Medaka as a model for human nonalcoholic steatohepatitis.
The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.
Matsumoto
Toshihiko
T
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, Japan.
Terai
Shuji
S
Oishi
Toshiyuki
T
Kuwashiro
Shinya
S
Fujisawa
Koichi
K
Yamamoto
Naoki
N
Fujita
Yusuke
Y
Hamamoto
Yoshihiko
Y
Furutani-Seiki
Makoto
M
Nishina
Hiroshi
H
Sakaida
Isao
I
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D005234:Fatty Liver / Q000150:complications / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D006949:Hyperlipidemias / Q000150:complications / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D009990:Oryzias / Q000378:metabolism*; D010641:Phenotype
D004041:Dietary Fats; D015118:Eicosapentaenoic Acid