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.

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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.

Clinical impact of protein-energy malnutrition (PEM) on the outcome of liver cirrhosis is well documented. As a candidate interventional modality to improve PEM in cirrhosis, effects of branched-chain amino acid (BCAA) supplementation on event-free survival and quality of life (QOL) was first reported by Yoshida et al. in 1989. Although critical arguments still continue regarding the effects of BCAA, several randomized trials in the last 5 years have brought positive results, and seem to have settled the discussion in a favorable direction for the efficacy of BCAA in liver cirrhosis. Actually, The European Society for Clinical Nutrition and Metabolism (ESPEN) upgraded the recommendation of BCAA supplementation in decompensated liver cirrhosis in the latest revision of its guidelines in 2006, by referring to the literatures from Italy and Japan. Particularly in these two long-term randomized studies with 1-2 years-supplementation, event-free survival was estimated by employing composite endpoints such as aggravation of hepatic failure (ascites, peripheral edema, hepatic encephalopathy, and jaundice), rupture of esophageal or gastric varices, development of liver cancer, and death from any cause. Both trials agreed on the effect of BCAA to reduce the incidence of hepatic failure, thus contributing to the rise in the event-free survival. Quality of life is another essential marker of outcome survey. Marchesini, Muto, and Nakaya reported the improved QOL in cirrhotics with BCAA supplementation. In particular, quantitative analysis of QOL measured by Short Form 36 (SF-36) questionnaire demonstrated a significant recovery of general heath perception score in BCAA supplemented patients in a randomized trial. In this article, the long-term outcome of BCAA treatment in liver cirrhosis will be reviewed with its action mechanisms. In addition, the effects of BCAA treatment on the incidence of liver cancer in obese patients with type C liver cirrhosis, significance of obesity as a risk factor for type C liver cancer, and a possible role of Body Mass Index to estimate the histological grade of fat deposition in the liver will be briefly discussed.

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Summary Energy malnutrition worsens survival in patients with liver cirrhosis, and is currently defined as non-protein respiratory quotient (npRQ) Ͻ 0.85, as measured by indirect calorimetry. However, measurement of this npRQ is limited because of the high cost of indirect calorimetry. Therefore, we sought an alternative marker that can be used in the routine clinical setting. Forty-four inpatients with cirrhosis were recruited in this study. The last meal was served at 18:00 h on the previous day, and indirect calorimetry was performed between 07:00 and 09:00 h while the patients were still in bed. Fasting blood samples were collected in the early morning on the day of the test. Anthropometry was performed by an expert dietician. The correlations among npRQ, Child-Pugh score of disease severity, laboratory parameters, %AC (arm circumference), %TSF (triceps skinfold thickness), and %AMC (arm muscle circumference) were studied using simple linear regression analysis. ROC (Receviver operating characteristic) analysis was used to identify the cut-off values that would best predict npRQ ϭ 0.85. npRQ correlated significantly with %AC ( r 2 ϭ 0.204, p ϭ 0.0021) and %AMC ( r 2 ϭ 0.178, p ϭ 0.0043) but not with %TSF. npRQ was not significantly correlated with other laboratory or anthropometric measurements. The cut-off value for %AC that showed the largest AUC (area under the curve) by ROC analysis was 95, while that for %AMC was 92. Multiple regression analysis yielded an equation; npRQ ϭ 0.0019 ϫ (%AC) Ϫ 0.0134 ϫ (Child-Pugh score) ϩ 0.7791. Patient stratification by %AC ϭ 95 or by regression equation-based npRQ ϭ 0.85, but not by %AMC ϭ 92, produced significant difference in survival curves. %AC and regression equation could represent npRQ to some extent as parameters of energy nutrition in cirrhosis. Key Words indirect calorimetry, protein-energy malnutrition, non-protein respiratory quotient, arm circumference, arm muscle circumference Protein-energy malnutrition (PEM) is common in patients with liver cirrhosis ( 1 , 2 ), and leads to poor prognosis in this cohort ( 3-5 ). Indirect calorimetry is an established method to diagnose energy malnutrition ( 6 ) as it gives substrate oxidation rates and non-protein respiratory quotient (npRQ) as useful markers to estimate energy metabolism. In particular, npRQ Ͻ 0.85, obtained in patients with liver cirrhosis after overnight bed-rest and fasting, predicted significantly lower survival than in patients with higher scores ( 5 ). Such patients with energy malnutrition are good candidates to receive nutrition support as recommended in US, European, and Japanese guidelines ( 7-9 ). However, measurement of npRQ is limited in daily practice because of the high cost of indirect calorimetry. Thus, it is important to find an alternative marker to npRQ that can be used in the routine clinical setting. We conducted the present study to investigate which anthropometric or biochemical parameters could best represent npRQ in cirrhosis. PATIENTS AND METHODSPatients. Forty-four inpatients...