Functional analysis of retinoic acid receptor in liver

Research Project

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 *help	¥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.