Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice.
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.
Yanagitani
Atsushi
A
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University, Yonago, Japan.
Yamada
Sadako
S
Yasui
Sakiko
S
Shimomura
Takashi
T
Murai
Rie
R
Murawaki
Yoshiyuki
Y
Hashiguchi
Koichi
K
Kanbe
Takamasa
T
Saeki
Toshiya
T
Ichiba
Miho
M
Tanabe
Yoshitada
Y
Yoshida
Yoko
Y
Morino
Shin-Ichi
S
Kurimasa
Akihiro
A
Usuda
Nobumitsu
N
Yamazaki
Hidetoshi
H
Kunisada
Takahiro
T
Ito
Hisao
H
Murawaki
Yoshikazu
Y
Shiota
Goshi
G
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
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