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

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. 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 alpha-smooth muscle actin (alpha SMA) expression, and hepatic levels of transforming growth factor-beta 1 (TGF-beta 1), fibrogenic gene expression, reactive oxygen species (ROS), and triglyceride (TG) content were determined. Serum oxidative markers were also measured. 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, alpha SMA expression, TGF-beta 1 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. 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.