Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model

BMC Gastroenterology

Research Article

Yasuo Terauchi¹  Makoto Nakamuta²  Yoji Nagashima³  Koichiro Wada⁴  Atsushi Nakajima⁵  Yoshiyasu Shinohara⁵  Koji Fujita⁵  Takaomi Kessoku⁵  Kento Imajo⁵  Yuji Ogawa⁵  Masato Yoneda⁵  Satoru Saito⁵  Yuichi Nozaki⁶  Naohiko Masaki⁷ 

[1] Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Japan;Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, 1-8-1, Jigyohama, Chuo-ku, 810-8563, Fukuoka, Japan;Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Japan;Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, 565-0871, Osaka, Japan;Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Japan;Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Japan;Department of Gastroenterology, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, 162-8655, Tokyo, Japan;The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1, Konodai, 272-8516, Ichikawa, Japan;

关键词: NOS;    NASH;    Inflammation;    Fibrosis;    NF-kB;   

DOI  :  10.1186/s12876-015-0269-3

 received in 2014-08-17, accepted in 2015-02-27,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAlthough many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions.MethodsiNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed.ResultsMarked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions.ConclusionsiNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.

【 授权许可】

Unknown   
© Nozaki et al.; licensee BioMed Central. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.