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Activation of regeneration capacity of the cirrhotic livers based on the molecular and genetic biology

基于分子和遗传生物学的肝硬化肝脏再生能力的激活

基本信息

批准号：
11307022
负责人：
YAMAOKA Yoshio
金额：
$ 25.96万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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 … More 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

在35例接受肝切除术的患者中，评价了血清瘦素浓度与术后肝脏再生率的关系。血清瘦素浓度与体重指数（BMI）呈正相关（r=0.73）。女性术前体脂量与瘦素呈正相关（r=0.72），男性术前体脂量与瘦素无相关性（r=0.48）。在日本，瘦素浓度与肝硬化之间没有关系。这一事实与国外报道的酒精性肝硬化的处理不同。男性糖尿病患者瘦素水平显著高于女性（p=0.0127），但女性糖尿病患者瘦素水平与糖尿病的关系不明显。Leptin值与口服GTT值和IRI值无相关性。有趣的是，在女性中，术后肝再生率与瘦素之间观察到强负相关（r=-0.88）。这一事实表明，瘦素抑制肝再生只在 ...更多信息女性瘦素和雌激素之间的进一步研究将是有趣的。在基础研究中，我们检测了肝硬化大鼠模型中瘦素及其受体（Ob-R）的表达。血清瘦素水平与肝硬化的发生、发展无关。RT-PCR显示Ob-R在肝脏中有表达。在肝硬化组中，Ob-Ra的表达较正常组明显降低。导致肝硬化的主要因素之一是星状细胞的活化，即其向肌成纤维细胞的转化。然而，我们发现在肝细胞培养物中星状细胞的存在促进肝细胞的生长而不是抑制细胞的生长。在大鼠70%肝切除模型中，星状细胞的活化首先发生在再生的非常早期，随后是HSP 47的诱导，然后HSP 47产生胶原蛋白以制造用于组织再生的基质。除了这些事实，作为一种新的策略，以抑制肝纤维化，N-乙酰-L-半胱氨酸的管理是有效的，通过干扰信号转导在肝星状细胞。热休克预处理和Racl显性负性基因转移可抑制NF-κ B的活化，减轻肝缺血后易导致肝纤维化的炎症反应。少