Eicosapentaenoic acid ameliorates steatollepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice

Background/Aims: Eicosapentaenoic acid (EPA) has been known as a reagent for improving lipid metabolism and inflammation. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). Therefore, we administered EPA to Pten-deficient mice to investigate the mechanisms of NASH. Methods: Pten-deficient mice were assigned to a control group fed with a standard chow or an EPA group fed with a 5% EPA-supplemented standard chow. At 40 weeks, livers from each group were processed to measure triglyceride content, gene expression analysis, Western blotting analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Forty- and 76-week-old mice were used in tumor burden experiments. Results: EPA-ameliorated hepatic steatosis in Pten-deficient mice was based on decreased expression of AMPK alpha 1-mediated SREBP-1c and increased PPAR alpha expression. The EPA group exhibited less severe chronic hepatic inflammation compared to the control group, resulting from decreased ROS formation and a dramatically low ratio of arachidonic acid to EPA. Moreover, EPA inhibited development of hepatocellular carcinoma (HCC) in Pten-deficient mice based on an inhibition of MAPK activity and a low ratio of oleic to stealic acid, and a reduction in ROS formation. Conclusions: EPA ameliorated steatohepatitis and development of HCC in Pten-deficient mice. C 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.