トランスジェニックマウスを用いた肝臓切除におけるエネルギー代謝の研究-遺伝子治療の肝臓外科への導入

点击翻译按钮获取中文摘要

The catalysis of creatine/phsophocreatine system by creatine kinase is not expressed in the liver. Promoting effect of liver regeneration after hepatectomy and induction of endotoxin tolerance were studied using transgenic mouse liver expressing creatine kinase in 1994 and 1995, respectively. In the presence of phosphocreatine in the liver by feeding creatine, decrease in ATP accompanied with liver regeneration was inhibited, and intramitochondrial ATP was maintained at high level. Consequently, mitochondrial oxidative phosphorylation was enhanced, resulting in rapid recovery of liver weight and acceleration of DNA synthesis. In the second study of endotoxin administration, the presence of phosphocreatine caused attenuation of inflamatory cytokine response, inhibition of generation of reactive oxygen species in the liver, down-regulation of ICAM-1, resulting in decrease in lethal effect of endotoxin. These results indicate that transfection of creatine kinase gene into the liver has a prophylactic effect for liver failure induced by surgical stresses. In the third study using isolated hepatocyte from the transgenic mouse liver, addition of creatine into the culture medium prevented decrease in hepatocellular ATP level by challenge with ammonium load. In the fourth study of fulminant hepatitis model using combination of galactosamine and endotoxin, the presence of phosphocreatine inhibited hemorrhagic necrosis with apoptosis. In summary, transfection of creatine kinase gene into the liver provides a possible treatment for liver failure.