Functional analysis of retinoic acid receptor in liver

肝脏视黄酸受体的功能分析

• 批准号: 10670473
• 负责人: SHIOTA Goshi
• 金额: $ 2.11万
• 依托单位: Second Department of Internal Medicine, Faculty of Medicine, Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670473/
• 关键词: retinoic acid receptor; transgenic mice; liver; steatohepatitis; fatty acid; beta oxidation; hepatocellular carcinoma; 肝細胞特異的; レチノイン酸レセプター; トラシスジェニックマウス; 肝臓; レチノイドリセプター; レケノイドレセプター

We developed transgenic mice which express retinoic acid receptor dominant negative form in hepatocytes using albumin enhancer and promoter. At 3 months old, the transgenic mice (Tg) developed severe steatohepatitis. The droplet of steatosis is microvesicular, and the focal necrosis is scattered in the lobule. The growth of hepatocytes was enhanced, indicated by proliferating cell nuclear antigen expression, and the liver showed hepatomegaly. In addition to these changes, liver cell dysplasia including increased nuclear cytoplasmic ratio and abnormal staining distribution. At 12 months old, the mice developed hepatocellular carcinoma. The beta oxidation of fatty acid is impaired in mitochondria, and instead it was accelerated in peroxisome. Furthermore, omega oxidation of fatty acid in the endoplasmic reticulum was increased, resulting in production of reactive oxygen species. These data suggest that retinoic acid is essential for maintain the proper development of liver, and that retinoic acid depresses liver cancer development.

我们利用白蛋白增强子和启动子开发了在肝细胞中表达视黄酸受体显性阴性形式的转基因小鼠。在3个月大时，转基因小鼠（Tg）发生了严重的脂肪性肝炎。脂肪变性液滴呈微泡状，小叶内散在灶性坏死。增殖细胞核抗原表达表明肝细胞生长增强，肝脏显示肝肿大。除这些变化外，肝细胞发育异常包括核质比增加和染色分布异常。在12个月大时，小鼠患上了肝细胞癌。脂肪酸的β氧化在线粒体中受损，而在过氧化物酶体中加速。此外，内质网中脂肪酸的ω氧化增加，导致活性氧的产生。这些数据表明，维甲酸是维持肝脏正常发育所必需的，维甲酸抑制肝癌的发展。

项目成果

Tsutsumi A et al.: "Accelerated growth of hepatocytes in association with uprepla of cyclin E in transgeic mice expressing the dominant negative for of retinoic acid receptor."Biochem.Biophys.Res.Commun.. 278. 229-235 (2000)

Tsutsumi A 等人：“表达视黄酸受体显性失活的转基因小鼠中肝细胞的加速生长与细胞周期蛋白 E 的增加有关。”Biochem.Biophys.Res.Commun. 278. 229-235 (2000)

Tsutsumi A et al.: "Accelerated grawth of hepalocytes in association with uprepla of cyclin E in transgenic mice expressing the dominant negative for of retinoic acid receptor"Biochem Biophys Res Commun. 278. 229-235 (2000)

Tsutsumi A 等人：“表达视黄酸受体显性失活的转基因小鼠中肝细胞的加速生长与细胞周期蛋白 E 的增加相关”Biochem Biophys Res Commun。