Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor.
In the present study, we investigated the effect of leptin on proliferation of hepatic stellate cells (HSCs) in vitro. Proliferation of 3-day cultured rat HSCs was assessed by incorporation of 5-bromo-2'-deoxyuridine (BrdU) into the nuclei. The percentages of BrdU-positive cells were increased in the presence of PDGF-BB (5 ng/ml) for 8h as expected. Co-incubation with leptin (10-100 nM) potentiates this PDGF-dependent increase in BrdU positive cells in a dose-dependent manner. Messenger RNA for PDGF receptor alpha and beta subunits was increased almost 2- to 3-fold by incubation with leptin for 6h. Further, pre-incubation with leptin for 6h enhanced PDGF-induced increases in phospho-p44/42 MAP kinase and phospho-Akt levels in a dose-dependent manner. In the same condition, however, leptin per se did not increase phospho-STAT 3 and phospho-p44/42 MAP kinase levels. Instead, leptin increased phospho-Akt levels in HSCs within 30 min, suggesting that the phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in the mechanism by which leptin accelerates the proliferation of HSCs. In conclusion, the present study clearly indicated that leptin potentiates PDGF-dependent proliferative responses of HSCs in vitro.
Lang
Tie
T
Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
Ikejima
Kenichi
K
Yoshikawa
Mutsuko
M
Enomoto
Nobuyuki
N
Iijima
Katsuyori
K
Kitamura
Tsuneo
T
Takei
Yoshiyuki
Y
Sato
Nobuhiro
N
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D020738:Leptin; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor