caa a22 4500 445795859 CHVBK 20180317145125.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s10620-010-1400-5 doi (NATIONALLICENCE)springer-10.1007/s10620-010-1400-5 Eicosapentaenoic Acid Attenuates Progression of Hepatic Fibrosis with Inhibition of Reactive Oxygen Species Production in Rats Fed Methionine- and Choline-Deficient Diet [Elektronische Daten] [Satoshi Kajikawa, Kazunori Imada, Takashi Takeuchi, Yutaka Shimizu, Akiko Kawashima, Tsuyoshi Harada, Kiyoshi Mizuguchi] Background and Aims: Nonalcoholic steatohepatitis (NASH) is associated with fat accumulation in the liver, and develops to cirrhosis with the progression of hepatic fibrosis. Eicosapentaenoic acid (EPA) is used to treat hyperlipidemia, and suppresses hepatic fat accumulation. As the effect of EPA on NASH remains unclear, we assessed the therapeutic effect of EPA and its mechanisms in an animal model of NASH. Methods: Wistar rats were fed a methionine- and choline-deficient (MCD) diet for 20weeks, and given EPA ethyl ester (EPA-E, 1,000mg/kg/day) or vehicle by gavage from week12, at which hepatic fibrosis has already established. The liver was histologically analyzed for fibrosis and α-smooth muscle actin (αSMA) expression, and hepatic levels of transforming growth factor-β1 (TGF-β1), fibrogenic gene expression, reactive oxygen species (ROS), and triglyceride (TG) content were determined. Serum oxidative markers were also measured. Results: EPA-E treatment significantly suppressed the MCD-induced increase in fibrotic area of liver sections, with repressed macronodule formation. EPA-E also suppressed increases in hepatic fibrogenic factors, αSMA expression, TGF-β1 level, and messenger RNA (mRNA) levels of procollagens and connective tissue growth factor. EPA-E reduced MCD-induced increases in hepatic ROS level, serum oxidative markers, 8-isoprostane and ferritin, and hepatic TG content. Attenuation of hepatic fibrosis by EPA-E was significantly correlated with hepatic ROS level, but not TG content. Conclusions: EPA-E attenuates progression of hepatic fibrosis in developed steatohepatitis, and this effect is likely mediated by inhibition of ROS production. These actions may elicit the therapeutic effect of EPA-E against NASH. Springer Science+Business Media, LLC, 2010 Eicosapentaenoic acid nationallicence Fibrosis nationallicence Reactive oxygen species nationallicence Oxidative stress nationallicence Nonalcoholic steatohepatitis nationallicence Methionine- and choline-deficient diet nationallicence Kajikawa Satoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Imada Kazunori Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Takeuchi Takashi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Shimizu Yutaka Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Kawashima Akiko Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Harada Tsuyoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Mizuguchi Kiyoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1065-1074 0163-2116 56:4<1065 2011 56 10620 https://doi.org/10.1007/s10620-010-1400-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10620-010-1400-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kajikawa Satoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Imada Kazunori Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Takeuchi Takashi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Shimizu Yutaka Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Kawashima Akiko Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Harada Tsuyoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 700 1- Mizuguchi Kiyoshi Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, 412-8524, Gotemba, Shizuoka, Japan aut NATIONALLICENCE 773 0- Digestive Diseases and Sciences Springer US; http://www.springer-ny.com 56/4(2011-04-01), 1065-1074 0163-2116 56:4<1065 2011 56 10620 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer