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Obesity, Inflammation, Nonalcoholic Fatty Liver Disease, and Hepatocellular Carcinoma

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References

  1. Ferlay J, Shin HR, Bray F et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917

    Article  PubMed  CAS  Google Scholar 

  2. Nordenstedt H, White DL, El-Serag HB (2010) The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 42(suppl 3):S206–S214

    Article  PubMed  Google Scholar 

  3. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127

    Article  PubMed  CAS  Google Scholar 

  4. McGlynn KA, London WT (2011) The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis 15:223–243, vii–x

    Google Scholar 

  5. Page JM, Harrison SA (2009) NASH and HCC. Clin Liver Dis 13:631–647

    Article  PubMed  Google Scholar 

  6. Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638

    Article  PubMed  Google Scholar 

  7. Moller H, Mellemgaard A, Lindvig K et al (1994) Obesity and cancer risk: a Danish record-­linkage study. Eur J Cancer 30A:344–350

    Article  PubMed  CAS  Google Scholar 

  8. Wolk A, Gridley G, Svensson M et al (2001) A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 12:13–21

    Article  PubMed  CAS  Google Scholar 

  9. El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4:369–380

    Article  PubMed  Google Scholar 

  10. El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468

    Article  PubMed  Google Scholar 

  11. Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51:1820–1832

    Article  PubMed  Google Scholar 

  12. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119

    PubMed  CAS  Google Scholar 

  13. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867

    Article  PubMed  CAS  Google Scholar 

  14. Weisberg SP, McCann D, Desai M et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    PubMed  CAS  Google Scholar 

  15. Jou J, Choi SS, Diehl AM (2008) Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 28:370–379

    Article  PubMed  CAS  Google Scholar 

  16. Wree A, Kahraman A, Gerken G et al (2010) Obesity affects the liver—the link between adipocytes and hepatocytes. Digestion 83:124–133

    Article  PubMed  Google Scholar 

  17. Alkhouri N, Dixon LJ, Feldstein AE (2009) Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev Gastroenterol Hepatol 3:445–451

    Article  PubMed  CAS  Google Scholar 

  18. Listenberger LL, Han X, Lewis SE et al (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100:3077–3082

    Article  PubMed  CAS  Google Scholar 

  19. Unger RH (2002) Lipotoxic diseases. Annu Rev Med 53:319–336

    Article  PubMed  CAS  Google Scholar 

  20. Guicciardi ME, Gores GJ (2005) Apoptosis: a mechanism of acute and chronic liver injury. Gut 54:1024–1033

    Article  PubMed  CAS  Google Scholar 

  21. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    PubMed  CAS  Google Scholar 

  22. Friedman SL (2003) Liver fibrosis—from bench to bedside. J Hepatol 38(suppl 1):S38–S53

    Article  PubMed  Google Scholar 

  23. Seitz HK, Stickel F (2006) Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 387:349–360

    Article  PubMed  CAS  Google Scholar 

  24. Zhang DY, Friedman SL (2012) Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56:769–775

    Article  PubMed  CAS  Google Scholar 

  25. Tanaka S, Mohr L, Schmidt EV et al (1997) Biological effects of human insulin receptor substrate-­1 overexpression in hepatocytes. Hepatology 26:598–604

    Article  PubMed  CAS  Google Scholar 

  26. Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    Article  PubMed  CAS  Google Scholar 

  27. Puri P, Mirshahi F, Cheung O et al (2008) Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134:568–576

    Article  PubMed  CAS  Google Scholar 

  28. Chang Q, Zhang Y, Beezhold KJ et al (2009) Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol 50:323–333

    Article  PubMed  CAS  Google Scholar 

  29. Hui L, Zatloukal K, Scheuch H et al (2008) Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest 118:3943–3953

    Article  PubMed  CAS  Google Scholar 

  30. Shen C, Zhao CY, Zhang R et al (2012) Obesity-related hepatocellular carcinoma: roles of risk factors altered in obesity. Front Biosci 17:2356–2370

    Article  PubMed  Google Scholar 

  31. Siddique A, Kowdley KV (2011) Insulin resistance and other metabolic risk factors in the pathogenesis of hepatocellular carcinoma. Clin Liver Dis 15:281–296, vii–x

    Google Scholar 

  32. Kurmasheva RT, Houghton PJ (2006) IGF-I mediated survival pathways in normal and malignant cells. Biochim Biophys Acta 1766:1–22

    PubMed  CAS  Google Scholar 

  33. Chen JS, Wang Q, Fu XH et al (2009) Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 39:177–186

    Article  PubMed  CAS  Google Scholar 

  34. Lawlor MA, Alessi DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114:2903–2910

    PubMed  CAS  Google Scholar 

  35. Nam SY, Lee EJ, Kim KR et al (1997) Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21:355–359

    Article  PubMed  CAS  Google Scholar 

  36. Aishima S, Basaki Y, Oda Y et al (2006) High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma. Cancer Sci 97:1182–1190

    Article  PubMed  CAS  Google Scholar 

  37. Huynh H, Chow PK, Ooi LL et al (2002) A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ 13:115–122

    PubMed  CAS  Google Scholar 

  38. Alison MR, Nicholson LJ, Lin WR (2011) Chronic inflammation and hepatocellular carcinoma. Recent results in cancer research. Fortschr Krebsforsch 185:135–148

    CAS  Google Scholar 

  39. Park EJ, Lee JH, Yu GY et al (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140:197–208

    Article  PubMed  CAS  Google Scholar 

  40. Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12:715–723

    Article  PubMed  CAS  Google Scholar 

  41. Pikarsky E, Porat RM, Stein I et al (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466

    Article  PubMed  CAS  Google Scholar 

  42. Luedde T, Beraza N, Kotsikoris V et al (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–132

    Article  PubMed  CAS  Google Scholar 

  43. He G, Karin M (2011) NF-kappaB and STAT3—key players in liver inflammation and cancer. Cell Res 21:159–168

    Article  PubMed  CAS  Google Scholar 

  44. He G, Yu GY, Temkin V et al (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17:286–297

    Article  PubMed  CAS  Google Scholar 

  45. Ogata H, Kobayashi T, Chinen T et al (2006) Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131:179–193

    Article  PubMed  CAS  Google Scholar 

  46. Jequier E (2002) Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci 967:379–388

    Article  PubMed  CAS  Google Scholar 

  47. Sun B, Karin M (2012) Obesity, inflammation, and liver cancer. J Hepatol 56:704–713

    Article  PubMed  CAS  Google Scholar 

  48. Saxena NK, Sharma D, Ding X et al (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 67:2497–2507

    Article  PubMed  CAS  Google Scholar 

  49. Chen C, Chang YC, Liu CL et al (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 14:513–529

    Article  PubMed  CAS  Google Scholar 

  50. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451

    Article  PubMed  CAS  Google Scholar 

  51. Hotta K, Funahashi T, Arita Y et al (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599

    Article  PubMed  CAS  Google Scholar 

  52. Jiang LL, Li L, Hong XF et al (2009) Patients with nonalcoholic fatty liver disease display increased serum resistin levels and decreased adiponectin levels. Eur J Gastroenterol Hepatol 21:662–666

    Article  PubMed  CAS  Google Scholar 

  53. Skrabal CA, Czaja J, Honz K et al (2011) Adiponectin—its potential to predict and prevent coronary artery disease. Thorac Cardiovasc Surg 59:201–206

    Article  PubMed  CAS  Google Scholar 

  54. Man K, Ng KT, Xu A et al (2010) Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling. Clin Cancer Res 16:967–977

    Article  PubMed  CAS  Google Scholar 

  55. Saxena NK, Fu PP, Nagalingam A et al (2010) Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology 139:1762–1773, 1773e1–5

    Google Scholar 

  56. Sharma D, Wang J, Fu PP et al (2010) Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 52:1713–1722

    Article  PubMed  CAS  Google Scholar 

  57. Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97:1005–1008

    PubMed  CAS  Google Scholar 

  58. Oh SW, Yoon YS, Shin SA (2005) Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 23:4742–4754

    Article  PubMed  Google Scholar 

  59. Nair S, Mason A, Eason J et al (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36:150–155

    Article  PubMed  Google Scholar 

  60. N’Kontchou G, Paries J, Htar MT et al (2006) Risk factors for hepatocellular carcinoma in patients with alcoholic or viral C cirrhosis. Clin Gastroenterol Hepatol 4:1062–1068

    Article  PubMed  Google Scholar 

  61. Ohki T, Tateishi R, Shiina S et al (2009) Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH. Gut 58:839–844

    Article  PubMed  CAS  Google Scholar 

  62. Petrides AS, Vogt C, Schulze-Berge D et al (1994) Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis. Hepatology 19:616–627

    Article  PubMed  CAS  Google Scholar 

  63. Zein CO, Levy C, Basu A et al (2005) Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol 100:48–55

    Article  PubMed  Google Scholar 

  64. Angulo P, Keach JC, Batts KP et al (1999) Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30:1356–1362

    Article  PubMed  CAS  Google Scholar 

  65. Adami HO, Chow WH, Nyren O et al (1996) Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 88:1472–1477

    Article  PubMed  CAS  Google Scholar 

  66. Wideroff L, Gridley G, Mellemkjaer L et al (1997) Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 89:1360–1365

    Article  PubMed  CAS  Google Scholar 

  67. El-Serag HB (2004) Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127:S27–S34

    Article  PubMed  Google Scholar 

  68. Wang P, Kang D, Cao W et al (2012) Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis. Diabetes Metab Res Rev 28:109–122

    Article  PubMed  Google Scholar 

  69. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210

    Article  PubMed  CAS  Google Scholar 

  70. Donadon V, Balbi M, Ghersetti M et al (2009) Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease. World J Gastroenterol 15:2506–2511

    Article  PubMed  CAS  Google Scholar 

  71. Hassan MM, Curley SA, Li D et al (2010) Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 116:1938–1946

    Article  PubMed  Google Scholar 

  72. Chen HP, Shieh JJ, Chang CC et al (2013) Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 62(4):606–615

    Google Scholar 

  73. Blanco-Colio LM, Villa A, Ortego M et al (2002) 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 161:17–26

    Article  PubMed  CAS  Google Scholar 

  74. Rombouts K, Kisanga E, Hellemans K et al (2003) Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells. J Hepatol 38:564–572

    Article  PubMed  CAS  Google Scholar 

  75. El-Serag HB, Johnson ML, Hachem C et al (2009) Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 136:1601–1608

    Article  PubMed  CAS  Google Scholar 

  76. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231

    Article  PubMed  CAS  Google Scholar 

  77. Browning JD, Szczepaniak LS, Dobbins R et al (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:1387–1395

    Article  PubMed  Google Scholar 

  78. Fan JG, Zhu J, Li XJ et al (2005) Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 43:508–514

    Article  PubMed  Google Scholar 

  79. Brunt EM (2005) Pathology of nonalcoholic steatohepatitis. Hepatol Res 33:68–71

    Article  PubMed  CAS  Google Scholar 

  80. Torres DM, Harrison SA (2008) Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 134:1682–1698

    Article  PubMed  CAS  Google Scholar 

  81. Williams CD, Stengel J, Asike MI et al (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 140:124–131

    Article  PubMed  Google Scholar 

  82. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA (2011) Frequency and outcomes of Liver transplantation for nonalcoholic streatohepatitis in the United States. Gastroenterology 141:1249–1253

    Article  PubMed  Google Scholar 

  83. Falck-Ytter Y, Younossi ZM, Marchesini G et al (2001) Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 21:17–26

    Article  PubMed  CAS  Google Scholar 

  84. Caldwell SH, Oelsner DH, Iezzoni JC et al (1999) Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29:664–669

    Article  PubMed  CAS  Google Scholar 

  85. Poonawala A, Nair SP, Thuluvath PJ (2000) Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case–control study. Hepatology 32:689–692

    Article  PubMed  CAS  Google Scholar 

  86. Bugianesi E, Leone N, Vanni E et al (2002) Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123:134–140

    Article  PubMed  Google Scholar 

  87. Marrero JA, Fontana RJ, Su GL et al (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36:1349–1354

    PubMed  Google Scholar 

  88. Ratziu V, Bonyhay L, Di Martino V et al (2002) Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 35:1485–1493

    Article  PubMed  Google Scholar 

  89. Sorensen HT, Mellemkjaer L, Jepsen P et al (2003) Risk of cancer in patients hospitalized with fatty liver: a Danish cohort study. J Clin Gastroenterol 36:356–359

    Article  PubMed  Google Scholar 

  90. Sanyal AJ, Banas C, Sargeant C et al (2006) Similarities and differences in outcomes of ­cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 43:682–689

    Article  PubMed  Google Scholar 

  91. Hashimoto E, Yatsuji S, Tobari M et al (2009) Hepatocellular carcinoma in patients with ­nonalcoholic steatohepatitis. J Gastroenterol 44(suppl 19):89–95

    Article  PubMed  Google Scholar 

  92. Ascha MS, Hanouneh IA, Lopez R et al (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51:1972–1978

    Article  PubMed  Google Scholar 

  93. Hashizume H, Sato K, Takagi H et al (2007) Primary liver cancers with nonalcoholic ­steatohepatitis. Eur J Gastroenterol Hepatol 19:827–834

    Article  PubMed  Google Scholar 

  94. Tokushige K, Hashimoto E, Horie Y et al (2011) Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey. J Gastroenterol 46:1230–1237

    Article  PubMed  Google Scholar 

  95. Ertle J, Dechene A, Sowa JP et al (2011) Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 128:2436–2443

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Naim Alkhouri M.D. .

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Alkhouri, N., McCullough, A. (2013). Obesity, Inflammation, Nonalcoholic Fatty Liver Disease, and Hepatocellular Carcinoma. In: Dannenberg, A., Berger, N. (eds) Obesity, Inflammation and Cancer. Energy Balance and Cancer, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6819-6_9

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