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Eicosapentaenoic Acid Attenuates Progression of Hepatic Fibrosis with Inhibition of Reactive Oxygen Species Production in Rats Fed Methionine- and Choline-Deficient Diet

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Abstract

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 20 weeks, and given EPA ethyl ester (EPA-E, 1,000 mg/kg/day) or vehicle by gavage from week 12, 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.

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Acknowledgments

We thank Ms. Reiko Ono and Mr. Shin-ichi Akimoto for their skillful assistance.

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Authors and Affiliations

  1. Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, Gotemba, Shizuoka, 412-8524, Japan

    Satoshi Kajikawa, Kazunori Imada, Takashi Takeuchi, Yutaka Shimizu, Akiko Kawashima, Tsuyoshi Harada & Kiyoshi Mizuguchi

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  1. Satoshi Kajikawa
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  2. Kazunori Imada
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  3. Takashi Takeuchi
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  4. Yutaka Shimizu
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Correspondence to Satoshi Kajikawa.

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Kajikawa, S., Imada, K., Takeuchi, T. et al. Eicosapentaenoic Acid Attenuates Progression of Hepatic Fibrosis with Inhibition of Reactive Oxygen Species Production in Rats Fed Methionine- and Choline-Deficient Diet. Dig Dis Sci 56, 1065–1074 (2011). https://doi.org/10.1007/s10620-010-1400-5

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