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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model
Toshiaki Okamoto, Masahiko Koda, Kennichi Miyoshi, Takumi Onoyama, Manabu Kishina, Tomomitsu Matono, Takaaki Sugihara, Keiko Hosho, Junichi Okano, Hajime Isomoto, Yoshikazu Murawaki
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
Masahiko Koda, Second Department of Internal Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
Author contributions: Okamoto T and Koda M contributed equally to this work; Koda M designed the research; Okamoto T, Koda M, Miyoshi K, Onoyama T, Kishina M, Matono T, Sugihara T, Hosho K and Okano J performed the research; Okamoto T and Koda M analyzed the data; Okamoto T, Koda M, Isomoto H and Murawaki Y wrote the paper.
Institutional review board statement: All experiments were performed in accordance with the Animal Experimentation Guidelines of Tottori University (Yonago, Japan). The study was reviewed and approved by the ethics committee of Tottori University. All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Tottori University (approval number; 14-Y-8).
Conflict-of-interest statement: All authors declare that they have no conflict of interest. All authors certify that this article is not under consideration for publication elsewhere. Publication is approved by all authors and by the responsible authorities where the work was carried out.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Masahiko Koda, MD, PhD, Associate Professor, Second Department of Internal Medicine, Tottori University, Nishi-cho 36-1, Yonago, Tottori 683-8504, Japan. masakoda@grape.med.tottori-u.ac.jp
Telephone: +81-859-386527 Fax: +81-859-386529
Received: February 24, 2016
Peer-review started: March 4, 2016
First decision: April 15, 2016
Revised: June 22, 2016
Accepted: July 11, 2016
Article in press: July 13, 2016
Published online: August 8, 2016
AIM: 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.
CONCLUSION: 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.
Core tip: Endothelin (ET) can activate hepatic stellate cells, leading to the progression of hepatic fibrosis. Furthermore, ET-1 may increase the inflow of free fatty acids from the fat tissue into the liver and exacerbate hepatic steatosis. Therefore, ET-1 antagonism may be a novel target for steatohepatitis. The present study showed that ambrisentan, an ET type A receptor antagonist, attenuated hepatic fibrosis by inhibiting hepatic stellate cell activation, without affecting hepatic steatosis, in a non-alcoholic steatohepatitis mouse model.
