2001 Fiscal Year Final Research Report Summary
Activation of regeneration capacity of the cirrhotic livers based on the molecular and genetic biology
| Project/Area Number |
11307022
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
YAMAOKA Yoshio Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (90089102)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Naritaka Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (30253298)
YAMAMOTO Yuzo Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (70281730)
SHIMAHARA Yasuyuki Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (30196498)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Liver regeneration / Hepatectomy / Leptin / Liver cirrhosis / Signal pathway / Gene / Fibrosis / Ischemia / reperfusion |
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| Research Abstract |
In the 35 patients who underwent major hepatectomy, serum leptin concentrations were evaluated in relation to the regeneration rates of the liver after surgery. Serum leptin concentration was positively correlated with the body mass index (BMI) with r=0.73. Preperative body fat mass showed a positive correlation with leptin in female (r=0.72), but did not in male (r=0.48). There was no relationship between leptin concentration and liver cirrhosis in Japan. This fact was different from the report in abroad, in which alcoholic liver cirrhosis is dealed with. In the male, patients with diabetes mellitus showed significantly higher level of leptin value (p=0.0127), but this relationship was not observed in female. Leptin value had no relationship with oral GTT value or IRI value. Interestingly, in the female, strong negative correlation was observed between postoperative liver regeneration rate and leptin (r=-0.88). This fact indicates that leptin suppresses liver regeneration only in the
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females. Further investigation between leptin and estrogen will be interesting. In the basic research, we measured leptin and leptin receptor (Ob-R) in the rat cirrhosis model. Serum leptin level did not have connection with the development of liver cirrhosis in our model. RT-PCR revealed the expression of Ob-R in the liver. In the liver with cirrhosis, expression of Ob-Ra was more suppressed than the normal liver. One of the major factors that lead the liver to cirrhosis is the activation of stellate cells, i.e,, its transformation to myofibroblasts. However, we found that the presence of stellate cells in the hepatocyte-culture facilitated the growth of hepatocytes instead of suppressing the cell growth. In the 70% hepatectomy model of rats, activation of stellate cells occurred first in the very early period of regeneration followed by the induction of HSP47, which then worked to produce collagen to make a matrix for regeneration of the tissue. Besides these facts, as a novel strategy to suppress the fibrogenesis of the liver, administration of N-acethly-L-cysteine was effective by interfering the signal transductions in the hepatic stellate cells. Heat shock preconditioning and dominant negative gene transfer of Racl could suppressed the activation of NF-kB and ameliorated the inflammatory reactions after ischemia of the liver that often lead the liver to fibrosis. Less
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