Leucine stimulates HGF production by hepatic stellate cells through mTOR pathway.
Branched chain amino acids modulate various cellular functions in addition to providing substrates for the production of proteins. We examined the mechanism underlying the stimulation by leucine of hepatocyte growth factor (HGF) production by hepatic stellate cells. Both p70 S6 kinase activity and phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) were up-regulated rapidly after leucine treatment of a rat hepatic stellate cell clone. No such activation was observed following treatment with valine or isoleucine. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suppressed leucine-induced activation of p70 S6 kinase and 4E-BP1 and negated the stimulatory effect of leucine on HGF production. An mTOR-dependent signaling pathway mediates the stimulatory effect of leucine on the production of HGF by hepatic stellate cells.
Tomiya
Tomoaki
T
Department of Gastroenterology, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. tomiya-1im@h.u-tokyo.ac.jp
Nishikawa
Takako
T
Inoue
Yukiko
Y
Ohtomo
Natsuko
N
Ikeda
Hitoshi
H
Tejima
Kazuaki
K
Watanabe
Naoko
N
Tanoue
Yasushi
Y
Omata
Masao
M
Fujiwara
Kenji
K
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D007930:Leucine