Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis

International Journal of Molecular Sciences

Volumn 13, Issue 1, 2012, Pages 579-595

  Shimizu, Masahito ^a   Kubota, Masaya ^a   Tanaka, Takuji ^b   Moriwaki, Hisataka ^a  

^a GIFU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b Tohkai Cytopathology Institute: Cancer Research and Prevention   (Japan)

Author keywords

Branched chain amino acids; Chemoprevention; Colorectal cancer; Green tea catechins; Hepatocellular carcinoma; Obesity

Indexed keywords

BRANCHED CHAIN AMINO ACID; CATECHIN; EPIGALLOCATECHIN GALLATE; GREEN TEA CATECHIN; NUTRACEUTICAL; SOMATOMEDIN C; SOMATOMEDIN C RECEPTOR; UNCLASSIFIED DRUG; CYTOKINE;

ANTIDIABETIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CARCINOGENESIS; CHEMOPROPHYLAXIS; CHRONIC INFLAMMATION; CHRONIC LIVER DISEASE; COLORECTAL CANCER; COLORECTAL CARCINOGENESIS; DIET SUPPLEMENTATION; DRUG TARGETING; HUMAN; INSULIN RESISTANCE; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FAILURE; METABOLIC DISORDER; NONHUMAN; NUTRITION; OBESITY; PROTEIN MALNUTRITION; RISK REDUCTION; ANTAGONISTS AND INHIBITORS; COLORECTAL NEOPLASMS; COMPLICATION; LIVER NEOPLASMS; METABOLISM; PATHOPHYSIOLOGY; RISK FACTOR;

AMINO ACIDS, BRANCHED-CHAIN; CARCINOGENESIS; CATECHIN; COLORECTAL NEOPLASMS; CYTOKINES; DIETARY SUPPLEMENTS; HUMANS; LIVER NEOPLASMS; OBESITY; RISK FACTORS;

EID: 84863030134     PISSN: None     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms13010579     Document Type: Article

References (104)

1. WHO: World Health Organization Fact Sheet for World Wide Prevalence of Obesity. Available online: http://www.who.int/mediacentre/factsheets/fs311/en/indexhtml(accessed on 27 December 2011).
2. Calle, E.E.; Kaaks, R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 2004, 4, 579-591.
3. Anderson, A.S.; Caswell, S. Obesity management-An opportunity for cancer prevention. Surgeon 2009, 7, 282-285.
4. Giovannucci, E.; Michaud, D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 2007, 132, 2208-2225.
5. Frezza, E.E.; Wachtel, M.S.; Chiriva-Internati, M. Influence of obesity on the risk of developing colon cancer. Gut 2006, 55, 285-291.
6. El-Serag, H.B.; Rudolph, K.L. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007, 132, 2557-2576.
7. El-Serag, H.B.; Tran, T.; Everhart, J.E. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004, 126, 460-468.
8. Muto, Y.; Sato, S.; Watanabe, A.; Moriwaki, H.; Suzuki, K.; Kato, A.; Kato, M.; Nakamura, T.; Higuchi, K.; Nishiguchi, S, et al. Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched-chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis. Hepatol. Res. 2006, 35, 204-214.
9. World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical activity, and the Prevention of Cancer: A Global Perspective 2007; AICR: Washington, DC, USA, 2007.
10. Renehan, A.G.; Tyson, M.; Egger, M.; Heller, R.F.; Zwahlen, M. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008, 371, 569-578.
11. Calle, E.E.; Rodriguez, C.; Walker-Thurmond, K.; Thun, M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003, 348, 1625-1638.
12. Yasuda, Y.; Shimizu, M.; Shirakami, Y.; Sakai, H.; Kubota, M.; Hata, K.; Hirose, Y.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci. 2010, 101, 1701-1707.
13. Shimizu, M.; Yasuda, Y.; Sakai, H.; Kubota, M.; Terakura, D.; Baba, A.; Ohno, T.; Kochi, T.; Tsurumi, H.; Tanaka, T, et al. Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 2011, 11, doi: 10.1186/1471-2407-11-281.
14. Kubota, M.; Shimizu, M.; Sakai, H.; Yasuda, Y.; Ohno, T.; Kochi, T.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Biochem. Biophys. Res. Commun. 2011, 410, 108-113.
15. Kao, Y.H.; Chang, H.H.; Lee, M.J.; Chen, C.L. Tea, obesity, and diabetes. Mol. Nutr. Food Res. 2006, 50, 188-210.
16. Yang, C.S.; Wang, X.; Lu, G.; Picinich, S.C. Cancer prevention by tea: Animal studies, molecular mechanisms and human relevance. Nat. Rev. Cancer 2009, 9, 429-439.
17. Shimizu, M.; Shirakami, Y.; Moriwaki, H. Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG. Int. J. Mol. Sci. 2008, 9, 1034-1049.
18. Shimizu, M.; Adachi, S.; Masuda, M.; Kozawa, O.; Moriwaki, H. Cancer chemoprevention with green tea catechins by targeting receptor tyrosine kinases. Mol. Nutr. Food Res. 2011, 55, 832-843.
19. Shimizu, M.; Weinstein, I.B. Modulation of signal transduction by tea catechins and related phytochemicals. Mutat. Res. 2005, 591, 147-160.
20. Muto, Y.; Sato, S.; Watanabe, A.; Moriwaki, H.; Suzuki, K.; Kato, A.; Kato, M.; Nakamura, T.; Higuchi, K.; Nishiguchi, S. et al. Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin. Gastroenterol. Hepatol. 2005, 3, 705-713.
21. Marchesini, G.; Bianchi, G.; Merli, M.; Amodio, P.; Panella, C.; Loguercio, C.; Fanelli, F.R.; Abbiati, R.; Italian BCAA Study Group. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: A double-blind, randomized trial. Gastroenterology 2003, 124, 1792-1801.
22. Kawaguchi, T.; Nagao, Y.; Matsuoka, H.; Ide, T.; Sata, M. Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int. J. Mol. Med. 2008, 22, 105-112.
23. Chang, C.K.; Ulrich, C.M. Hyperinsulinaemia and hyperglycaemia: Possible risk factors of colorectal cancer among diabetic patients. Diabetologia 2003, 46, 595-607.
24. Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 2008, 8, 915-928.
25. Clayton, P.E.; Banerjee, I.; Murray, P.G.; Renehan, A.G. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat. Rev. Endocrinol. 2011, 7, 11-24.
26. Bjork, J.; Nilsson, J.; Hultcrantz, R.; Johansson, C. Growth-regulatory effects of sensory neuropeptides, epidermal growth factor, insulin, and somatostatin on the non-transformed intestinal epithelial cell line IEC-6 and the colon cancer cell line HT 29. Scand. J. Gastroenterol. 1993, 28, 879-884.
27. Tran, T.T.; Medline, A.; Bruce, W.R. Insulin promotion of colon tumors in rats. Cancer Epidemiol. Biomark. Prev. 1996, 5, 1013-1015.
28. Singh, P.; Rubin, N. Insulinlike growth factors and binding proteins in colon cancer. Gastroenterology 1993, 105, 1218-1237.
29. Kajantie, E.; Fall, C.H.; Seppala, M.; Koistinen, R.; Dunkel, L.; Yliharsila, H.; Osmond, C.; Andersson, S.; Barker, D.J.; Forsen, T, et al. Serum insulin-like growth factor (IGF)-I and IGF-binding protein-1 in elderly people: Relationships with cardiovascular risk factors, body composition, size at birth, and childhood growth. J. Clin. Endocrinol. Metab. 2003, 88, 1059-1065.
30. Esposito, K.; Nappo, F.; Marfella, R.; Giugliano, G.; Giugliano, F.; Ciotola, M.; Quagliaro, L.; Ceriello, A.; Giugliano, D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: Role of oxidative stress. Circulation 2002, 106, 2067-2072.
31. Hotamisligil, G.S.; Shargill, N.S.; Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: Direct role in obesity-linked insulin resistance. Science 1993, 259, 87-91.
32. Hotamisligil, G.S.; Peraldi, P.; Budavari, A.; Ellis, R.; White, M.F.; Spiegelman, B.M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996, 271, 665-668.
33. Kern, P.A.; Ranganathan, S.; Li, C.; Wood, L.; Ranganathan, G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 2001, 280, E745-E751.
34. Szlosarek, P.; Charles, K.A.; Balkwill, F.R. Tumour necrosis factor-alpha as a tumour promoter. Eur. J. Cancer 2006, 42, 745-750.
35. Valko, M.; Izakovic, M.; Mazur, M.; Rhodes, C.J.; Telser, J. Role of oxygen radicals in DNA damage and cancer incidence. Mol. Cell. Biochem. 2004, 266, 37-56.
36. Leslie, N.R. The redox regulation of PI 3-kinase-dependent signaling. Antioxid. Redox Signal. 2006, 8, 1765-1774.
37. Considine, R.V.; Sinha, M.K.; Heiman, M.L.; Kriauciunas, A.; Stephens, T.W.; Nyce, M.R.; Ohannesian, J.P.; Marco, C.C.; McKee, L.J.; Bauer, T.L, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 1996, 334, 292-295.
38. Barb, D.; Williams, C.J.; Neuwirth, A.K.; Mantzoros, C.S. Adiponectin in relation to malignancies: A review of existing basic research and clinical evidence. Am. J. Clin. Nutr. 2007, 86, s858-s866.
39. Amemori, S.; Ootani, A.; Aoki, S.; Fujise, T.; Shimoda, R.; Kakimoto, T.; Shiraishi, R.; Sakata, Y.; Tsunada, S.; Iwakiri, R, et al. Adipocytes and preadipocytes promote the proliferation of colon cancer cells in vitro. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 292, G923-G929.
40. Stattin, P.; Lukanova, A.; Biessy, C.; Soderberg, S.; Palmqvist, R.; Kaaks, R.; Olsson, T.; Jellum, E. Obesity and colon cancer: Does leptin provide a link? Int. J. Cancer 2004, 109, 149-152.
41. Faggioni, R.; Feingold, K.R.; Grunfeld, C. Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J. 2001, 15, 2565-2571.
42. Molina, A.; Vendrell, J.; Gutierrez, C.; Simon, I.; Masdevall, C.; Soler, J.; Gomez, J.M. Insulin resistance, leptin and TNF-alpha system in morbidly obese women after gastric bypass. Obes. Surg. 2003, 13, 615-621.
43. Fenton, J.I.; Hursting, S.D.; Perkins, S.N.; Hord, N.G. Interleukin-6 production induced by leptin treatment promotes cell proliferation in an ApcMin/+ colon epithelial cell line. Carcinogenesis 2006, 27, 1507-1515.
44. Kang, S.; Song, J.; Kang, H.; Kim, S.; Lee, Y.; Park, D. Insulin can block apoptosis by decreasing oxidative stress via phosphatidylinositol 3-kinase- and extracellular signal-regulated protein kinase-dependent signaling pathways in HepG2 cells. Eur. J. Endocrinol. 2003, 148, 147-155.
45. Tornkvist, A.; Parpal, S.; Gustavsson, J.; Stralfors, P. Inhibition of Raf-1 kinase expression abolishes insulin stimulation of DNA synthesis in H4IIE hepatoma cells. J. Biol. Chem. 1994, 269, 13919-13921.
46. Imai, K.; Takai, K.; Nishigaki, Y.; Shimizu, S.; Naiki, T.; Hayashi, H.; Uematsu, T.; Sugihara, J.; Tomita, E.; Shimizu, M, et al. Insulin resistance raises the risk for recurrence of stage I hepatocellular carcinoma after curative radiofrequency ablation in hepatitis C virus-positive patients: A prospective, case series study. Hepatol. Res. 2010, 40, 376-382.
47. Powell, E.E.; Jonsson, J.R.; Clouston, A.D. Steatosis: Co-factor in other liver diseases. Hepatology 2005, 42, 5-13.
48. Alexia, C.; Fallot, G.; Lasfer, M.; Schweizer-Groyer, G.; Groyer, A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem. Pharmacol. 2004, 68, 1003-1015.
49. Shimizu, M.; Shirakami, Y.; Sakai, H.; Tatebe, H.; Nakagawa, T.; Hara, Y.; Weinstein, I.B.; Moriwaki, H. EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett. 2008, 262, 10-18.
50. Chen, C.; Chang, Y.C.; Liu, C.L.; Liu, T.P.; Chang, K.J.; Guo, I.C. Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway. Endocr. Relat. Cancer 2007, 14, 513-529.
51. Watanabe, N.; Takai, K.; Imai, K.; Shimizu, M.; Naiki, T.; Nagaki, M.; Moriwaki, H. Increased levels of serum leptin are a risk factor for the recurrence of stage I/II hepatocellular carcinoma after curative treatment. J. Clin. Biochem. Nutr. 2011, 49, 153-158.
52. Angulo, P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 2002, 346, 1221-1231.
53. Siegel, A.B.; Zhu, A.X. Metabolic syndrome and hepatocellular carcinoma: Two growing epidemics with a potential link. Cancer 2009, 115, 5651-5661.
54. Ratziu, V.; Bonyhay, L.; Di Martino, V.; Charlotte, F.; Cavallaro, L.; Sayegh-Tainturier, M.H.; Giral, P.; Grimaldi, A.; Opolon, P.; Poynard, T. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002, 35, 1485-1493.
55. Day, C.P.; James, O.F. Steatohepatitis: A tale of two "hits"? Gastroenterology 1998, 114, 842-845.
56. Chitturi, S.; Abeygunasekera, S.; Farrell, G.C.; Holmes-Walker, J.; Hui, J.M.; Fung, C.; Karim, R.; Lin, R.; Samarasinghe, D.; Liddle, C, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002, 35, 373-379.
57. Feldstein, A.E.; Werneburg, N.W.; Canbay, A.; Guicciardi, M.E.; Bronk, S.F.; Rydzewski, R.; Burgart, L.J.; Gores, G.J. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004, 40, 185-194.
58. Crespo, J.; Cayon, A.; Fernandez-Gil, P.; Hernandez-Guerra, M.; Mayorga, M.; Dominguez-Diez, A.; Fernandez-Escalante, J.C.; Pons-Romero, F. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 2001, 34, 1158-1163.
59. Chitturi, S.; Farrell, G.; Frost, L.; Kriketos, A.; Lin, R.; Fung, C.; Liddle, C.; Samarasinghe, D.; George, J. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: A manifestation of lipotoxicity? Hepatology 2002, 36, 403-409.
60. Wong, V.W.; Wong, G.L.; Tsang, S.W.; Fan, T.; Chu, W.C.; Woo, J.; Chan, A.W.; Choi, P.C.; Chim, A.M.; Lau, J.Y, et al. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut 2011, 60, 829-836.
61. Hursel, R.; Viechtbauer, W.; Westerterp-Plantenga, M.S. The effects of green tea on weight loss and weight maintenance: A meta-analysis. Int. J. Obes. 2009, 33, 956-961.
62. Rains, T.M.; Agarwal, S.; Maki, K.C. Antiobesity effects of green tea catechins: A mechanistic review. J. Nutr. Biochem. 2011, 22, 1-7.
63. Grove, K.A.; Lambert, J.D. Laboratory, epidemiological, and human intervention studies show that tea (Camellia sinensis) may be useful in the prevention of obesity. J. Nutr. 2010, 140, 446-453.
64. Thielecke, F.; Boschmann, M. The potential role of green tea catechins in the prevention of the metabolic syndrome-A review. Phytochemistry 2009, 70, 11-24.
65. Ramadan, G.; El-Beih, N.M.; El-Ghffar, E.A.A. Modulatory effects of black v. green tea aqueous extract on hyperglycaemia, hyperlipidaemia and liver dysfunction in diabetic and obese rat models. Br. J. Nutr. 2009, 102, 1611-1619.
66. Murase, T.; Nagasawa, A.; Suzuki, J.; Hase, T.; Tokimitsu, I. Beneficial effects of tea catechins on diet-induced obesity: Stimulation of lipid catabolism in the liver. Int. J. Obes. 2002, 26, 1459-1464.
67. Bose, M.; Lambert, J.D.; Ju, J.; Reuhl, K.R.; Shapses, S.A.; Yang, C.S. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J. Nutr. 2008, 138, 1677-1683.
68. Qin, B.; Polansky, M.M.; Harry, D.; Anderson, R.A. Green tea polyphenols improve cardiac muscle mRNA and protein levels of signal pathways related to insulin and lipid metabolism and inflammation in insulin-resistant rats. Mol. Nutr. Food Res. 2010, 54, S14-S23.
69. Bettuzzi, S.; Brausi, M.; Rizzi, F.; Castagnetti, G.; Peracchia, G.; Corti, A. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: A preliminary report from a one-year proof-of-principle study. Cancer Res. 2006, 66, 1234-1240.
70. Li, N.; Sun, Z.; Han, C.; Chen, J. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc. Soc. Exp. Biol. Med. 1999, 220, 218-224.
71. Shimizu, M.; Fukutomi, Y.; Ninomiya, M.; Nagura, K.; Kato, T.; Araki, H.; Suganuma, M.; Fujiki, H.; Moriwaki, H. Green tea extracts for the prevention of metachronous colorectal adenomas: A pilot study. Cancer Epidemiol. Biomark. Prev. 2008, 17, 3020-3025.
72. Shirakami, Y.; Shimizu, M.; Tsurumi, H.; Hara, Y.; Tanaka, T.; Moriwaki, H. EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS. Mol. Med. Rep. 2008, 1, 355-361.
73. Adachi, S.; Nagao, T.; Ingolfsson, H.I.; Maxfield, F.R.; Andersen, O.S.; Kopelovich, L.; Weinstein, I.B. The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells. Cancer Res. 2007, 67, 6493-6501.
74. Adachi, S.; Nagao, T.; To, S.; Joe, A.K.; Shimizu, M.; Matsushima-Nishiwaki, R.; Kozawa, O.; Moriwaki, H.; Maxfield, F.R.; Weinstein, I.B. (-)-Epigallocatechin gallate causes internalization of the epidermal growth factor receptor in human colon cancer cells. Carcinogenesis 2008, 29, 1986-1993.
75. Shimizu, M.; Deguchi, A.; Hara, Y.; Moriwaki, H.; Weinstein, I.B. EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem. Biophys. Res. Commun. 2005, 334, 947-953.
76. Yasuda, Y.; Shimizu, M.; Sakai, H.; Iwasa, J.; Kubota, M.; Adachi, S.; Osawa, Y.; Tsurumi, H.; Hara, Y.; Moriwaki, H. (-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. Chem. Biol. Interact. 2009, 182, 159-164.
77. Moriwaki, H.; Miwa, Y.; Tajika, M.; Kato, M.; Fukushima, H.; Shiraki, M. Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem. Biophys. Res. Commun. 2004, 313, 405-409.
78. Kawaguchi, T.; Izumi, N.; Charlton, M.R.; Sata, M. Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology 2011, 54, 1063-1070.
79. Petrides, A.S.; Vogt, C.; Schulze-Berge, D.; Matthews, D.; Strohmeyer, G. Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 1994, 19, 616-627.
80. Mehta, S.H.; Brancati, F.L.; Sulkowski, M.S.; Strathdee, S.A.; Szklo, M.; Thomas, D.L. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann. Intern. Med. 2000, 133, 592-599.
81. She, P.; Reid, T.M.; Bronson, S.K.; Vary, T.C.; Hajnal, A.; Lynch, C.J.; Hutson, S.M. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. 2007, 6, 181-194.
82. Zhang, Y.; Guo, K.; LeBlanc, R.E.; Loh, D.; Schwartz, G.J.; Yu, Y.H. Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 2007, 56, 1647-1654.
83. Ikehara, O.; Kawasaki, N.; Maezono, K.; Komatsu, M.; Konishi, A. Acute and chronic treatment of L-isoleucine ameliorates glucose metabolism in glucose-intolerant and diabetic mice. Biol. Pharm. Bull. 2008, 31, 469-472.
84. Higuchi, N.; Kato, M.; Miyazaki, M.; Tanaka, M.; Kohjima, M.; Ito, T.; Nakamuta, M.; Enjoji, M.; Kotoh, K.; Takayanagi, R. Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liver. J. Cell. Biochem. 2011, 112, 30-38.
85. Hinault, C.; Mothe-Satney, I.; Gautier, N.; Lawrence, J.C., Jr.; van Obberghen, E. Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice. FASEB J. 2004, 18, 1894-1896.
86. Nishitani, S.; Takehana, K.; Fujitani, S.; Sonaka, I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G1292-G1300.
87. Arakawa, M.; Masaki, T.; Nishimura, J.; Seike, M.; Yoshimatsu, H. The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice. Endocr. J. 2011, 58, 161-170.
88. Nishimura, J.; Masaki, T.; Arakawa, M.; Seike, M.; Yoshimatsu, H. Isoleucine prevents the accumulation of tissue triglycerides and upregulates the expression of PPARalpha and uncoupling protein in diet-induced obese mice. J. Nutr. 2010, 140, 496-500.
89. Sakaida, I.; Tsuchiya, M.; Okamoto, M.; Okita, K. Late evening snack and the change of blood glucose level in patients with liver cirrhosis. Hepatol. Res. 2004, 30, 67-72.
90. Urata, Y.; Okita, K.; Korenaga, K.; Uchida, K.; Yamasaki, T.; Sakaida, I. The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol. Res. 2007, 37, 510-516.
91. Hagiwara, A.; Nishiyama, M.; Ishizaki, S. Branched-chain amino acids prevent insulin-induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2-dependent mechanisms. J. Cell. Physiol. 2011, doi: 10.1002/jcp.22941.
92. Forte, A.; de Sanctis, R.; Leonetti, G.; Manfredelli, S.; Urbano, V.; Bezzi, M. Dietary chemoprevention of colorectal cancer. Ann. Ital. Chir. 2008, 79, 261-267.
93. Hirose, Y.; Hata, K.; Kuno, T.; Yoshida, K.; Sakata, K.; Yamada, Y.; Tanaka, T.; Reddy, B.S.; Mori, H. Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Carcinogenesis 2004, 25, 821-825.
94. Lee, G.H.; Proenca, R.; Montez, J.M.; Carroll, K.M.; Darvishzadeh, J.G.; Lee, J.I.; Friedman, J.M. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996, 379, 632-635.
95. Shimizu, M.; Shirakami, Y.; Sakai, H.; Adachi, S.; Hata, K.; Hirose, Y.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. (-)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. Cancer Prev. Res. 2008, 1, 298-304.
96. Suzuki, R.; Kohno, H.; Yasui, Y.; Hata, K.; Sugie, S.; Miyamoto, S.; Sugawara, K.; Sumida, T.; Hirose, Y.; Tanaka, T. Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice. Int. J. Cancer 2007, 120, 252-258.
97. Hayashi, K.; Suzuki, R.; Miyamoto, S.; Shin-Ichiroh, Y.; Kohno, H.; Sugie, S.; Takashima, S.; Tanaka, T. Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice. Nutr. Cancer 2007, 58, 75-84.
98. Miyamoto, S.; Yasui, Y.; Ohigashi, H.; Tanaka, T.; Murakami, A. Dietary flavonoids suppress azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Chem. Biol. Interact. 2010, 183, 276-283.
99. Shimizu, M.; Shirakami, Y.; Iwasa, J.; Shiraki, M.; Yasuda, Y.; Hata, K.; Hirose, Y.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Clin. Cancer Res. 2009, 15, 3068-3075.
100. Gupta, R.A.; Dubois, R.N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat. Rev. Cancer 2001, 1, 11-21.
101. Iwasa, J.; Shimizu, M.; Shiraki, M.; Shirakami, Y.; Sakai, H.; Terakura, Y.; Takai, K.; Tsurumi, H.; Tanaka, T.; Moriwaki, H. Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci. 2010, 101, 460-467.
102. db mice. Cancer Prev. Res. 2011, 4, 128-136.
103. Shimizu, M.; Sakai, H.; Shirakami, Y.; Yasuda, Y.; Kubota, M.; Terakura, D.; Baba, A.; Ohno, T.; Hara, Y.; Tanaka, T, et al. Preventive Effects of (-)-Epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Prev. Res. 2011, 4, 396-403.
104. Yoshiji, H.; Noguchi, R.; Kitade, M.; Kaji, K.; Ikenaka, Y.; Namisaki, T.; Yoshii, J.; Yanase, K.; Yamazaki, M.; Tsujimoto, T, et al. Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J. Gastroenterol. 2009, 44, 483-491.