Highly Purified Eicosapentaenoic Acid Ethyl Ester Prevents Development of Steatosis and Hepatic Fibrosis in Rats

Abstract

Pathogenesis of nonalcoholic steatohepatitis (NASH) is considered to be involved in fat accumulation, oxidative stress, inflammation, and fibrosis in liver, but no drug therapy has been established as yet. Eicosapentaenoic acid (EPA) is an agent used clinically to treat hypertriglyceridemia, and has been reported to suppress reactive oxygen species and inflammation. Here, we aimed to assess the effect of EPA on progression of hepatic fibrosis in an animal model of NASH. Wistar rats were fed a methionine- and choline-deficient (MCD) diet and given EPA ethyl ester (EPA-E) (1,000 mg/kg/day) or vehicle by gavage for 8 or 20 weeks. The MCD diet caused development of hepatic fibrosis and nodule formation at 20 weeks. EPA-E treatment significantly suppressed MCD-induced increase in fibrosis and hepatic hydroxyproline, and inhibited nodule formation. EPA-E treatment also decreased hepatic transforming growth factor (TGF)-beta1, and messenger RNA (mRNA) levels of connective tissue growth factor. EPA-E suppressed MCD-induced elevation of serum levels of ferritin, 8-isoprostane, soluble tumor necrosis factor receptor 1 (sTNFR1), and sTNFR2 at 20 weeks, and hepatic triglyceride accumulation at 8 weeks. EPA-E prevents progression of hepatic fibrosis in an MCD-induced NASH model with reduction of oxidative stress, inflammation, and initial hepatic steatosis. Thus, EPA-E treatment may be a potential therapy to treat NASH.