Retinoic acid receptor ? 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) ␣-dominant negative form in hepatocytes using albumin promoter and enhancer. At 4 months of age, the RAR ␣-dominant negative form transgenic mice developed microvesicular steatosis and spotty focal necrosis. Mitochondrial ␤-oxidation activity of fatty acids and expression of its related enzymes, including VLCAD, LCAD, and HCD, were down-regulated; on the other hand, peroxisomal ␤-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 -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 carcinoma and adenoma of the liver. The incidence of tumor formation increased with age. Expression of ␤-catenin and cyclin D1 was enhanced and the TCF-4/␤-catenin complex was increased, whereas the RAR ␣/ ␤-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. (HEPATOLOGY 2004;40:366-375.)

Trim24 (Tif1α): An essential ‘brake’ for retinoic acid-induced transcription to prevent liver cancer

“…These researchers have demonstrated that mice expressing a dominant-negative form of Rara in hepatocytes developed steatohepatitis and liver tumors, while feeding on high RA diet reversed and inhibited the carcinogenesis process. 78 These findings further reinforce the view that the liver is a highly susceptible organ to alterations in the RA signaling pathway and, along with the study described here and the above-mentioned published reports, depict a quite complex scenario in which it seems clear that increasing or blocking RA signaling can be deleterious to liver homeostasis, both leading to the occurrence of HCC. This duality has considerable implications for cancer therapy, indicating that the use of retinoids should proceed with caution as long as no clear concept has emerged regarding the mechanisms and contexts that determine whether a retinoid will act as a carcinogen or as a beneficial chemotherapeutic agent.…”

“…75 In addition to these effects seen in the late phase of the carcinogenetic process, ACR may also interfere with early steps by reducing the emergence of TGFa-expressing oval-like cells and activated hepatic stellate cells, as recently shown in a rat model of chemically-induced HCC. 76,77 Another report of interest in support for an essential role of the RA signaling in preventing hepatocarcinogenesis is that of Yanagitani et al (2004). These researchers have demonstrated that mice expressing a dominant-negative form of Rara in hepatocytes developed steatohepatitis and liver tumors, while feeding on high RA diet reversed and inhibited the carcinogenesis process.…”

Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway

“…19 It has a 1/10 weaker action on leukemia differentiation, 20 and a 1/100 weaker carcinogenic action in transgenic mice that express the dominant-negative form of retinoic acid receptor. 21,22 On the other hand, accumulating evidence shows that ACR, but not atRA, has apoptosisinducing activity in HCC cells, as well as in smooth muscle cells and vascular neointima. 23,24 We found that ACR acts as either a kinase inhibitor or a phosphatase stimulator and prevents hyperphosphorylation of RXR, 9 and now VEGFR2.…”

Mice With a Deletion in the Gene for CCAAT/Enhancer-Binding Protein β Are Protected Against Diet-Induced Obesity

“…In the C/EPB␤ Ϫ/Ϫ mice, the BAT has 1.4-fold increased gene expression of AOX and 2.0-fold increase of LCAD gene expression over wild-type gene expression. Peroxisomal ␤-oxidation produces an increase of short-and mediumchain fatty acids that can now then enter the mitochondria for ␤-oxidation (25). The increase of LCAD gene expression would also contribute to the increased overall oxidation of fatty acids on a high-fat diet.…”