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The indole derivative NecroX‐7 improves nonalcoholic steatohepatitis in ob/ob mice through suppression of mitochondrial ROS / RNS and inflammation
Author(s) -
Chung Hyo Kyun,
Kim Yong Kyung,
Park JiHoon,
Ryu Min Jeong,
Chang Joon Young,
Hwang Jung Hwan,
Lee ChulHo,
Kim SoonHa,
Kim Hyun Jin,
Kweon Gi Ryang,
Kim Koon Soon,
Shong Minho
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12741
Subject(s) - steatosis , medicine , endocrinology , fibrosis , nonalcoholic fatty liver disease , reactive oxygen species , cirrhosis , chemistry , methionine , inflammation , lipid peroxidation , oxidative stress , fatty liver , biochemistry , disease , amino acid
Background & Aims Nonalcoholic steatohepatitis ( NASH ) is associated with cirrhosis and hepatocellular carcinoma. Reactive oxygen species ( ROS ) and reactive nitrogen species ( RNS ) play key roles in the development of the disease. However, the therapeutic target of NASH has not been fully defined and new treatments are needed. We investigated the protective effects of the antioxidant indole‐derived NecroX‐7 in a NASH mouse model using leptin‐deficient ob/ob and methionine‐ and choline‐deficient ( MCD ) diet‐fed ob/ob mice. Methods Six‐week‐old male mice were divided into three groups: ob/+ mice, ob/ob mice treated with vehicle and ob/ob mice treated daily with NecroX‐7 (20 mg/kg) for 4 weeks. To study the effects of NecroX‐7 in a fibrosis model, NASH was induced by feeding ob/ob mice an MCD diet. The effects of NecroX‐7 on NASH progression were evaluated using biochemical, histological and molecular markers. Results NecroX‐7‐treated ob/ob mice had a marked decrease in serum aspartate aminotransferase and alanine transaminase compared with vehicle‐treated controls. Interestingly, hepatic steatosis and lipid peroxidation were significantly improved by NecroX‐7 treatment. NecroX‐7 inhibited tert ‐butylhydroperoxide‐ and H 2 O 2 ‐induced mitochondrial ROS / RNS in primary hepatocytes and attenuated mitochondrial dysfunction in vitro and in vivo . Furthermore, NecroX‐7‐treated mice exhibited fewer infiltrating macrophages and reduced hepatic tumour necrosis factor‐alpha expression. Hepatic fibrosis in MCD ‐fed ob/ob mice was significantly decreased by NecroX‐7 treatment. Conclusions NecroX‐7 treatment improved hepatic steatosis and fibrosis in murine NASH models. These effects occurred through the suppression of whole‐cell ROS / RNS and inflammatory responses and suggest that NecroX‐7 has a potential therapeutic benefit in steatohepatitis.