Retinoic acid receptor α dominant negative form causes steatohepatitis and liver tumors in transgenic mice
Retinoic acid receptor α dominant negative form causes steatohepatitis and liver tumors in transgenic mice
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DOI：
10.1002/hep.20335
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发表时间：
2004-08-01
期刊：
影响因子：
13.5
通讯作者：
Shiota, G
中科院分区：
文献类型：
--
作者：
Yanagitani, A;Yamada, S;Shiota, G
尽管人们的注意力集中在视黄酸（RA）在肝癌发生中的化学预防作用，但 RA 在肝脏中的功能作用尚未阐明。为了探索 RA 在肝脏中的作用，我们使用白蛋白启动子和增强子开发了在肝细胞中表达 RA 受体 (RAR) α 显性阴性形式的转基因小鼠。 4个月大时，RAR显性失活形式转基因小鼠出现微泡脂肪变性和点状局灶性坏死。线粒体脂肪酸β-氧化活性及其相关酶（包括VLCAD、LCAD和HCD）的表达下调；另一方面，过氧化物酶体β-氧化及其相关酶，包括AOX和BFE，则上调。细胞色素p4504a10、细胞色素p4504a12和细胞色素p4504a14的表达增加，表明微粒体中脂肪酸的omega氧化加速。此外，H2O2 和 8-羟基-2'-脱氧鸟苷的形成也增加。 12 个月大后，这些小鼠患上了肝细胞癌和肝腺瘤。肿瘤形成的发生率随着年龄的增长而增加。 β-连环蛋白和细胞周期蛋白 D1 的表达增强，TCF-4/β-连环蛋白复合物增加，而 RAR α/β-连环蛋白复合物减少。高RA饮食可逆转组织学和生化异常，并抑制肝脏肿瘤的发生。这些结果表明，RA 功能的肝脏丧失会导致脂肪性肝炎和肝脏肿瘤的发生。总之，RA 在预防肝癌中发挥着重要作用，与脂肪酸代谢和 Wnt 信号传导有关。
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 die 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 a- 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.