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


METHODS
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.


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
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.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.
Ki Cheong
KC
Park
Ji Hyun
JH
Park
Jeong Yong
JY
Jeon
Sang Yong
SY
Kim
Jung Min
JM
Kim
Chang Yong
CY
Lim
Tae Hyung
TH
Lee
Hyung Kwan
HK
Kim
Hyun Gyu
HG
Lee
Sung Min
SM
Kim
Ho Jeong
HJ
Kwon
Jin Suck
JS
Suh
Seung Won
SW
Kim
Seung Hoon
SH
Choi
D000199:Actins / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D051546:Cyclooxygenase 2; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009281:Naphthalenes; D053773:Transforming Growth Factor beta1; C520433:N-hydroxy-7-(2-naphthylthio)heptanamide; C498862:Acta2 protein, rat; C489691:Ptgs2 protein, rat; C522363:Mmp2 protein, rat; C572337:Mmp9 protein, rat