Effect of rapamycin on hepatocyte function and proliferation induced by growth factors.
BACKGROUND
Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). The effect of rapamycin on proliferation and cellular function was studied in hepatocytes stimulated by hepatocyte growth factor (HGF) or transforming growth factor-alpha (TGFalpha).


RESULTS
When isolated rat hepatocytes were cultured at low density, the addition of HGF or TGFalpha increased DNA synthesis but did not affect albumin or fibrinogen concentrations in the medium. In contrast, in hepatocytes cultured at high density, the albumin and fibrinogen concentrations, but not DNA synthesis, were increased by HGF or TGFalpha. The HGF- or TGFalpha-induced increase in DNA synthesis and in albumin or fibrinogen concentrations was suppressed by the addition of rapamycin, as well as wortmannin, a phosphatidylinositol-3 kinase inhibitor.


CONCLUSIONS
HGF and TGFalpha stimulate proliferation and function of hepatocytes depending upon the conditions, and rapamycin inhibited these stimulatory effects, possibly by inhibiting the mTOR-dependent signaling pathway.
Tomiya
Tomoaki
T
Department of Gastroenterology, Fuculty of Medicine, University of Tokyo, Tokyo, Japan. tomiya-lim@h.u-tokyo.ac.jp
Yamaoka
Miho
M
Inoue
Yukiko
Y
Nishikawa
Takako
T
Yanase
Mikio
M
Ikeda
Hitoshi
H
Tejima
Kazuaki
K
Nagashima
Kayo
K
Watanabe
Naoko
N
Omata
Masao
M
Fujiwara
Kenji
K
D000418:Albumins / Q000032:analysis / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D004261:DNA Replication / Q000187:drug effects; D005340:Fibrinogen / Q000032:analysis / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000077191:Wortmannin
D000418:Albumins; D000730:Androstadienes; D000903:Antibiotics, Antineoplastic; D003470:Culture Media; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D005340:Fibrinogen; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000077191:Wortmannin