2004 Fiscal Year Final Research Report Summary
Induction of hepatocyte growth factor by physiological agents : its effects on hepatocyte proliferation and protein production
| Project/Area Number |
15590625
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TOMIYA Tomoaki The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (90227637)
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| Co-Investigator(Kenkyū-buntansha) |
IKEDA Hitoshi The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (80202422)
YANASE Mikio The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (50334397)
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| Project Period (FY) |
2003 – 2004
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| Keywords | HGF / Leucine / Hepatocytes |
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| Research Abstract |
Hepatocyte growth factor (HGF) is considered to be a pleiotropic factor, and is reported to modulate gene expression and to stimulate the proliferation and functions of many cell types, including hepatocytes. A potential application of HGF for several types of diseases has been postulated. Amino acids can serve as regulatory molecules that modulate numerous cellular functions. Branched chain amino acids (BCAAs) are known to exert influences on cellular metabolism, amino acid transport and gene expression. BCAA supplementation therapy is a current treatment for patients with liver cirrhosis, therefore, specific BCAA activities should be examined. In this research project, we found the potential of BCAAs for stimulating HGF synthesis in the liver. A hepatic stellate cell clone was cultured in medium supplemented with various concentrations of valine, leucine or isoleucine. Of these BCAAs, leucine markedly induced an increase in the levels of HGF in the medium in a dose-dependent manner.
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The addition of valine or isoleucine had no significant effect on the HGF levels. When rats received intraperitoneal injections of valine, leucine or isoleucine, only leucine treatment increased both hepatic and circulating levels of HGF in a dose-dependent manner, than in controls. In patient study, serum HGF levels were significantly higher in patients with liver cirrhosis who received BCAA-mixture granules orally than in control patients. Next, to clarify the mechanisms of stimulatory effect of leucine on HGF production, we studied intracellular signaling pathway. p70 S6 kinase activity and phosphorylation of the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) were up-regulated rapidly after leucine treatment in a 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 completely the stimulatory effect of leucine on HGF production in a dose-dependent manner. Leucine stimulates HGF production by hepatic stellate cells through an mTOR-dependent signaling pathway. Less
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