Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Lepr(db)/+Lepr(db) Mice

Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) alpha due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXR alpha, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J- +Lepr(db)/+Lepr(db) (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signal-regulated kinase) and RXRa proteins in the livers of experimental mice. It also increased the expression of RAR beta and p21(CIP1) mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRa function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-alpha and the expression levels of TNF-alpha, IL-6, and IL-1 beta mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC. Cancer Prev Res; 4(1); 128-36. (C) 2010 AACR.