Pharmacology. 2014 ; Vol. 171, No. 21. pp. 4820-4830.
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title = "A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells",
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.",
author = "Park, {Ki Cheong} and Park, {Ji Hyun} and Jeon, {Jeong Yong} and Kim, {Sang Yong} and Kim, {Jung Min} and Lim, {Chang Yong} and Lee, {Tae Hyung} and Kim, {Hyung Kwan} and Lee, {Hyun Gyu} and Kim, {Sung Min} and Kwon, {Ho Jeong} and Jinsuck Suh and Kim, {Seung Won} and Choi, {Seung Hoon}",
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Park, KC, Park, JH, Jeon, JY, Kim, SY, Kim, JM, Lim, CY, Lee, TH, Kim, HK, Lee, HG, Kim, SM, Kwon, HJ, Suh, J, Kim, SW & Choi, SH 2014, 'A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells', British Journal of Pharmacology, vol. 171, no. 21, pp. 4820-4830. https://doi.org/10.1111/bph.12590

A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. / 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, Jinsuck; Kim, Seung Won; Choi, Seung Hoon.

In: British Journal of Pharmacology, Vol. 171, No. 21, 01.01.2014, p. 4820-4830.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells

AU - Park, Ki Cheong

AU - Park, Ji Hyun

AU - Jeon, Jeong Yong

AU - Kim, Sang Yong

AU - Kim, Jung Min

AU - Lim, Chang Yong

AU - Lee, Tae Hyung

AU - Kim, Hyung Kwan

AU - Lee, Hyun Gyu

AU - Kim, Sung Min

AU - Kwon, Ho Jeong

AU - Suh, Jinsuck

AU - Kim, Seung Won

AU - Choi, Seung Hoon

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

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