[Mouse NASH model using retinoic acid receptor alpha].
To explore the role of retinoic acid (RA) in the liver, we developed transgenic mice expressing RA receptor a-dominant negative form (RARE) in hepatocytes using albumin promoter and enhancer. The RARE m ice developed microvesicular steatosis andspotty focal necrosis. Mitochondrial beta-oxidation activity of fatty acids and related enzymes were down-regulated, while peroxisomal beta-oxidation and related enzymes were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased. Formation of H2O2 and 8-OHdG was increased. With age, these mice developed liver tumor. 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.
Shiota
Goushi
G
Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University.
Tuchiya
Hiroyuki
H
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008113:Liver Neoplasms / Q000209:etiology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000008:administration & dosage / Q000502:physiology*
D005227:Fatty Acids; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System