Skip to main content
Top
Published in: Seminars in Immunopathology 2/2013

01-03-2013 | Review

Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis

Authors: Masahito Shimizu, Takuji Tanaka, Hisataka Moriwaki

Published in: Seminars in Immunopathology | Issue 2/2013

Login to get access

Abstract

Obesity and related metabolic abnormalities, including a state of chronic inflammation, increase the risk of hepatocellular carcinoma (HCC). Adipose tissue constitutively expresses the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are important tumor promoters in inflammation-related carcinogenesis. Dysregulation of TNF-α and IL-6 is associated with the development of steatosis and inflammation within the liver. These cytokines also lie at the core of the association between obesity and insulin resistance, which is a key factor in the development of obesity-related HCC. Here we present a detailed review of the relationship between metabolic abnormalities and the development of HCC, focusing on the role played by inflammation. Drawing from our basic and clinical research, the present report also reviews evidence that targeting metabolic abnormalities, such as attenuation of chronic inflammation and improvement of insulin resistance by either pharmaceutical or nutritional intervention, may be an effective strategy in preventing the development of HCC in obese individuals.
Literature
3.
go back to reference Siegel AB, Zhu AX (2009) Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 115(24):5651–5661PubMedCrossRef Siegel AB, Zhu AX (2009) Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer 115(24):5651–5661PubMedCrossRef
4.
go back to reference Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4(8):579–591PubMedCrossRef Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4(8):579–591PubMedCrossRef
5.
go back to reference Anderson AS, Caswell S (2009) Obesity management—an opportunity for cancer prevention. Surgeon 7(5):282–285PubMedCrossRef Anderson AS, Caswell S (2009) Obesity management—an opportunity for cancer prevention. Surgeon 7(5):282–285PubMedCrossRef
7.
go back to reference El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576PubMedCrossRef El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576PubMedCrossRef
8.
go back to reference El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126(2):460–468PubMedCrossRef El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126(2):460–468PubMedCrossRef
9.
go back to reference Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB (2005) Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 54(4):533–539PubMedCrossRef Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB (2005) Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 54(4):533–539PubMedCrossRef
10.
go back to reference El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4(3):369–380PubMedCrossRef El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4(3):369–380PubMedCrossRef
11.
go back to reference Wang P, Kang D, Cao W, Wang Y, Liu Z (2012) Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 28(2):109–122PubMedCrossRef Wang P, Kang D, Cao W, Wang Y, Liu Z (2012) Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 28(2):109–122PubMedCrossRef
12.
go back to reference Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Ohashi Y, Long-Term Survival Study Group (2006) 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 35(3):204–214PubMed Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Ohashi Y, Long-Term Survival Study Group (2006) 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 35(3):204–214PubMed
13.
go back to reference Imai K, Takai K, Nishigaki Y, Shimizu S, Naiki T, Hayashi H, Uematsu T, Sugihara J, Tomita E, Shimizu M, Nagaki M, Moriwaki H (2010) 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 40(4):376–382PubMedCrossRef Imai K, Takai K, Nishigaki Y, Shimizu S, Naiki T, Hayashi H, Uematsu T, Sugihara J, Tomita E, Shimizu M, Nagaki M, Moriwaki H (2010) 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 40(4):376–382PubMedCrossRef
14.
go back to reference Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97(7):1005–1008PubMed Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97(7):1005–1008PubMed
15.
go back to reference Nair S, Mason A, Eason J, Loss G, Perrillo RP (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36(1):150–155PubMedCrossRef Nair S, Mason A, Eason J, Loss G, Perrillo RP (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36(1):150–155PubMedCrossRef
16.
go back to reference Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, Degos F, Farges O, Belghiti J (2004) Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 10(2 Suppl 1):S69–S73PubMedCrossRef Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, Degos F, Farges O, Belghiti J (2004) Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 10(2 Suppl 1):S69–S73PubMedCrossRef
17.
go back to reference Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17):1625–1638PubMedCrossRef Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348(17):1625–1638PubMedCrossRef
18.
go back to reference Shimizu M, Kubota M, Tanaka T, Moriwaki H (2012) Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis. Int J Mol Sci 13(1):579–595PubMedCrossRef Shimizu M, Kubota M, Tanaka T, Moriwaki H (2012) Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis. Int J Mol Sci 13(1):579–595PubMedCrossRef
19.
go back to reference Kubota M, Shimizu M, Sakai H, Yasuda Y, Terakura D, Baba A, Ohno T, Tsurumi H, Tanaka T, Moriwaki H (2012) Preventive effects of curcumin on the development of azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db obese mice. Nutr Cancer 64(1):72–79PubMedCrossRef Kubota M, Shimizu M, Sakai H, Yasuda Y, Terakura D, Baba A, Ohno T, Tsurumi H, Tanaka T, Moriwaki H (2012) Preventive effects of curcumin on the development of azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db obese mice. Nutr Cancer 64(1):72–79PubMedCrossRef
20.
go back to reference Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H (2011) Renin–angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Biochem Biophys Res Commun 410(1):108–113PubMedCrossRef Kubota M, Shimizu M, Sakai H, Yasuda Y, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H (2011) Renin–angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Biochem Biophys Res Commun 410(1):108–113PubMedCrossRef
21.
go back to reference Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2010) Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 101(7):1701–1707PubMedCrossRef Yasuda Y, Shimizu M, Shirakami Y, Sakai H, Kubota M, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2010) Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice. Cancer Sci 101(7):1701–1707PubMedCrossRef
22.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRef Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRef
23.
go back to reference Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, Sun CA, Lu SN, Chen DS, Chen CJ (2008) Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 135(1):111–121PubMedCrossRef Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, Wang LY, Sun CA, Lu SN, Chen DS, Chen CJ (2008) Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 135(1):111–121PubMedCrossRef
24.
go back to reference Kaddai V, Negro F (2011) Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 5(4):503–516PubMedCrossRef Kaddai V, Negro F (2011) Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 5(4):503–516PubMedCrossRef
25.
go back to reference Negro F (2010) Abnormalities of lipid metabolism in hepatitis C virus infection. Gut 59(9):1279–1287PubMedCrossRef Negro F (2010) Abnormalities of lipid metabolism in hepatitis C virus infection. Gut 59(9):1279–1287PubMedCrossRef
26.
go back to reference Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ (2002) Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36(5):1206–1213PubMedCrossRef Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ (2002) Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36(5):1206–1213PubMedCrossRef
27.
go back to reference Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47(6):1856–1862PubMedCrossRef Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, de Knegt RJ, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47(6):1856–1862PubMedCrossRef
28.
go back to reference Wang CS, Yao WJ, Chang TT, Wang ST, Chou P (2009) The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses. Cancer Epidemiol Biomarkers Prev 18(7):2054–2060PubMedCrossRef Wang CS, Yao WJ, Chang TT, Wang ST, Chou P (2009) The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses. Cancer Epidemiol Biomarkers Prev 18(7):2054–2060PubMedCrossRef
29.
go back to reference Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC (2012) Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 107(1):46–52PubMedCrossRef Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC (2012) Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 107(1):46–52PubMedCrossRef
30.
go back to reference Nkontchou G, Bastard JP, Ziol M, Aout M, Cosson E, Ganne-Carrie N, Grando-Lemaire V, Roulot D, Capeau J, Trinchet JC, Vicaut E, Beaugrand M (2010) Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol 53(5):827–833PubMedCrossRef Nkontchou G, Bastard JP, Ziol M, Aout M, Cosson E, Ganne-Carrie N, Grando-Lemaire V, Roulot D, Capeau J, Trinchet JC, Vicaut E, Beaugrand M (2010) Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J Hepatol 53(5):827–833PubMedCrossRef
31.
go back to reference Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH (2009) Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci 116(7):539–564PubMedCrossRef Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH (2009) Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci 116(7):539–564PubMedCrossRef
32.
go back to reference Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140(1):124–131PubMedCrossRef Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140(1):124–131PubMedCrossRef
33.
go back to reference Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N (1999) Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107(5):450–455PubMedCrossRef Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N (1999) Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107(5):450–455PubMedCrossRef
34.
go back to reference Yang S, Lin HZ, Hwang J, Chacko VP, Diehl AM (2001) Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? Cancer Res 61(13):5016–5023PubMed Yang S, Lin HZ, Hwang J, Chacko VP, Diehl AM (2001) Hepatic hyperplasia in noncirrhotic fatty livers: is obesity-related hepatic steatosis a premalignant condition? Cancer Res 61(13):5016–5023PubMed
35.
go back to reference Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51(5):1820–1832PubMedCrossRef Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51(5):1820–1832PubMedCrossRef
36.
go back to reference Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129(1):113–121PubMedCrossRef Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129(1):113–121PubMedCrossRef
37.
go back to reference Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51(6):1972–1978PubMedCrossRef Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51(6):1972–1978PubMedCrossRef
38.
go back to reference Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K (2009) Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 24(2):248–254PubMedCrossRef Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K (2009) Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 24(2):248–254PubMedCrossRef
39.
go back to reference Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845PubMedCrossRef Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845PubMedCrossRef
40.
go back to reference Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120(5):1183–1192PubMedCrossRef Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120(5):1183–1192PubMedCrossRef
41.
go back to reference Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8(12):915–928PubMedCrossRef Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8(12):915–928PubMedCrossRef
42.
go back to reference Clayton PE, Banerjee I, Murray PG, Renehan AG (2011) Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7(1):11–24PubMedCrossRef Clayton PE, Banerjee I, Murray PG, Renehan AG (2011) Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7(1):11–24PubMedCrossRef
43.
go back to reference Kang S, Song J, Kang H, Kim S, Lee Y, Park D (2003) 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 148(1):147–155PubMedCrossRef Kang S, Song J, Kang H, Kim S, Lee Y, Park D (2003) 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 148(1):147–155PubMedCrossRef
44.
go back to reference Tornkvist A, Parpal S, Gustavsson J, Stralfors P (1994) Inhibition of Raf-1 kinase expression abolishes insulin stimulation of DNA synthesis in H4IIE hepatoma cells. J Biol Chem 269(19):13919–13921PubMed Tornkvist A, Parpal S, Gustavsson J, Stralfors P (1994) Inhibition of Raf-1 kinase expression abolishes insulin stimulation of DNA synthesis in H4IIE hepatoma cells. J Biol Chem 269(19):13919–13921PubMed
45.
go back to reference Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R (1993) Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci U S A 90(23):11217–11221PubMedCrossRef Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R (1993) Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci U S A 90(23):11217–11221PubMedCrossRef
46.
go back to reference Shimizu M, Shirakami Y, Sakai H, Tatebe H, Nakagawa T, Hara Y, Weinstein IB, Moriwaki H (2008) EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett 262:10–18PubMedCrossRef Shimizu M, Shirakami Y, Sakai H, Tatebe H, Nakagawa T, Hara Y, Weinstein IB, Moriwaki H (2008) EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett 262:10–18PubMedCrossRef
47.
go back to reference Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A (2004) 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 68(6):1003–1015PubMedCrossRef Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A (2004) 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 68(6):1003–1015PubMedCrossRef
48.
go back to reference Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Sole M, Thung S, Moyano S, Toffanin S, Minguez B, Cabellos L, Peix J, Schwartz M, Mazzaferro V, Bruix J, Llovet JM (2010) IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 52(4):550–559PubMedCrossRef Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Sole M, Thung S, Moyano S, Toffanin S, Minguez B, Cabellos L, Peix J, Schwartz M, Mazzaferro V, Bruix J, Llovet JM (2010) IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 52(4):550–559PubMedCrossRef
49.
go back to reference Iwasa J, Shimizu M, Shiraki M, Shirakami Y, Sakai H, Terakura Y, Takai K, Tsurumi H, Tanaka T, Moriwaki H (2010) Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci 101(2):460–467PubMedCrossRef Iwasa J, Shimizu M, Shiraki M, Shirakami Y, Sakai H, Terakura Y, Takai K, Tsurumi H, Tanaka T, Moriwaki H (2010) Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Sci 101(2):460–467PubMedCrossRef
50.
go back to reference Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D, Baba A, Ohno T, Hara Y, Tanaka T, Moriwaki H (2011) Preventive effects of (−)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Prev Res 4(3):396–403CrossRef Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D, Baba A, Ohno T, Hara Y, Tanaka T, Moriwaki H (2011) Preventive effects of (−)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Prev Res 4(3):396–403CrossRef
51.
go back to reference Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1(11):1155–1161PubMedCrossRef Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1(11):1155–1161PubMedCrossRef
52.
go back to reference Watanabe N, Takai K, Imai K, Shimizu M, Naiki T, Nagaki M, Moriwaki H (2011) 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 49(3):153–158PubMedCrossRef Watanabe N, Takai K, Imai K, Shimizu M, Naiki T, Nagaki M, Moriwaki H (2011) 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 49(3):153–158PubMedCrossRef
53.
go back to reference Chen C, Chang YC, Liu CL, Liu TP, Chang KJ, Guo IC (2007) 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 14(2):513–529PubMedCrossRef Chen C, Chang YC, Liu CL, Liu TP, Chang KJ, Guo IC (2007) 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 14(2):513–529PubMedCrossRef
54.
go back to reference Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67(6):2497–2507PubMedCrossRef Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA (2007) Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 67(6):2497–2507PubMedCrossRef
55.
go back to reference Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T, Sato N (2002) Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122(5):1399–1410PubMedCrossRef Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T, Sato N (2002) Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122(5):1399–1410PubMedCrossRef
56.
go back to reference Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20(6):1595–1599PubMedCrossRef Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20(6):1595–1599PubMedCrossRef
57.
go back to reference Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, Igura T, Maeda N, Kihara S, Funahashi T, Matsuzawa Y, Shimomura I, Hayashi N (2007) Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 47(4):556–564PubMedCrossRef Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, Igura T, Maeda N, Kihara S, Funahashi T, Matsuzawa Y, Shimomura I, Hayashi N (2007) Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 47(4):556–564PubMedCrossRef
58.
go back to reference Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112(1):91–100PubMed Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112(1):91–100PubMed
59.
go back to reference Saxena NK, Fu PP, Nagalingam A, Wang J, Handy J, Cohen C, Tighiouart M, Sharma D, Anania FA (2010) Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 139(5):1762–1773, 1773 e1761-1765PubMedCrossRef Saxena NK, Fu PP, Nagalingam A, Wang J, Handy J, Cohen C, Tighiouart M, Sharma D, Anania FA (2010) Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 139(5):1762–1773, 1773 e1761-1765PubMedCrossRef
60.
go back to reference Shimizu M, Yasuda Y, Sakai H, Kubota M, Terakura D, Baba A, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H (2011) Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 11(1):281PubMedCrossRef Shimizu M, Yasuda Y, Sakai H, Kubota M, Terakura D, Baba A, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H (2011) Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 11(1):281PubMedCrossRef
61.
go back to reference Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808PubMed Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808PubMed
62.
go back to reference Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830PubMed Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830PubMed
63.
go back to reference Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91PubMedCrossRef Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91PubMedCrossRef
64.
go back to reference Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity–diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 94(4):1543–1549PubMedCrossRef Hotamisligil GS, Budavari A, Murray D, Spiegelman BM (1994) Reduced tyrosine kinase activity of the insulin receptor in obesity–diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 94(4):1543–1549PubMedCrossRef
65.
go back to reference Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614PubMedCrossRef Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614PubMedCrossRef
66.
go back to reference Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208PubMedCrossRef Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208PubMedCrossRef
67.
go back to reference Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51(12):3391–3399PubMedCrossRef Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51(12):3391–3399PubMedCrossRef
68.
go back to reference Pickup JC, Mattock MB, Chusney GD, Burt D (1997) NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40(11):1286–1292PubMedCrossRef Pickup JC, Mattock MB, Chusney GD, Burt D (1997) NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40(11):1286–1292PubMedCrossRef
69.
go back to reference Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107PubMedCrossRef Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107PubMedCrossRef
70.
go back to reference Nov O, Kohl A, Lewis EC, Bashan N, Dvir I, Ben-Shlomo S, Fishman S, Wueest S, Konrad D, Rudich A (2010) Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology 151(9):4247–4256PubMedCrossRef Nov O, Kohl A, Lewis EC, Bashan N, Dvir I, Ben-Shlomo S, Fishman S, Wueest S, Konrad D, Rudich A (2010) Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology 151(9):4247–4256PubMedCrossRef
71.
go back to reference Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52(3):812–817PubMedCrossRef Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52(3):812–817PubMedCrossRef
72.
go back to reference Faggioni R, Feingold KR, Grunfeld C (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15(14):2565–2571PubMedCrossRef Faggioni R, Feingold KR, Grunfeld C (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15(14):2565–2571PubMedCrossRef
73.
go back to reference Molina A, Vendrell J, Gutierrez C, Simon I, Masdevall C, Soler J, Gomez JM (2003) Insulin resistance, leptin and TNF-alpha system in morbidly obese women after gastric bypass. Obes Surg 13(4):615–621PubMedCrossRef Molina A, Vendrell J, Gutierrez C, Simon I, Masdevall C, Soler J, Gomez JM (2003) Insulin resistance, leptin and TNF-alpha system in morbidly obese women after gastric bypass. Obes Surg 13(4):615–621PubMedCrossRef
74.
go back to reference Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190PubMedCrossRef Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190PubMedCrossRef
75.
go back to reference Solinas G, Karin M (2010) JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J 24(8):2596–2611PubMedCrossRef Solinas G, Karin M (2010) JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J 24(8):2596–2611PubMedCrossRef
76.
go back to reference Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420(6913):333–336PubMedCrossRef Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420(6913):333–336PubMedCrossRef
77.
go back to reference Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116(7):1793–1801PubMedCrossRef Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116(7):1793–1801PubMedCrossRef
78.
go back to reference Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114(12):1752–1761PubMed Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114(12):1752–1761PubMed
79.
go back to reference Solinas G, Naugler W, Galimi F, Lee MS, Karin M (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A 103(44):16454–16459PubMedCrossRef Solinas G, Naugler W, Galimi F, Lee MS, Karin M (2006) Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci U S A 103(44):16454–16459PubMedCrossRef
80.
go back to reference Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276(20):16683–16689PubMedCrossRef Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276(20):16683–16689PubMedCrossRef
81.
go back to reference Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ (2007) Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56(8):1124–1131PubMedCrossRef Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ (2007) Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56(8):1124–1131PubMedCrossRef
82.
go back to reference Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004) Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40(1):185–194PubMedCrossRef Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004) Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40(1):185–194PubMedCrossRef
83.
go back to reference Malhi H, Gores GJ (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28(4):360–369PubMedCrossRef Malhi H, Gores GJ (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28(4):360–369PubMedCrossRef
84.
go back to reference Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43(1):163–172PubMedCrossRef Schattenberg JM, Singh R, Wang Y, Lefkowitch JH, Rigoli RM, Scherer PE, Czaja MJ (2006) JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 43(1):163–172PubMedCrossRef
85.
go back to reference Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD (2009) Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 124(3):540–546PubMedCrossRef Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD (2009) Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 124(3):540–546PubMedCrossRef
86.
go back to reference Shimizu M, Sakai H, Shirakami Y, Iwasa J, Yasuda Y, Kubota M, Takai K, Tsurumi H, Tanaka T, Moriwaki H (2011) Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J-+(db)/+Lepr(db) mice. Cancer Prev Res 4(1):128–136CrossRef Shimizu M, Sakai H, Shirakami Y, Iwasa J, Yasuda Y, Kubota M, Takai K, Tsurumi H, Tanaka T, Moriwaki H (2011) Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J-+(db)/+Lepr(db) mice. Cancer Prev Res 4(1):128–136CrossRef
87.
go back to reference He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17(3):286–297PubMedCrossRef He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17(3):286–297PubMedCrossRef
88.
go back to reference Giovannucci E, Michaud D (2007) The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132(6):2208–2225PubMedCrossRef Giovannucci E, Michaud D (2007) The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology 132(6):2208–2225PubMedCrossRef
89.
go back to reference Frezza EE, Wachtel MS, Chiriva-Internati M (2006) Influence of obesity on the risk of developing colon cancer. Gut 55(2):285–291PubMedCrossRef Frezza EE, Wachtel MS, Chiriva-Internati M (2006) Influence of obesity on the risk of developing colon cancer. Gut 55(2):285–291PubMedCrossRef
90.
go back to reference Hirose Y, Hata K, Kuno T, Yoshida K, Sakata K, Yamada Y, Tanaka T, Reddy BS, Mori H (2004) Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Carcinogenesis 25(5):821–825PubMedCrossRef Hirose Y, Hata K, Kuno T, Yoshida K, Sakata K, Yamada Y, Tanaka T, Reddy BS, Mori H (2004) Enhancement of development of azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice. Carcinogenesis 25(5):821–825PubMedCrossRef
91.
go back to reference Shimizu M, Shirakami Y, Iwasa J, Shiraki M, Yasuda Y, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2009) Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Clin Cancer Res 15(9):3068–3075PubMedCrossRef Shimizu M, Shirakami Y, Iwasa J, Shiraki M, Yasuda Y, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2009) Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice. Clin Cancer Res 15(9):3068–3075PubMedCrossRef
92.
go back to reference Shimizu M, Shirakami Y, Sakai H, Adachi S, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2008) (−)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. Cancer Prev Res 1(4):298–304CrossRef Shimizu M, Shirakami Y, Sakai H, Adachi S, Hata K, Hirose Y, Tsurumi H, Tanaka T, Moriwaki H (2008) (−)-Epigallocatechin gallate suppresses azoxymethane-induced colonic premalignant lesions in male C57BL/KsJ-db/db mice. Cancer Prev Res 1(4):298–304CrossRef
93.
go back to reference Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M (2004) Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 313(2):405–409PubMedCrossRef Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M (2004) Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 313(2):405–409PubMedCrossRef
94.
go back to reference Kawaguchi T, Izumi N, Charlton MR, Sata M (2011) Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology 54(3):1063–1070PubMedCrossRef Kawaguchi T, Izumi N, Charlton MR, Sata M (2011) Branched-chain amino acids as pharmacological nutrients in chronic liver disease. Hepatology 54(3):1063–1070PubMedCrossRef
95.
go back to reference Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Long-Term Survival Study Group (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3(7):705–713PubMedCrossRef Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, Kumada H, Long-Term Survival Study Group (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3(7):705–713PubMedCrossRef
96.
go back to reference Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124(7):1792–1801PubMedCrossRef Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124(7):1792–1801PubMedCrossRef
97.
go back to reference Kao YH, Chang HH, Lee MJ, Chen CL (2006) Tea, obesity, and diabetes. Mol Nutr Food Res 50(2):188–210PubMedCrossRef Kao YH, Chang HH, Lee MJ, Chen CL (2006) Tea, obesity, and diabetes. Mol Nutr Food Res 50(2):188–210PubMedCrossRef
98.
go back to reference Hursel R, Viechtbauer W, Westerterp-Plantenga MS (2009) The effects of green tea on weight loss and weight maintenance: a meta-analysis. Int J Obes 33(9):956–961CrossRef Hursel R, Viechtbauer W, Westerterp-Plantenga MS (2009) The effects of green tea on weight loss and weight maintenance: a meta-analysis. Int J Obes 33(9):956–961CrossRef
99.
go back to reference Yang CS, Wang X, Lu G, Picinich SC (2009) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9(6):429–439PubMedCrossRef Yang CS, Wang X, Lu G, Picinich SC (2009) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9(6):429–439PubMedCrossRef
100.
go back to reference Shimizu M, Adachi S, Masuda M, Kozawa O, Moriwaki H (2011) Cancer chemoprevention with green tea catechins by targeting receptor tyrosine kinases. Mol Nutr Food Res 55(6):832–843PubMedCrossRef Shimizu M, Adachi S, Masuda M, Kozawa O, Moriwaki H (2011) Cancer chemoprevention with green tea catechins by targeting receptor tyrosine kinases. Mol Nutr Food Res 55(6):832–843PubMedCrossRef
101.
go back to reference Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T (1996) Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 334(24):1561–1567PubMedCrossRef Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E, Nakamura T, Kojima T (1996) Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 334(24):1561–1567PubMedCrossRef
102.
go back to reference Muto Y, Moriwaki H, Saito A (1999) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 340(13):1046–1047PubMedCrossRef Muto Y, Moriwaki H, Saito A (1999) Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 340(13):1046–1047PubMedCrossRef
103.
go back to reference Shimizu M, Takai K, Moriwaki H (2009) Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. Cancer Sci 100(3):369–374PubMedCrossRef Shimizu M, Takai K, Moriwaki H (2009) Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention. Cancer Sci 100(3):369–374PubMedCrossRef
104.
go back to reference Shimizu M, Sakai H, Moriwaki H (2011) Chemoprevention of hepatocellular carcinoma by acyclic retinoid. Front Biosci 16:759–769PubMedCrossRef Shimizu M, Sakai H, Moriwaki H (2011) Chemoprevention of hepatocellular carcinoma by acyclic retinoid. Front Biosci 16:759–769PubMedCrossRef
105.
go back to reference Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G (1994) Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 19(3):616–627PubMedCrossRef Petrides AS, Vogt C, Schulze-Berge D, Matthews D, Strohmeyer G (1994) Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 19(3):616–627PubMedCrossRef
106.
go back to reference Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL (2000) Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 133(8):592–599PubMed Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL (2000) Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 133(8):592–599PubMed
107.
go back to reference She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM (2007) Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab 6(3):181–194PubMedCrossRef She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM (2007) Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab 6(3):181–194PubMedCrossRef
108.
go back to reference Higuchi N, Kato M, Miyazaki M, Tanaka M, Kohjima M, Ito T, Nakamuta M, Enjoji M, Kotoh K, Takayanagi R (2011) 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 112(1):30–38PubMedCrossRef Higuchi N, Kato M, Miyazaki M, Tanaka M, Kohjima M, Ito T, Nakamuta M, Enjoji M, Kotoh K, Takayanagi R (2011) 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 112(1):30–38PubMedCrossRef
109.
go back to reference Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M (2008) Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med 22(1):105–112PubMed Kawaguchi T, Nagao Y, Matsuoka H, Ide T, Sata M (2008) Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. Int J Mol Med 22(1):105–112PubMed
110.
go back to reference Urata Y, Okita K, Korenaga K, Uchida K, Yamasaki T, Sakaida I (2007) The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res 37(7):510–516PubMedCrossRef Urata Y, Okita K, Korenaga K, Uchida K, Yamasaki T, Sakaida I (2007) The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res 37(7):510–516PubMedCrossRef
111.
go back to reference Hagiwara A, Nishiyama M, Ishizaki S (2012) Branched-chain amino acids prevent insulin-induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2-dependent mechanisms. J Cell Physiol 227(5):2097–2105PubMedCrossRef Hagiwara A, Nishiyama M, Ishizaki S (2012) Branched-chain amino acids prevent insulin-induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2-dependent mechanisms. J Cell Physiol 227(5):2097–2105PubMedCrossRef
112.
go back to reference Yoshiji H, Noguchi R, Kitade M, Kaji K, Ikenaka Y, Namisaki T, Yoshii J, Yanase K, Yamazaki M, Tsujimoto T, Akahane T, Kawaratani H, Uemura M, Fukui H (2009) Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 44(5):483–491PubMedCrossRef Yoshiji H, Noguchi R, Kitade M, Kaji K, Ikenaka Y, Namisaki T, Yoshii J, Yanase K, Yamazaki M, Tsujimoto T, Akahane T, Kawaratani H, Uemura M, Fukui H (2009) Branched-chain amino acids suppress insulin-resistance-based hepatocarcinogenesis in obese diabetic rats. J Gastroenterol 44(5):483–491PubMedCrossRef
113.
go back to reference Qin B, Polansky MM, Harry D, Anderson RA (2010) 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 54(Suppl 1):S14–S23PubMedCrossRef Qin B, Polansky MM, Harry D, Anderson RA (2010) 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 54(Suppl 1):S14–S23PubMedCrossRef
114.
go back to reference Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS (2008) The major green tea polyphenol, (−)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 138(9):1677–1683PubMed Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS (2008) The major green tea polyphenol, (−)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr 138(9):1677–1683PubMed
115.
go back to reference Ramadan G, El-Beih NM, Abd El-Ghffar E (2009) Modulatory effects of black v. green tea aqueous extract on hyperglycaemia, hyperlipidaemia and liver dysfunction in diabetic and obese rat models. Br J Nutr 102(11):1611–1619PubMedCrossRef Ramadan G, El-Beih NM, Abd El-Ghffar E (2009) Modulatory effects of black v. green tea aqueous extract on hyperglycaemia, hyperlipidaemia and liver dysfunction in diabetic and obese rat models. Br J Nutr 102(11):1611–1619PubMedCrossRef
116.
go back to reference Shirakami Y, Shimizu M, Tsurumi H, Hara Y, Tanaka T, Moriwaki H (2008) EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS. Mol Med Report 1(3):355–361PubMed Shirakami Y, Shimizu M, Tsurumi H, Hara Y, Tanaka T, Moriwaki H (2008) EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS. Mol Med Report 1(3):355–361PubMed
117.
go back to reference Shimizu M, Deguchi A, Hara Y, Moriwaki H, Weinstein IB (2005) EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem Biophys Res Commun 334(3):947–953PubMedCrossRef Shimizu M, Deguchi A, Hara Y, Moriwaki H, Weinstein IB (2005) EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem Biophys Res Commun 334(3):947–953PubMedCrossRef
118.
go back to reference Yasuda Y, Shimizu M, Sakai H, Iwasa J, Kubota M, Adachi S, Osawa Y, Tsurumi H, Hara Y, Moriwaki H (2009) (−)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. Chem Biol Interact 182(2–3):159–164PubMedCrossRef Yasuda Y, Shimizu M, Sakai H, Iwasa J, Kubota M, Adachi S, Osawa Y, Tsurumi H, Hara Y, Moriwaki H (2009) (−)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. Chem Biol Interact 182(2–3):159–164PubMedCrossRef
119.
go back to reference Shimizu M, Fukutomi Y, Ninomiya M, Nagura K, Kato T, Araki H, Suganuma M, Fujiki H, Moriwaki H (2008) Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev 17(11):3020–3025PubMedCrossRef Shimizu M, Fukutomi Y, Ninomiya M, Nagura K, Kato T, Araki H, Suganuma M, Fujiki H, Moriwaki H (2008) Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev 17(11):3020–3025PubMedCrossRef
120.
go back to reference Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A (2006) 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 66(2):1234–1240PubMedCrossRef Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A (2006) 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 66(2):1234–1240PubMedCrossRef
121.
go back to reference Li N, Sun Z, Han C, Chen J (1999) The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med 220(4):218–224PubMedCrossRef Li N, Sun Z, Han C, Chen J (1999) The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med 220(4):218–224PubMedCrossRef
122.
go back to reference Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58(4):760–772PubMedCrossRef Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58(4):760–772PubMedCrossRef
123.
go back to reference Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58(4):712–725PubMedCrossRef Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H (2006) International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58(4):712–725PubMedCrossRef
124.
go back to reference Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1(3):181–193PubMedCrossRef Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1(3):181–193PubMedCrossRef
125.
go back to reference Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H (2007) RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6(10):793–810PubMedCrossRef Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H (2007) RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov 6(10):793–810PubMedCrossRef
126.
go back to reference Ando N, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Tanaka T, Moriwaki H (2007) Expression of retinoid X receptor alpha is decreased in 3′-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma in rats. Oncol Rep 18(4):879–884PubMed Ando N, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Tanaka T, Moriwaki H (2007) Expression of retinoid X receptor alpha is decreased in 3′-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma in rats. Oncol Rep 18(4):879–884PubMed
127.
go back to reference Matsushima-Nishiwaki R, Okuno M, Adachi S, Sano T, Akita K, Moriwaki H, Friedman SL, Kojima S (2001) Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. Cancer Res 61(20):7675–7682PubMed Matsushima-Nishiwaki R, Okuno M, Adachi S, Sano T, Akita K, Moriwaki H, Friedman SL, Kojima S (2001) Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma. Cancer Res 61(20):7675–7682PubMed
128.
go back to reference Matsushima-Nishiwaki R, Okuno M, Takano Y, Kojima S, Friedman SL, Moriwaki H (2003) Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis 24(8):1353–1359PubMedCrossRef Matsushima-Nishiwaki R, Okuno M, Takano Y, Kojima S, Friedman SL, Moriwaki H (2003) Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis 24(8):1353–1359PubMedCrossRef
129.
go back to reference Adachi S, Okuno M, Matsushima-Nishiwaki R, Takano Y, Kojima S, Friedman SL, Moriwaki H, Okano Y (2002) Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma. Hepatology 35(2):332–340PubMedCrossRef Adachi S, Okuno M, Matsushima-Nishiwaki R, Takano Y, Kojima S, Friedman SL, Moriwaki H, Okano Y (2002) Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma. Hepatology 35(2):332–340PubMedCrossRef
130.
go back to reference Yoshimura K, Muto Y, Shimizu M, Matsushima-Nishiwaki R, Okuno M, Takano Y, Tsurumi H, Kojima S, Okano Y, Moriwaki H (2007) Phosphorylated retinoid X receptor alpha loses its heterodimeric activity with retinoic acid receptor beta. Cancer Sci 98(12):1868–1874PubMedCrossRef Yoshimura K, Muto Y, Shimizu M, Matsushima-Nishiwaki R, Okuno M, Takano Y, Tsurumi H, Kojima S, Okano Y, Moriwaki H (2007) Phosphorylated retinoid X receptor alpha loses its heterodimeric activity with retinoic acid receptor beta. Cancer Sci 98(12):1868–1874PubMedCrossRef
131.
go back to reference Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, Moriwaki H (2007) Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells. Cancer Sci 98(3):431–437PubMedCrossRef Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, Moriwaki H (2007) Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells. Cancer Sci 98(3):431–437PubMedCrossRef
132.
go back to reference Okita K, Matsui O, Kumada H, Tanaka K, Kaneko S, Moriwaki H, Izumi N, Okusaka T, Ohashi Y, Makuuchi M (2010) Effect of peretinoin on recurrence of hepatocellular carcinoma (HCC): results of a phase II/III randomized placebo-controlled trial. J Clin Oncol 28(Suppl 7s):4024 Okita K, Matsui O, Kumada H, Tanaka K, Kaneko S, Moriwaki H, Izumi N, Okusaka T, Ohashi Y, Makuuchi M (2010) Effect of peretinoin on recurrence of hepatocellular carcinoma (HCC): results of a phase II/III randomized placebo-controlled trial. J Clin Oncol 28(Suppl 7s):4024
Metadata
Title
Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis
Authors
Masahito Shimizu
Takuji Tanaka
Hisataka Moriwaki
Publication date
01-03-2013
Publisher
Springer-Verlag
Published in
Seminars in Immunopathology / Issue 2/2013
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-012-0336-6

Other articles of this Issue 2/2013

Seminars in Immunopathology 2/2013 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.