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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 
 BRITISH JOURNAL OF PHARMACOLOGY, Vol.171(21) : 4820-4830, 2014 
Journal Title
Issue Date
Actins/metabolism ; Animals ; Bile Ducts/surgery ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Collagen Type I/metabolism ; Cyclooxygenase 2/metabolism ; Hepatic Stellate Cells/cytology ; Hepatic Stellate Cells/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use* ; Humans ; Hydroxamic Acids/pharmacology ; Hydroxamic Acids/therapeutic use* ; Ligation ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver Cirrhosis/drug therapy* ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Inbred C57BL ; Naphthalenes/pharmacology ; Naphthalenes/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism
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-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 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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1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sang Yong(김상용)
Kim, Seung Won(김승원) ORCID logo https://orcid.org/0000-0002-1692-1192
Park, Ki Cheong(박기청) ORCID logo https://orcid.org/0000-0002-3435-3985
Park, Ji Hyun(박지현)
Suh, Jin Suck(서진석) ORCID logo https://orcid.org/0000-0001-9455-9240
Lee, Hyun Gyu(이현규)
Choi, Seung Hoon(최승훈)
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