Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat.
OBJECTIVE
In this study, we investigated the role of leptin and its receptors (Ob-R) in profibrogenic responses in the liver using Zucker (fa/fa) rats, a natural occurring Ob-R-deficient animal.


METHODS
Male Zucker (fa/fa) rats and their lean (+/?) littermates were given intraperitoneal injections of thioacetamide (TAA) (200 mg/kg body wt, 3 times/wk) for 4-8 weeks, and progression of hepatic fibrosis was evaluated. In vitro transactivation of hepatic stellate cells (HSCs) isolated from Zucker rats was evaluated by Western blotting and immunocytochemistry for alpha-smooth muscle actin and type I collagen. Further, a long-form Ob-R (Ob-Rb) in sinusoidal endothelial cells (SECs) and Kupffer cells was identified by reverse-transcription polymerase chain reaction. Moreover, transforming growth factor (TGF)-beta1 messenger RNA in LSE cells, a human SEC-derived cell line, was measured by Northern blotting.


RESULTS
Although the normal liver does not produce leptin, activated HSCs produced leptin in vivo during fibrogenesis caused by TAA. In Zucker rats, TAA-induced hepatic fibrosis was prevented almost completely, whereas induction of TGF-beta1 and activation of HSCs were abolished. It is less likely, however, that leptin plays an essential role in the activation of HSCs as a strong autocrine regulator, because HSCs isolated from Zucker rats undergo normal transactivation process in vitro. In contrast, SECs and Kupffer cells contain Ob-Rb, through which leptin up-regulates the expression of matrix remodeling genes including TGF-beta1.


CONCLUSIONS
Collectively, these findings indicated that leptin and its functional receptors (Ob-Rb) play a pivotal role in profibrogenic responses in the liver.
Ikejima
Kenichi
K
Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
Takei
Yoshiyuki
Y
Honda
Hajime
H
Hirose
Miyoko
M
Yoshikawa
Mutsuko
M
Zhang
Yan-Jun
YJ
Lang
Tie
T
Fukuda
Toru
T
Yamashina
Shunhei
S
Kitamura
Tsuneo
T
Sato
Nobuhiro
N
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000096:biosynthesis; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1