title: Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice.
abstract: Although attention has focused on the chemopreventive action of retinoic acid (RA) in hepatocarcinogenesis, the functional role of RA in the liver has yet to be clarified. To explore the role of RA in the liver, we developed transgenic mice expressing RA receptor (RAR) alpha- dominant negative form in hepatocytes using albumin promoter and enhancer. At 4 months of age, the RAR alpha- dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial beta-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal beta-oxidation and its related enzymes, including AOX and BFE, were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased, suggesting that omega-oxidation of fatty acids in microsomes was accelerated. In addition, formation of H2O2 and 8-hydroxy-2'-deoxyguanosine was increased. After 12 months of age, these mice developed hepatocellular carcinoma and 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 RAR alpha/ 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.
authors.affiliation: Department of Genetic Medicine and Regenerative Therapeutics, Tottori University, Yonago, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yanagitani
authors.forename: Sadako
authors.initials: S
authors.lastname: Yamada
authors.forename: Sakiko
authors.initials: S
authors.lastname: Yasui
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimomura
authors.forename: Rie
authors.initials: R
authors.lastname: Murai
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Murawaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kanbe
authors.forename: Toshiya
authors.initials: T
authors.lastname: Saeki
authors.forename: Miho
authors.initials: M
authors.lastname: Ichiba
authors.forename: Yoshitada
authors.initials: Y
authors.lastname: Tanabe
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Morino
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kurimasa
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Usuda
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kunisada
authors.forename: Hisao
authors.initials: H
authors.lastname: Ito
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005799:Genes, Dominant; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage; D051176:beta Catenin
chemical_list: C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004798:Enzymes; D005227:Fatty Acids; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; D051176:beta Catenin; D014212:Tretinoin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine