Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL ⁄ KsJ-db ⁄ db (db ⁄ db) mice with diabetes mellitus. Male db ⁄ db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of a-smooth muscle actin in the DEN-treated db ⁄ db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice. (Cancer Sci 2010; 101: 460-467) H epatocellular carcinoma is a major health problem worldwide. The development of HCC is frequently associated with chronic inflammation of the liver induced by a persistent infection with the hepatitis B virus or hepatitis C virus.(1) The risk of HCC is also elevated in those with metabolic syndrome, also called insulin resistance syndrome, which is commonly associated with obesity and impaired glucose tolerance.(1-4) Non-alcoholic fatty liver disease is known to be a hepatic manifestation of the metabolic syndrome. Diabetes mellitus, a condition associated with hyperinsulinemia, has been proposed as a risk factor for both chronic liver disease and HCC through the development of NASH, which is observed in a subset of patients with non-alcoholic fatty liver disease and involves inflammation, cell damage, and ⁄ or fibrosis in the liver.(5-7) In 1998, Day and James proposed, in their ''two hit theory,'' that insulin resistance is regarded as a critical factor in the etiology of NASH. (8) C57BL ⁄ KsJ-db ⁄ db (db ⁄ db) mice are a genetically altered animal model with phenotypes of obesity and diabetes mellitus. A functional defect in t...
Purpose: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia. Experimental Design: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content^matched control diet, for 7 weeks. Results: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and h-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet^fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3h, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA. Conclusion: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.
Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1β, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.
Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) a 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 RXRa, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J-þLepr db /þLepr 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 signalregulated kinase) and RXRa proteins in the livers of experimental mice. It also increased the expression of RARb 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-a and the expression levels of TNF-a, IL-6, and IL-1b mRNA in the livers of DENtreated 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.
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