Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin.
OBJECTIVE
Obesity is one of the risk factors for liver fibrosis, in which plasma adiponectin, an adipocytokine, levels are decreased. Hepatic stellate cells play central roles in liver fibrosis. When they are activated, they undergo transformation to myofibroblast-like cells. Adiponectin suppresses the proliferation and migration of vascular smooth muscle cells, whose characteristics are similar to those of hepatic stellate cells. Adiponectin could have biological significances in liver fibrosis.


METHODS
The role of adiponectin on liver fibrosis induced by the administration of carbon tetrachloride twice a week for 12 weeks was tested by using adiponectin-knockout mice and an adenovirus-mediated adiponectin-expression system. We also investigated the effect of adiponectin in activated hepatic stellate cells.


RESULTS
When mice were administered carbon tetrachloride (300 microL/kg body weight) twice a week for 12 weeks, knockout mice showed extensive liver fibrosis with an enhanced expression of transforming growth factor-beta 1 and connective tissue growth factor compared with wild-type mice (P < 0.05). Injection of adenovirus producing adiponectin (AdADN) before carbon tetrachloride (1000 microL/kg body weight) treatment prevented liver fibrosis in wild-type mice (P < 0.001). Injection of AdADN at 6 weeks attenuated liver fibrosis even though carbon tetrachloride was given for an additional 6 weeks (total of 12 weeks). In cultured hepatic stellate cells, adiponectin suppressed platelet-derived growth factor-induced proliferation and migration and attenuated the effect of transforming growth factor-beta 1 on the gene expression of transforming growth factor-beta 1 and connective tissue growth factor and on nuclear translocation of Smad2.


CONCLUSIONS
The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention.
Kamada
Yoshihiro
Y
Department of Internal Medicine and Molecular Science, Osaka University, Graduate School of Medicine, Suita, Japan.
Tamura
Shinji
S
Kiso
Shinichi
S
Matsumoto
Hitoshi
H
Saji
Yukiko
Y
Yoshida
Yuichi
Y
Fukui
Koji
K
Maeda
Norikazu
N
Nishizawa
Hitoshi
H
Nagaretani
Hiroyuki
H
Okamoto
Yoshihisa
Y
Kihara
Shinji
S
Miyagawa
Jun-Ichiro
J
Shinomura
Yasuhisa
Y
Funahashi
Tohru
T
Matsuzawa
Yuji
Y
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D052242:Adiponectin; D000818:Animals; D000077214:Becaplermin; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011506:Proteins / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000032:analysis; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface / Q000502:physiology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
C475418:ADIPOR1 protein, human; D052242:Adiponectin; C526318:CCN2 protein, mouse; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D011956:Receptors, Cell Surface; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D000077214:Becaplermin; D002251:Carbon Tetrachloride