Acyclic retinoid NIK-333 accelerates liver regeneration and lowers serum transaminase activities in 70% partially hepatectomized rats, in vivo.

The effect of an acyclic synthetic retinoid analogue NIK-333, on the restoration of liver mass and recovery of liver function after 70% partial hepatectomy, was compared with natural retinoids in rats in vivo. NIK-333 (0.4 mg/kg/day, p.o.)- and all-trans-retinoic acid (ATRA: 4 mg/kg/day, p.o.)-treated rats showed an approximately 1.3- and 1.2-fold increase in liver-to-body weight ratio, respectively, compared to solvent-administered control rats on day 3 after 70% partial hepatectomy. Accordingly, 5-bromo-2'-deoxyuridine (BrdU)-labeling index in the regenerating liver was significantly higher in NIK-333- and ATRA-treated rats compared with control rats on days 0.5 and 1. However, retinol (40 mg/kg/day, p.o.) did not significantly increase either the liver-to-body weight ratio or the BrdU labeling index. In control rats, liver-related serum transaminase activities such as alanine aminotransferase and aspartate aminotransferase, were rapidly elevated on day 1 and then decreased to near pre-operative levels on day 5 following 70% partial hepatectomy. NIK-333 significantly lowered serum transaminases on days 1 and 3 after 70% partial hepatectomy compared with solvent-administered control rats. The transaminase-lowering effect of NIK-333 was more effective than that of ATRA. Retinol did not significantly decrease serum transaminases compared with the control. These results demonstrate that of the three retinoids, NIK-333 was the most potent in promoting the regeneration of liver mass and function with full recovery after 70% partial hepatectomy.

Suppressive effects of retinoids on iron-induced oxidative stress in the liver.

BACKGROUND & AIMS: We previously reported that impaired retinoid signaling in the liver causes steatohepatitis and hepatocellular carcinoma. Recently, oxidative stress induced by hepatic iron overload has emerged as an important factor for the progression of liver disease in patients with chronic hepatitis C, alcoholic liver disease, and nonalcoholic steatohepatitis. In this study, the relationship between retinoid signaling and iron metabolism in the liver was investigated. METHODS: The effect of retinoids on the iron metabolism was examined in HuH7 cells treated with all-trans retinoic acid and acyclic retinoid NIK-333. In in vivo experiments, we used the mice expressing the dominant negative form of retinoic acid receptor alpha gene under the control of albumin enhancer/promoter (RAR-E Tg) and iron-overloaded wild mice fed with retinoid-deficient and retinoid-excess diets. RESULTS: Hepatic iron accumulation and increased expression of hemojuvelin were observed in RAR-E Tg mouse liver. Retinoid treatment significantly suppressed expression of hemojuvelin and mildly suppressed expression of transferrin receptor type 2 and hepcidin, accompanied by decreased hepatic iron content and iron-induced oxidative stress in vitro and in vivo. Overexpression of hemojuvelin in HuH7 hepatoma cells led to a significant increase in cellular iron content. CONCLUSIONS: Our results suggest that retinoids are involved in hepatic iron metabolism through transcriptional regulation of hemojuvelin. This study demonstrated a novel functional role of retinoids in preventing iron-induced oxidative stress in the liver.

An antioxidant effect by acyclic retinoid suppresses liver tumor in mice.

The mechanisms of prevention of the development of liver cancer by NIK-333, an acyclic retinoid (ACR), were investigated. The transgenic mice expressing the dominant negative form of retinoic acid receptor alpha (RARE mice), that produce reactive oxygen species and lead to development of liver tumor were used. The effect of NIK-333 on hepatocarcinogenesis in RARE mice was studied. The RARE mice were examined after feeding 0.03% and 0.06% NIK-333 diets at 12 months of age. In the mice fed 0.06% NIK-333 diet, tumor incidence was greatly suppressed, compared to that of wild type mice (0/9 versus 5/9, P<0.05), but not in the mice fed 0.03% NIK-333 diet. In addition, expression of cytochrome p450 4a14 and acyl-CoA oxidase was normalized, and the percentages of positive cells for 8-hydroxy-2'-deoxyguanosine, 4-hydroxy-2-nonenal and proliferating cell nuclear antigen were decreased. Furthermore, expression of beta-catenin and cyclin D1 was also depressed. These data suggest that NIK-333 suppressed liver tumor in association with repression of oxidative stress.