Role of adipocytokines in hepatic fibrogenesis.
Obesity and insulin resistance are the key factors for progression of hepatic fibrosis in various chronic liver diseases including non-alcoholic steatohepatitis (NASH). Recently it has been shown that leptin plays a pivotal role in development of hepatic fibrosis. Leptin promotes hepatic fibrogenesis through upregulation of transforming growth factor-beta in Kupffer cells and sinusoidal endothelial cells. Further, leptin facilitates proliferation and prevents apoptosis of hepatic stellate cells. There is a paradox, however, in that ob/ob mice and Zucker rats, which are the obese and diabetic strains, had minimal profibrogenic responses in the liver, most likely because they lack leptin and its receptors. To establish a more clinically relevant model to study the mechanism of fibrogenesis under steatohepatitis, fatty changes and profibrogenic responses in the liver caused by methionine-choline deficiency (MCD) were investigated in the KK-A(y) mouse, which is an obese and diabetic strain. KK-A(y) mice developed more severe hepatic steatosis, inflammation and fibrosis induced by an MCD diet as compared to C57Bl/6 controls. Importantly, KK-A(y) mice lack physiological upregulation of adiponectin levels, suggesting that adiponectin plays a pivotal role not only in regulation of insulin sensitivity but also in modulation of inflammatory and profibrogenic responses in dietary steatohepatitis. Collectively, these findings support the hypothesis that the balance of adipocytokine expression is a key regulator for the progression of hepatic fibrosis in the setting of steatohepatitis.
Ikejima
Kenichi
K
Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. ikejima@med.juntendo.ac.jp
Okumura
Kyoko
K
Kon
Kazuyoshi
K
Takei
Yoshiyuki
Y
Sato
Nobuhiro
N
D052242:Adiponectin / Q000494:pharmacology; D000818:Animals; D002796:Choline Deficiency; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology*; D007728:Kupffer Cells / Q000378:metabolism; D020738:Leptin / Q000502:physiology*; D008099:Liver / Q000166:cytology; D008103:Liver Cirrhosis / Q000503:physiopathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
D052242:Adiponectin; D020738:Leptin; D053773:Transforming Growth Factor beta1; D008715:Methionine