Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model.
OBJECTIVE
Adipose tissue produces a number of adipocytokines, including adiponectin, leptin, and tumor necrosis factor-alpha. Obesity, which is associated with low plasma adiponectin levels, is an independent risk factor for various liver diseases including nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the effects of adiponectin on the progression of NASH to cirrhosis and tumor formation using adiponectin-knockout (KO) mice.


METHODS
Using a choline-deficient L-amino acid-defined (CDAA) diet-induced mouse NASH model, liver histology and oxidative stress markers were investigated in KO and wild-type (WT) mice.


RESULTS
Hepatic steatosis was enhanced to a greater extent in KO mice, compared to WT mice after a 1-week CDAA diet. After 24 weeks, 6 out of 14 KO mice developed liver cirrhosis and hepatic tumors, whereas the 15 WT mice showed only simple steatosis. In KO mice, hepatic cytochrome P450 2E1 levels were upregulated, and markers of oxidative stress (thiobarbituric acid reactive substances, 8-hydroxydeoxyguanosine-positive cells) were significantly increased compared with WT mice.


CONCLUSIONS
Our results indicate that lack of adiponectin enhances the progression of hepatic steatosis, fibrosis, and hepatic tumor formation in an animal model of NASH. Hypoadiponectinemia in obesity could be a risk factor for NASH-related hepatic tumor formation.
Kamada
Yoshihiro
Y
Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, 2-2, K1, Yamada-oka, Suita, Osaka 565-0871, Japan.
Matsumoto
Hitoshi
H
Tamura
Shinji
S
Fukushima
Juichi
J
Kiso
Shinichi
S
Fukui
Koji
K
Igura
Takumi
T
Maeda
Norikazu
N
Kihara
Shinji
S
Funahashi
Tohru
T
Matsuzawa
Yuji
Y
Shimomura
Iichiro
I
Hayashi
Norio
N
D052242:Adiponectin / Q000097:blood* / Q000235:genetics; D000596:Amino Acids / Q000008:administration & dosage; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002796:Choline Deficiency; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000150:complications* / Q000473:pathology; D006520:Hepatitis, Animal / Q000150:complications* / Q000473:pathology; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout
D052242:Adiponectin; D000596:Amino Acids; D015415:Biomarkers; D019392:Cytochrome P-450 CYP2E1