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Semin Liver Dis 2012; 32(01): 030-038
DOI: 10.1055/s-0032-1306424
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nonalcoholic Steatohepatitis and Noncirrhotic Hepatocellular Carcinoma: Fertile Soil

Dawn M. Torres
1   Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, D.C.
,
Stephen A. Harrison
2   San Antonio Military Medical Center, Fort Sam Houston, Texas.
› Author Affiliations
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Publication History

Publication Date:
13 March 2012 (online)

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening.

Keywords

Nonalcoholic fatty liver disease - nonalcoholic steatohepatitis - insulin resistance - hepatocellular carcinoma
 

  • References

  • 1 Williams CD, Stengel J, Asike MI , et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (1) 124-131
    CrossrefPubMedGoogle Scholar
  • 2 Bruix J, Sherman M ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5) 1208-1236
    CrossrefPubMedGoogle Scholar
  • 3 Blonski W, Kotlyar DS, Forde KA. Non-viral causes of hepatocellular carcinoma. World J Gastroenterol 2010; 16 (29) 3603-3615
    CrossrefPubMedGoogle Scholar
  • 4 Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006; 40 (Suppl 1) S5-S10
    PubMedGoogle Scholar
  • 5 Bosch FX, Ribes J, Diaz M, Cléries R. Primary liver cancer: world-wide incidence and trends. Gastroenterology 2004; 127: S3-S16
    CrossrefPubMedGoogle Scholar
  • 6 El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340 (10) 745-750
    CrossrefPubMedGoogle Scholar
  • 7 Gomaa AI, Khan SA, Toledano MB, Waked I, Taylor-Robinson SD. Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis. World J Gastroenterol 2008; 14 (27) 4300-4308
    CrossrefPubMedGoogle Scholar
  • 8 Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51 (6) 1972-1978
    CrossrefPubMedGoogle Scholar
  • 9 O'Leary JG, Landaverde C, Jennings L, Goldstein RM, Davis GL. Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants. Clin Gastroenterol Hepatol 2011; 9 (8) 700-704 , e1
    CrossrefPubMedGoogle Scholar
  • 10 Lok AS, Seeff LB, Morgan TR , et al; HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology 2009; 136 (1) 138-148
    CrossrefPubMedGoogle Scholar
  • 11 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51 (5) 1820-1832
    CrossrefPubMedGoogle Scholar
  • 12 Kawada N, Imanaka K, Kawaguchi T , et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (12) 1190-1194
    CrossrefPubMedGoogle Scholar
  • 13 Hashimoto E, Yatsuji S, Tobari M , et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol 2009; 44 (Suppl 19) 89-95
    CrossrefPubMedGoogle Scholar
  • 14 Chagas AL, Kikuchi LO, Oliveira CP , et al. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?. Braz J Med Biol Res 2009; 42 (10) 958-962
    CrossrefPubMedGoogle Scholar
  • 15 Ertle J, Dechêne A, Sowa JP , et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 2011; 128 (10) 2436-2443
    CrossrefPubMedGoogle Scholar
  • 16 Paradis V, Zalinski S, Chelbi E , et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 2009; 49 (3) 851-859
    CrossrefPubMedGoogle Scholar
  • 17 Yasui K, Hashimoto E, Komorizono Y , et al; Japan NASH Study Group, Ministry of Health, Labour, and Welfare of Japan. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011; 9 (5) 428-433 , quiz e50
    CrossrefPubMedGoogle Scholar
  • 18 Takuma Y, Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review. World J Gastroenterol 2010; 16 (12) 1436-1441
    CrossrefPubMedGoogle Scholar
  • 19 Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM. Obesity and hepatocellular carcinoma. Gastroenterology 2004; 127 (5, Suppl 1) S97-S103
    CrossrefPubMedGoogle Scholar
  • 20 Wolk A, Gridley G, Svensson M , et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 2001; 12 (1) 13-21
    CrossrefPubMedGoogle Scholar
  • 21 Nair S, Mason A, Eason J, Loss G, Perrillo RP. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?. Hepatology 2002; 36 (1) 150-155
    CrossrefPubMedGoogle Scholar
  • 22 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348 (17) 1625-1638
    CrossrefPubMedGoogle Scholar
  • 23 Møller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur J Cancer 1994; 30A (3) 344-350
    PubMedGoogle Scholar
  • 24 Oh SW, Yoon YS, Shin SA. 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 2005; 23 (21) 4742-4754
    CrossrefPubMedGoogle Scholar
  • 25 Chen CL, Yang HI, Yang WS , et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008; 135 (1) 111-121
    CrossrefPubMedGoogle Scholar
  • 26 Adami HO, Chow WH, Nyrén O , et al. Excess risk of primary liver cancer in patients with diabetes mellitus. J Natl Cancer Inst 1996; 88 (20) 1472-1477
    CrossrefPubMedGoogle Scholar
  • 27 Wideroff L, Gridley G, Mellemkjaer L , et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997; 89 (18) 1360-1365
    CrossrefPubMedGoogle Scholar
  • 28 Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 2000; 92 (13) 1096-1099
    CrossrefPubMedGoogle Scholar
  • 29 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4 (3) 369-380
    CrossrefPubMedGoogle Scholar
  • 30 El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126 (2) 460-468
    CrossrefPubMedGoogle Scholar
  • 31 Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010; 51 (6) 1972-1978
    CrossrefPubMedGoogle Scholar
  • 32 George DK, Goldwurm S, MacDonald GA , et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114 (2) 311-318
    CrossrefPubMedGoogle Scholar
  • 33 Sorrentino P, D'Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009; 50 (2) 351-357
    CrossrefPubMedGoogle Scholar
  • 34 Mendler MH, Turlin B, Moirand R , et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117 (5) 1155-1163
    CrossrefPubMedGoogle Scholar
  • 35 Fujita N, Miyachi H, Tanaka H , et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 2009; 18 (2) 424-432
    CrossrefPubMedGoogle Scholar
  • 36 Mínguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009; 25 (3) 186-194
    CrossrefPubMedGoogle Scholar
  • 37 Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007; 27 (1) 55-76
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008; 48 (4) 1312-1327
    CrossrefPubMedGoogle Scholar
  • 39 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (2) 281-297
    CrossrefPubMedGoogle Scholar
  • 40 Dara L, Ji C, Kaplowitz N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 2011; 53 (5) 1752-1763
    CrossrefPubMedGoogle Scholar
  • 41 Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011; 5 (2) 159-166
    CrossrefPubMedGoogle Scholar
  • 42 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52 (5) 1836-1846
    CrossrefPubMedGoogle Scholar
  • 43 Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Growing evidence of an epidemic?. Hepatol Res 2012; 42 (1) 1-14
    CrossrefPubMedGoogle Scholar
  • 44 Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD. Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 2009; 124 (3) 540-546
    CrossrefPubMedGoogle Scholar
  • 45 Park EJ, Lee JH, Yu GY , et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140 (2) 197-208
    CrossrefPubMedGoogle Scholar
  • 46 Roderburg C, Trautwein C. Obesity and liver cancer: a key role for interleukin-6 and signal transducer and activator of transcription 3?. Hepatology 2010; 51 (5) 1850-1852
    CrossrefPubMedGoogle Scholar
  • 47 Bettermann K, Vucur M, Haybaeck J , et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 2010; 17 (5) 481-496
    CrossrefPubMedGoogle Scholar
  • 48 Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol 2011; ; In press
    PubMedGoogle Scholar
  • 49 Bougoulia M, Triantos A, Koliakos G. Effect of weight loss with or without orlistat treatment on adipocytokines, inflammation, and oxidative markers in obese women. Hormones (Athens) 2006; 5 (4) 259-269
    PubMedGoogle Scholar
  • 50 Gannagé-Yared MH, Khalife S, Semaan M, Fares F, Jambart S, Halaby G. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur J Endocrinol 2006; 155 (1) 167-176
    CrossrefPubMedGoogle Scholar
  • 51 Asano T, Watanabe K, Kubota N , et al. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol 2009; 24 (10) 1669-1676
    CrossrefPubMedGoogle Scholar
  • 52 Kamada Y, Matsumoto H, Tamura S , et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol 2007; 47 (4) 556-564
    CrossrefPubMedGoogle Scholar
  • 53 Bråkenhielm E, Veitonmäki N, Cao R , et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 2004; 101 (8) 2476-2481
    CrossrefPubMedGoogle Scholar
  • 54 Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009: 831670
    PubMedGoogle Scholar
  • 55 Ikejima K, Honda H, Yoshikawa M , et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001; 34 (2) 288-297
    CrossrefPubMedGoogle Scholar
  • 56 Marra F. Leptin and liver fibrosis: a matter of fat. Gastroenterology 2002; 122: 1399-1410
    CrossrefPubMedGoogle Scholar
  • 57 Ish-Shalom D, Christoffersen CT, Vorwerk P , et al. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. Diabetologia 1997; 40 (Suppl 2) S25-S31
    CrossrefPubMedGoogle Scholar
  • 58 Buzzelli G, Dattolo P, Pinzani M, Brocchi A, Romano S, Gentilini P. Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm. Am J Gastroenterol 1993; 88 (10) 1744-1748
    PubMedGoogle Scholar
  • 59 Price JA, Kovach SJ, Johnson T , et al. Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology 2002; 36 (5) 1089-1097
    CrossrefPubMedGoogle Scholar
  • 60 Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR. Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology 1997; 26 (3) 598-604
    CrossrefPubMedGoogle Scholar
  • 61 Aleem E, Nehrbass D, Klimek F, Mayer D, Bannasch P. Upregulation of the insulin receptor and type I insulin-like growth factor receptor are early events in hepatocarcinogenesis. Toxicol Pathol 2011; 39 (3) 524-543
    CrossrefPubMedGoogle Scholar
  • 62 Longato L, de la Monte S, Kuzushita N , et al. Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology 2009; 49 (6) 1935-1943
    CrossrefPubMedGoogle Scholar
  • 63 Longato L, de la Monte S, Califano S, Wands JR. Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver. Hepatol Res 2008; 38 (9) 940-953
    CrossrefPubMedGoogle Scholar
  • 64 Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 2002; 109 (Suppl) S81-S96
    CrossrefPubMedGoogle Scholar
  • 65 Luedde T, Schwabe RF. NF-κB in the liver—linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8 (2) 108-118
    CrossrefPubMedGoogle Scholar
  • 66 Chiang SH, Bazuine M, Lumeng CN , et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009; 138 (5) 961-975
    CrossrefPubMedGoogle Scholar
  • 67 Sass G, Klinger N, Sirma H , et al. Inhibition of experimental HCC growth in mice by use of the kinase inhibitor DMAT. Int J Oncol 2011; 39 (2) 433-442
    PubMedGoogle Scholar
  • 68 Wree A, Kahraman A, Gerken G, Canbay A. Obesity affects the liver - the link between adipocytes and hepatocytes. Digestion 2011; 83 (1-2) 124-133
    CrossrefPubMedGoogle Scholar
  • 69 Feldstein AE, Canbay A, Angulo P , et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003; 125 (2) 437-443
    CrossrefPubMedGoogle Scholar
  • 70 Cho H, Black SC, Looper D , et al. Pharmacological characterization of a small molecule inhibitor of c-Jun kinase. Am J Physiol Endocrinol Metab 2008; 295 (5) E1142-E1151
    CrossrefPubMedGoogle Scholar
  • 71 Solinas G, Karin M. JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J 2010; 24 (8) 2596-2611
    CrossrefPubMedGoogle Scholar
  • 72 Ferreira DM, Castro RE, Machado MV , et al. Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease. Diabetologia 2011; 54 (7) 1788-1798
    CrossrefPubMedGoogle Scholar
  • 73 Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology 2009; 49 (1) 87-96
    CrossrefPubMedGoogle Scholar
  • 74 Schattenberg JM, Singh R, Wang Y , et al. JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology 2006; 43 (1) 163-172
    CrossrefPubMedGoogle Scholar
  • 75 Aghazadeh S, Yazdanparast R. Inhibition of JNK along with activation of ERK1/2 MAPK pathways improve steatohepatitis among the rats. Clin Nutr 2010; 29 (3) 381-385
    CrossrefPubMedGoogle Scholar
  • 76 Maeda S. NF-κB, JNK, and TLR signaling pathways in hepatocarcinogenesis. Gastroenterol Res Pract 2010; 2010: 367694
    PubMedGoogle Scholar
  • 77 Chang Q, Zhang Y, Beezhold KJ , et al. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol 2009; 50 (2) 323-333
    CrossrefPubMedGoogle Scholar
  • 78 Tarn C, Lee S, Hu Y, Ashendel C, Andrisani OM. Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes. J Biol Chem 2001; 276 (37) 34671-34680
    CrossrefPubMedGoogle Scholar
  • 79 Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 2006; 103 (28) 10544-10551
    CrossrefPubMedGoogle Scholar
  • 80 Eferl R, Ricci R, Kenner L , et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 2003; 112 (2) 181-192
    CrossrefPubMedGoogle Scholar
  • 81 He G, Yu GY, Temkin V , et al. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 2010; 17 (3) 286-297
    CrossrefPubMedGoogle Scholar
  • 82 Wu WY, Li J, Wu ZS, Zhang CL, Meng XL. STAT3 activation in monocytes accelerates liver cancer progression. BMC Cancer 2011; 11: 506
    CrossrefPubMedGoogle Scholar
  • 83 Gu FM, Li QL, Gao Q , et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer 2011; 10 (1) 150
    CrossrefPubMedGoogle Scholar
  • 84 Gu FM, Li QL, Gao Q , et al. Sorafenib inhibits growth and metastasis of hepatocellular carcinoma by blocking STAT3. World J Gastroenterol 2011; 17 (34) 3922-3932
    CrossrefPubMedGoogle Scholar
  • 85 Mueller KM, Kornfeld JW, Friedbichler K , et al. Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology 2011; 54 (4) 1398-1409
    CrossrefPubMedGoogle Scholar
  • 86 Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007; 8 (10) 774-785
    CrossrefPubMedGoogle Scholar
  • 87 Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115 (5) 577-590
    CrossrefPubMedGoogle Scholar
  • 88 Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009; 122 (Pt 20) 3589-3594
    CrossrefPubMedGoogle Scholar
  • 89 Lee JW, Park S, Takahashi Y, Wang HG. The association of AMPK with ULK1 regulates autophagy. PLoS ONE 2010; 5 (11) e15394
    CrossrefPubMedGoogle Scholar
  • 90 Sokollik C, Ang M, Jones N. Autophagy: a primer for the gastroenterologist/hepatologist. Can J Gastroenterol 2011; 25 (12) 667-674
    PubMedGoogle Scholar
  • 91 Singh R, Kaushik S, Wang Y , et al. Autophagy regulates lipid metabolism. Nature 2009; 458 (7242) 1131-1135
    CrossrefPubMedGoogle Scholar
  • 92 Dikic I, Johansen T, Kirkin V. Selective autophagy in cancer development and therapy. Cancer Res 2010; 70 (9) 3431-3434
    CrossrefPubMedGoogle Scholar
  • 93 Egan DF, Shackelford DB, Mihaylova MM , et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011; 331 (6016) 456-461
    CrossrefPubMedGoogle Scholar
  • 94 Chan EY. mTORC1 phosphorylates the ULK1-mAtg13–FIP200 autophagy regulatory complex. Sci Signal 2009; 2: 51
    PubMedGoogle Scholar
  • 95 Takamura A, Komatsu M, Hara T , et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 2011; 25 (8) 795-800
    CrossrefPubMedGoogle Scholar
  • 96 Qu X, Yu J, Bhagat G , et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112 (12) 1809-1820
    PubMedGoogle Scholar
  • 97 Ding ZB, Shi YH, Zhou J , et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res 2008; 68 (22) 9167-9175
    CrossrefPubMedGoogle Scholar
  • 98 Takeuchi O, Akira S. Toll-like receptors; their physiological role and signal transduction system. Int Immunopharmacol 2001; 1 (4) 625-635
    CrossrefPubMedGoogle Scholar
  • 99 Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 2008; 48 (1) 322-335
    CrossrefPubMedGoogle Scholar
  • 100 Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007; 47 (4) 571-579
    CrossrefPubMedGoogle Scholar
  • 101 Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998; 18 (10) 5652-5658
    PubMedGoogle Scholar
  • 102 Moreau A, Vilarem MJ, Maurel P, Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response. Mol Pharm 2008; 5 (1) 35-41
    CrossrefPubMedGoogle Scholar
  • 103 Huang W, Zhang J, Washington M , et al. Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 2005; 19 (6) 1646-1653
    CrossrefPubMedGoogle Scholar
  • 104 Takizawa D, Kakizaki S, Horiguchi N, Yamazaki Y, Tojima H, Mori M. Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. Carcinogenesis 2011; 32 (4) 576-583
    CrossrefPubMedGoogle Scholar
  • 105 Peyrou M, Bourgoin L, Foti M. PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis 2010; 28 (1) 236-246
    CrossrefPubMedGoogle Scholar
  • 106 Anezaki Y, Ohshima S, Ishii H , et al. Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis. Hepatol Res 2009; 39 (6) 609-618
    CrossrefPubMedGoogle Scholar
  • 107 Sze KM, Wong KL, Chu GK, Lee JM, Yau TO, Oi-Lin Ng I. Loss of phosphatase and tensin homolog enhances cell invasion and migration through AKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significance. Hepatology 2011; 53 (5) 1558-1569
    CrossrefPubMedGoogle Scholar
  • 108 Mínguez B, Tovar V, Chiang D, Villanueva A, Llovet JM. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009; 25 (3) 186-194
    CrossrefPubMedGoogle Scholar
  • 109 Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133 (2) 647-658
    CrossrefPubMedGoogle Scholar
  • 110 Wang B, Majumder S, Nuovo G , et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009; 50 (4) 1152-1161
    CrossrefPubMedGoogle Scholar