Abstract B55: Chemoprevention of obesity- and diabetes-related liver carcinogenesis by branched-chain amino acids and acyclic retinoid

Abstract

Abstract Obesity and diabetes-related metabolic abnormalities, including insulin resistance, alterations in the IGF/IGF-1R axis, state of chronic inflammation, and induction of oxidative stress increase the risk of hepatocellular carcinoma (HCC). Non-alcoholic steatohepatitis, which is frequently associated with obesity and diabetes, can progress to cirrhosis and HCC. On the other hand, these findings indicate that the metabolic disorders caused by obesity and diabetes might be effective targets to prevent HCC development. For instance, branched-chain amino acids (BCAA), which improve protein energy malnutrition in patients with liver cirrhosis, improve insulin resistance and reduce the risk of HCC in obese cirrhotic patients. In an experimental study, BCAA supplementation inhibits the development of liver tumors in obese and diabetic mice by inhibiting the activation of IGF/IGF-1R axis, improving insulin resistance, reducing serum leptin levels, and attenuating hepatic steatosis and fibrosis. BCAA supplementation also inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. In addition, acyclic retinoid (ACR), which is a promising agent for the chemoprevention of HCC, prevents liver tumorigenesis in obese and diabetic mice by inhibiting the activation of Ras and phosphorylation of ERK and RXRα proteins. ACR administration also inhibits this tumorigenesis via improvement of insulin sensitivity and attenuation of the chronic inflammation induced by excessive fatty deposits. These findings suggest that pharmaceutical and nutraceutical approaches for targeting and restoring metabolic disorders, especially insulin resistance and chronic inflammation, may be an effective strategy for preventing the development of obesity- and diabetes-related HCC. We indicate that BCAA and ACR are considered some of the most promising agents for achieving this purpose. Citation Format: Masahito Shimizu, Hisataka Moriwaki. Chemoprevention of obesity- and diabetes-related liver carcinogenesis by branched-chain amino acids and acyclic retinoid. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B55.