Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice.
OBJECTIVE
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 AMPKalpha1-mediated SREBP-1c and increased PPARalpha 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.
Ishii
Hajime
H
Department of Gastroenterology, Akita University School of Medicine, Akita, Japan.
Horie
Yasuo
Y
Ohshima
Shigetoshi
S
Anezaki
Yumiko
Y
Kinoshita
Nobukatsu
N
Dohmen
Takahiro
T
Kataoka
Ei
E
Sato
Wataru
W
Goto
Takashi
T
Sasaki
Junko
J
Sasaki
Takehiko
T
Watanabe
Sumio
S
Suzuki
Akira
A
Ohnishi
Hirohide
H
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D015118:Eicosapentaenoic Acid / Q000627:therapeutic use*; D005234:Fatty Liver / Q000188:drug therapy* / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D015118:Eicosapentaenoic Acid; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse