Functional analysis of retinoic acid receptor in liver

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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.