Functional analysis of retinoic acid receptor in liver

• Project/Area Number: 10670473
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Second Department of Internal Medicine, Faculty of Medicine, Tottori University
• Principal Investigator: SHIOTA Goshi Second Department of Internal Medicine, Faculty of Medicine, Tottori University, Associate Professor, 医学部, 助教授 (70263457)
• Co-Investigator(Kenkyū-buntansha): KUNISADA Takahiro Department of hygiene, Faculty of Medicine, Gifu University, Associate Professor, 医学部, 教授 (30205108)
• Project Period (FY): 1998 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000); Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Publications] 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)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Tsutsumi A, Shiota G, Yamazaki H, Kunisada T, Terada T, Kawasaki H.: "Accelerated growth of hepatocytes in association with up-regulation of cyclin E in transgenic mice expressing the dominant negative form of retinoic acid receptor"Biochem Biophys Res Commun. 278. 229-235 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tastumi A et al.: "Accelerated growth of hepatocytes in association with up-regulator of cyclin E in Wansgenic mice expressing the daninant regahie form of retin cod receptn"Biochem Biophys Res Commun. 278. 229-235 (2000)
• [Publications] 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)