Research for usefulness of intestinal peptide, PYY_<3-36> for therapeutic agents of fatty liver and NASH

本研究观察了PYY_2对<3-36>肥胖和脂肪肝模型动物的治疗作用。本研究首先采用Zucker肥胖模型大鼠，观察PYY_2<3-36>对肥胖大鼠的影响。即每天腹腔注射PYY 0-5μg/100 g，连续30天，观察期内逐点测量体重。结果表明，5μg/100 g PYY处理组大鼠体重增长较未处理对照组明显受到抑制。然而，在这些模型大鼠的肝组织中未观察到含有非酒精性脂肪性肝炎（NASH）的非酒精性脂肪性肝病（NAFLD）。接着，我们向Zucker模型大鼠添加高热量饮食1个月，在肝脏标本中观察到NASH的特征性发现，如小叶内炎症、气球样肝细胞和马洛里体。另一方面，在PYY处理组的肝脏中几乎没有观察到NASH的组织学发现。然而，在该模型大鼠中，PYY治疗没有改善体重，因此我们放弃了对NAFLD和肥胖症患者进行PYY治疗的临床试验。就在那时，我们报道了在脂肪组织中过表达nSREBP-1c（核固醇调节元件结合蛋白1c）的转基因（Tg）小鼠引起NASH。我们检查了绿色茶（-）-表没食子儿茶素-3-没食子酸酯（EGCG）在该nSREBP-1 Tg NASH模型小鼠中的作用。也就是说，口服含有0.05- 0.1%EGCG的水3个月。结果表明，EGCG治疗显著抑制了体重和肝脏重量的增加以及NASH的进展。目前，我们正在研究是否改善脂质，氧化应激，胰岛素抵抗和肝脏组织中的炎症与EGCG治疗模型小鼠。

We examined the therapeutic effects of PYY_<3-36> on model animals showing obesity and fatty liver. Firstly, we studies using Zucker obesity model rats, and observed the effects of PYY_<3-36> in these rats. That is, 0-5μg/100g PYY per day was injected intraperitonialy for 30 days, and measured body weight point by point during observation term. In results, the increase of body weight of rats in the group treated with 5μg/100g PYY was significantly suppressed compared with that in the control group without treatment with PYY. However, nonalcoholic fatty liver diseases (NAFLD) containing nonalcoholic steatohepatitis (NASH) were not observed in liver tissues of these model rats. Next, we added the high calorie diet to the Zucker model rats for 1 month, and the characteristic findings of NASH such as intralobular inflammation, ballooning hepatocytes and Mallory's bodies were observed in the liver specimens. On the other hands, the histological findings of NASH were hardly observed in livers of the PYY-treated groups. However, the improvement of body weight was not recognized with PYY-treatment in this model rats, and we gave up a clinical trial, which treats with PYY in the patients with NAFLD and obesity.Just at that moment, we reported that transgenic (Tg) mice which over express nSREBP-1c (nuclear sterol regulatory element-binding protein 1c) in fat tissues cause NASH. We examined the effects of green tea (-)-epigallocatechin-3-gallate (EGCG) in this nSREBP-1 Tg NASH model mice. That is, Water containing 0.05-0.1% EGCG was orally administrated for 3 months. In results, the increases of body weight and liver weight, and the progression of NASH were significantly suppressed with treatment of EGCG. Presently, we are studying whether the improvement of lipids, oxidative stress, insulin resistance and inflammation in the liver tissues are brought with EGCG treatment in the model mice.