Abstract
Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) α 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 RXRα, 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 RXRα proteins in the livers of experimental mice. It also increased the expression of RAR β and p21(CIP1) mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα 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-α and the expression levels of TNF- α, IL-6, and IL-1 β 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.
Highlights
Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide
We examined whether acyclic retinoid (ACR) treatment improves the insulin resistance, liver steatosis, and inflammatory condition caused by obesity with DEN-treated db/db mice, a useful preclinical model, to evaluate the mechanisms underlying the inhibition of obesity-related liver tumorigenesis by chemopreventive drugs [4]
A recent clinical trial revealed that supplementation of food with branched-chain amino acids (BCAA), which improves insulin resistance [35], reduced the risk of HCC in obese patients with chronic viral liver disease [3]
Summary
Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide. The risk factors associated with the development of HCC include chronic hepatitis B and/or hepatitis C infection, with subsequent cirrhosis. ACR Inhibits Obesity-Related Liver Tumorigenesis growth of HCC-derived cells by inducing apoptosis and causing cell-cycle arrest in G0–G1 [11,12,13,14,15]. These effects of ACR are associated with its agonistic activity for distinct nuclear retinoid receptors—retinoid X receptors (RXR) and retinoic acid receptors (RAR), both of which have 3 subtypes (a, b, and g; 16)—and subsequent expression of the ACR target genes RARb and p21CIP1 [12,13,14,15]. We examined whether ACR treatment improves the insulin resistance, liver steatosis, and inflammatory condition caused by obesity with DEN-treated db/db mice, a useful preclinical model, to evaluate the mechanisms underlying the inhibition of obesity-related liver tumorigenesis by chemopreventive drugs [4]
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