(2e-4e-6e-10e)-3-7-11-15-tetramethyl-2-4-6-10-14-hexadecapentaenoic-acid and Obesity

Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC.

Topics: Amino Acids, Branched-Chain; Animals; Carcinoma, Hepatocellular; Catechin; Chemoprevention; Diabetes Mellitus, Experimental; Dietary Supplements; Humans; Liver Neoplasms; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Tea; Tretinoin

Topics: Amino Acids, Branched-Chain; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Carcinoma, Hepatocellular; Diabetes Mellitus; Humans; Immunotherapy, Adoptive; Interferons; Lamivudine; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Obesity; Randomized Controlled Trials as Topic; Risk Factors; Tretinoin; Vitamin K

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.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cytokines; Diabetes Complications; Diabetes Mellitus; Diethylnitrosamine; Insulin Resistance; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; ras Proteins; Receptors, Leptin; Retinoid X Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Tretinoin