title: Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model.
abstract: OBJECTIVE
  To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.
  
  
  METHODS
  Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.
  
  
  RESULTS
  In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups.
  
  
  CONCLUSIONS
  Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Toshiaki
authors: T
authors: Okamoto
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Masahiko
authors: M
authors: Koda
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Kennichi
authors: K
authors: Miyoshi
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Takumi
authors: T
authors: Onoyama
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Manabu
authors: M
authors: Kishina
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Tomomitsu
authors: T
authors: Matono
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Takaaki
authors: T
authors: Sugihara
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Keiko
authors: K
authors: Hosho
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Junichi
authors: J
authors: Okano
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Hajime
authors: H
authors: Isomoto
authors: Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki, Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.
authors: Yoshikazu
authors: Y
authors: Murawaki
keywords: Ambrisentan; Endothelin; Hepatic fibrosis; Hepatic hydroxyproline; Hepatic stellate cell; Oxidative stress; Steatohepatitis