Role of retinoic acid receptor in steatohepatitis‐related tumor formation

Abstract

Retinoic acid (RA) appears to play an important role in the pathophysiology of liver disease. However, this role remains to be clarified in detail. To explore the role of RA in the liver, transgenic mice that express RA receptor (RAR) alpha-dominant negative form in hepatocytes under the control of albumin promoter and enhancer, were developed. At 4 months of age the RAR alpha- dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. The enzymes that are involved in mitochondrial beta-oxidation of fatty acids, including very-long-acyl-CoA dehydrogenase, long-acyl-CoA dehydrogenase, and 3-hydroxyacyl-CoA dehydrogenase, were downregulated; in contrast, the enzymes that are involved in peroxisomal beta-oxidation, including acyl-CoA oxidase and bifunctional enzyme, were upregulated. Expression of cytochrome p4,504a10, cytochrome p4,504a12, and cytochrome p4,504a14 was increased, suggesting that omega-oxidation of fatty acids in microsomes was accelerated. In addition, formation of H(2)O(2) and 8-hydroxy-2'-deoxyguanosine was increased. After 12 months of age, these mice developed hepatocellular carcinomaand adenoma of the liver. The incidence of tumor formation increased with age. Expression of beta-catenin and cyclin D1 was enhanced and the TCF-4/beta-catenin complex was increased, whereas the RARalpha/beta-catenin complex was decreased. Feeding on a high-RA diet reversed histological and biochemical abnormalities and inhibited the occurrence of liver tumors. These results suggest that hepatic loss of RA function leads to the development of steatohepatitis and liver tumors. In conclusion, RA plays an important role in preventing hepatocarcinogenesis in association with fatty acid metabolism and Wnt signaling.