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

在35例接受主要肝切除术的患者中，评估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），而男性无相关（r=0.48）。在日本，瘦素浓度与肝硬化之间没有关系。这与国外有关酒精性肝硬化的报道不同。在男性中，糖尿病患者的瘦素水平显著升高（p=0.0127），但在女性中没有观察到这种关系。瘦素值与口服GTT值、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存在很强的负相关（r=-0.88）。这一事实表明瘦素仅在…更多的女性中抑制肝脏再生。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，我们在肝硬化大鼠模型中测定了瘦素和瘦素受体（Ob-R）。在我们的模型中，血清瘦素水平与肝硬化的发展没有关系。RT-PCR显示Ob-R在肝脏中的表达。在肝硬化肝脏中，Ob-Ra的表达比正常肝脏受到更大的抑制。导致肝硬化的主要因素之一是星状细胞的活化，即向肌成纤维细胞的转化。然而，我们发现在肝细胞培养中，星状细胞的存在促进了肝细胞的生长，而不是抑制细胞的生长。在70%的大鼠肝切除术模型中，星状细胞的激活首先发生在再生的早期，然后是HSP47的诱导，然后产生胶原蛋白，作为组织再生的基质。除此之外，n -乙酰- l -半胱氨酸作为一种抑制肝脏纤维化的新策略，通过干扰肝星状细胞的信号转导而有效。热休克预处理和Racl显性负基因转移可抑制NF-kB的激活，改善肝脏缺血后常导致肝脏纤维化的炎症反应。少

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