Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2009, Article ID 831670, 8 pages
http://dx.doi.org/10.1155/2009/831670
Review Article

Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy

2nd Department of Internal Medicine, Medical School of Athens University, Hippokration General Hospital, 115 27 Athens, Greece

Received 5 January 2009; Accepted 6 April 2009

Academic Editor: Fulvio D'Acquisto

Copyright © 2009 Emmanuel A. Tsochatzis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. G. Marchesini, E. Bugianesi, G. Forlani et al., “Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome,” Hepatology, vol. 37, no. 4, pp. 917–923, 2003. View at Publisher · View at Google Scholar · View at PubMed
  2. E. Tsochatzis, G. V. Papatheodoridis, E. K. Manesis, G. Kafiri, D. G. Tiniakos, and A. J. Archimandritis, “Metabolic syndrome is associated with severe fibrosis in chronic viral hepatitis and non-alcoholic steatohepatitis,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 1, pp. 80–89, 2008. View at Publisher · View at Google Scholar · View at PubMed
  3. E. A. Tsochatzis, S. Manolakopoulos, G. V. Papatheodoridis, and A. J. Archimandritis, “Insulin resistance and metabolic syndrome in chronic liver diseases: old entities with new implications,” Scandinavian Journal of Gastroenterology, vol. 44, no. 1, pp. 6–14, 2009. View at Publisher · View at Google Scholar · View at PubMed
  4. S. Bellentani, G. Saccoccio, F. Masutti et al., “Prevalence of and risk factors for hepatic steatosis in Northern Italy,” Annals of Internal Medicine, vol. 132, no. 2, pp. 112–117, 2000. View at Google Scholar
  5. J. D. Browning, L. S. Szczepaniak, R. Dobbins et al., “Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity,” Hepatology, vol. 40, no. 6, pp. 1387–1395, 2004. View at Publisher · View at Google Scholar · View at PubMed
  6. G. V. Papatheodoridis, J. Goulis, D. Christodoulou et al., “High prevalence of elevated liver enzymes in blood donors: associations with male gender and central adiposity,” European Journal of Gastroenterology & Hepatology, vol. 19, no. 4, pp. 281–287, 2007. View at Publisher · View at Google Scholar · View at PubMed
  7. G. C. Farrell and C. Z. Larter, “Nonalcoholic fatty liver disease: from steatosis to cirrhosis,” Hepatology, vol. 43, no. 2, supplement 1, pp. S99–S112, 2006. View at Publisher · View at Google Scholar · View at PubMed
  8. C. P. Day and O. F. W. James, “Steatohepatitis: a tale of two “hits”?,” Gastroenterology, vol. 114, no. 4, pp. 842–845, 1998. View at Publisher · View at Google Scholar
  9. L. A. Adams, J. F. Lymp, J. St. Sauver et al., “The natural history of nonalcoholic fatty liver disease: a population-based cohort study,” Gastroenterology, vol. 129, no. 1, pp. 113–121, 2005. View at Publisher · View at Google Scholar
  10. M. Ekstedt, L. E. Franzén, U. L. Mathiesen et al., “Long-term follow-up of patients with NAFLD and elevated liver enzymes,” Hepatology, vol. 44, no. 4, pp. 865–873, 2006. View at Publisher · View at Google Scholar · View at PubMed
  11. A. Wieckowska, A. J. McCullough, and A. E. Feldstein, “Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future,” Hepatology, vol. 46, no. 2, pp. 582–589, 2007. View at Publisher · View at Google Scholar · View at PubMed
  12. E. Tsochatzis, G. V. Papatheodoridis, and A. J. Archimandritis, “The evolving role of leptin and adiponectin in chronic liver diseases,” The American Journal of Gastroenterology, vol. 101, no. 11, pp. 2629–2640, 2006. View at Publisher · View at Google Scholar · View at PubMed
  13. A. S. Greenberg and M. S. Obin, “Obesity and the role of adipose tissue in inflammation and metabolism,” American Journal of Clinical Nutrition, vol. 83, no. 2, pp. 461S–465S, 2006. View at Google Scholar
  14. Y. Kamada, T. Takehara, and N. Hayashi, “Adipocytokines and liver disease,” Journal of Gastroenterology, vol. 43, no. 11, pp. 811–822, 2008. View at Publisher · View at Google Scholar · View at PubMed
  15. R. N. Bergman, “New concepts in extracellular signaling for insulin action: the single gateway hypothesis,” Recent Progress in Hormone Research, vol. 52, pp. 359–385, 1997. View at Google Scholar
  16. E. Bugianesi, A. J. McCullough, and G. Marchesini, “Insulin resistance: a metabolic pathway to chronic liver disease,” Hepatology, vol. 42, no. 5, pp. 987–1000, 2005. View at Publisher · View at Google Scholar · View at PubMed
  17. P. Angulo, “Nonalcoholic fatty liver disease,” The New England Journal of Medicine, vol. 346, no. 16, pp. 1221–1231, 2002. View at Publisher · View at Google Scholar · View at PubMed
  18. D. Pessayre and B. Fromenty, “NASH: a mitochondrial disease,” Journal of Hepatology, vol. 42, no. 6, pp. 928–940, 2005. View at Publisher · View at Google Scholar · View at PubMed
  19. M. Curzio, H. Esterbauer, G. Poli et al., “Possible role of aldehydic lipid peroxidation products as chemoattractants,” International Journal of Tissue Reactions, vol. 9, no. 4, pp. 295–306, 1987. View at Google Scholar
  20. H. Hug, S. Strand, A. Grambihler et al., “Reactive oxygen intermediates are involved in the induction of CD95 ligand mRNA expression by cytostatic drugs in hepatoma cells,” The Journal of Biological Chemistry, vol. 272, no. 45, pp. 28191–28193, 1997. View at Publisher · View at Google Scholar
  21. G. Leonarduzzi, A. Scavazza, F. Biasi et al., “The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis,” The FASEB Journal, vol. 11, no. 11, pp. 851–857, 1997. View at Google Scholar
  22. I. R. Wanless and K. Shiota, “The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis,” Seminars in Liver Disease, vol. 24, no. 1, pp. 99–106, 2004. View at Publisher · View at Google Scholar · View at PubMed
  23. Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, and J. M. Friedman, “Positional cloning of the mouse obese gene and its human homologue,” Nature, vol. 372, no. 6505, pp. 425–432, 1994. View at Publisher · View at Google Scholar · View at PubMed
  24. C. S. Mantzoros, “The role of leptin in human obesity and disease: a review of current evidence,” Annals of Internal Medicine, vol. 130, no. 8, pp. 671–680, 1999. View at Google Scholar
  25. R. H. Unger, “Lipotoxic diseases,” Annual Review of Medicine, vol. 53, pp. 319–336, 2002. View at Publisher · View at Google Scholar · View at PubMed
  26. T. Kakuma, Y. Lee, M. Higa et al., “Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 15, pp. 8536–8541, 2000. View at Publisher · View at Google Scholar
  27. K. Ikejima, H. Honda, M. Yoshikawa et al., “Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals,” Hepatology, vol. 34, no. 2, pp. 288–297, 2001. View at Publisher · View at Google Scholar · View at PubMed
  28. F. Marra, “Leptin and liver fibrosis: a matter of fat,” Gastroenterology, vol. 122, no. 5, pp. 1529–1532, 2002. View at Publisher · View at Google Scholar
  29. K. Ikejima, Y. Takei, H. Honda et al., “Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat,” Gastroenterology, vol. 122, no. 5, pp. 1399–1410, 2002. View at Publisher · View at Google Scholar
  30. N. K. Saxena, K. Ikeda, D. C. Rockey, S. L. Friedman, and F. A. Anania, “Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice,” Hepatology, vol. 35, no. 4, pp. 762–771, 2002. View at Publisher · View at Google Scholar · View at PubMed
  31. U. B. Pajvani, X. Du, T. P. Combs et al., “Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity,” The Journal of Biological Chemistry, vol. 278, no. 11, pp. 9073–9085, 2003. View at Publisher · View at Google Scholar · View at PubMed
  32. J. Bełtowski, “Adiponectin and resistin—new hormones of white adipose tissue,” Medical Science Monitor, vol. 9, no. 2, pp. RA55–RA61, 2003. View at Google Scholar
  33. F. A. Anania, “Adiponectin and alcoholic fatty liver: is it, after all, about what you eat?,” Hepatology, vol. 42, no. 3, pp. 530–532, 2005. View at Publisher · View at Google Scholar · View at PubMed
  34. M. You, R. V. Considine, T. C. Leone, D. P. Kelly, and D. W. Crabb, “Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice,” Hepatology, vol. 42, no. 3, pp. 568–577, 2005. View at Publisher · View at Google Scholar · View at PubMed
  35. S. Shklyaev, G. Aslanidi, M. Tennant et al., “Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 24, pp. 14217–14222, 2003. View at Publisher · View at Google Scholar · View at PubMed
  36. Y. Kamada, H. Matsumoto, S. Tamura et al., “Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model,” Journal of Hepatology, vol. 47, no. 4, pp. 556–564, 2007. View at Publisher · View at Google Scholar · View at PubMed
  37. T. Masaki, S. Chiba, H. Tatsukawa et al., “Adiponectin protects LPS-induced liver injury through modulation of TNF-α in KK-Ay obese mice,” Hepatology, vol. 40, no. 1, pp. 177–184, 2004. View at Publisher · View at Google Scholar · View at PubMed
  38. A. Xu, Y. Wang, H. Keshaw, L. Y. Xu, K. S. L. Lam, and G. J. S. Cooper, “The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice,” The Journal of Clinical Investigation, vol. 112, no. 1, pp. 91–100, 2003. View at Publisher · View at Google Scholar · View at PubMed
  39. K. Tomita, Y. Oike, T. Teratani et al., “Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice,” Hepatology, vol. 48, no. 2, pp. 458–473, 2008. View at Publisher · View at Google Scholar · View at PubMed
  40. G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993. View at Publisher · View at Google Scholar
  41. K. E. Wellen and G. S. Hotamisligil, “Obesity-induced inflammatory changes in adipose tissue,” The Journal of Clinical Investigation, vol. 112, no. 12, pp. 1785–1788, 2003. View at Publisher · View at Google Scholar
  42. L. Valenti, A. L. Fracanzani, P. Dongiovanni et al., “Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease,” Gastroenterology, vol. 122, no. 2, pp. 274–280, 2002. View at Publisher · View at Google Scholar
  43. K. Tokushige, M. Takakura, N. Tsuchiya-Matsushita, M. Taniai, E. Hashimoto, and K. Shiratori, “Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis,” Journal of Hepatology, vol. 46, no. 6, pp. 1104–1110, 2007. View at Publisher · View at Google Scholar · View at PubMed
  44. J. Poniachik, A. Csendes, J. C. Díaz et al., “Increased production of IL-1α and TNF-α in lipopolysaccharide-stimulated blood from obese patients with non-alcoholic fatty liver disease,” Cytokine, vol. 33, no. 5, pp. 252–257, 2006. View at Publisher · View at Google Scholar · View at PubMed
  45. A. E. Feldstein, N. W. Werneburg, A. Canbay et al., “Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway,” Hepatology, vol. 40, no. 1, pp. 185–194, 2004. View at Publisher · View at Google Scholar · View at PubMed
  46. K. Tomita, G. Tamiya, S. Ando et al., “Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice,” Gut, vol. 55, no. 3, pp. 415–424, 2006. View at Publisher · View at Google Scholar · View at PubMed
  47. Z. Li, S. Yang, H. Lin et al., “Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease,” Hepatology, vol. 37, no. 2, pp. 343–350, 2003. View at Publisher · View at Google Scholar · View at PubMed
  48. L. Patel, A. C. Buckels, I. J. Kinghorn et al., “Resistin is expressed in human macrophages and directly regulated by PPARγ activators,” Biochemical and Biophysical Research Communications, vol. 300, no. 2, pp. 472–476, 2003. View at Publisher · View at Google Scholar
  49. M. Pravenec, L. Kazdová, V. Landa et al., “Transgenic and recombinant resistin impair skeletal muscle glucose metabolism in the spontaneously hypertensive rat,” The Journal of Biological Chemistry, vol. 278, no. 46, pp. 45209–45215, 2003. View at Publisher · View at Google Scholar · View at PubMed
  50. M. W. Rajala, S. Obici, P. E. Scherer, and L. Rossetti, “Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production,” The Journal of Clinical Investigation, vol. 111, no. 2, pp. 225–230, 2003. View at Google Scholar
  51. S. M. Rangwala, A. S. Rich, B. Rhoades et al., “Abnormal glucose homeostasis due to chronic hyperresistinemia,” Diabetes, vol. 53, no. 8, pp. 1937–1941, 2004. View at Publisher · View at Google Scholar
  52. H. Satoh, M. T. A. Nguyen, P. D. G. Miles, T. Imamura, I. Usui, and J. M. Olefsky, “Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats,” The Journal of Clinical Investigation, vol. 114, no. 2, pp. 224–231, 2004. View at Publisher · View at Google Scholar
  53. R. Palanivel and G. Sweeney, “Regulation of fatty acid uptake and metabolism in L6 skeletal muscle cells by resistin,” FEBS Letters, vol. 579, no. 22, pp. 5049–5054, 2005. View at Publisher · View at Google Scholar · View at PubMed
  54. C. M. Steppan, J. Wang, E. L. Whiteman, M. J. Birnbaum, and M. A. Lazar, “Activation of SOCS-3 by resistin,” Molecular and Cellular Biology, vol. 25, no. 4, pp. 1569–1575, 2005. View at Publisher · View at Google Scholar · View at PubMed
  55. N. Silswal, A. K. Singh, B. Aruna, S. Mukhopadhyay, S. Ghosh, and N. Z. Ehtesham, “Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-κB-dependent pathway,” Biochemical and Biophysical Research Communications, vol. 334, no. 4, pp. 1092–1101, 2005. View at Publisher · View at Google Scholar · View at PubMed
  56. M. Bokarewa, I. Nagaev, L. Dahlberg, U. Smith, and A. Tarkowski, “Resistin, an adipokine with potent proinflammatory properties,” The Journal of Immunology, vol. 174, no. 9, pp. 5789–5795, 2005. View at Google Scholar
  57. C. Bertolani, P. Sancho-Bru, P. Failli et al., “Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells,” American Journal of Pathology, vol. 169, no. 6, pp. 2042–2053, 2006. View at Publisher · View at Google Scholar
  58. D. E. Cressman, L. E. Greenbaum, R. A. DeAngelis et al., “Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice,” Science, vol. 274, no. 5291, pp. 1379–1383, 1996. View at Publisher · View at Google Scholar
  59. O. El-Assal, F. Hong, W. H. Kim, S. Radaeva, and B. Gao, “IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver,” Cellular & Molecular Immunology, vol. 1, no. 3, pp. 205–211, 2004. View at Google Scholar
  60. N. Teoh, J. Field, and G. Farrell, “Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice,” Journal of Hepatology, vol. 45, no. 1, pp. 20–27, 2006. View at Publisher · View at Google Scholar · View at PubMed
  61. A. Blindenbacher, X. Wang, I. Langer, R. Savino, L. Terracciano, and M. H. Heim, “Interleukin 6 is important for survival after partial hepatectomy in mice,” Hepatology, vol. 38, no. 3, pp. 674–682, 2003. View at Publisher · View at Google Scholar · View at PubMed
  62. X. Jin, T. A. Zimmers, E. A. Perez, R. H. Pierce, Z. Zhang, and L. G. Koniaris, “Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair,” Hepatology, vol. 43, no. 3, pp. 474–484, 2006. View at Publisher · View at Google Scholar · View at PubMed
  63. Q. Yang, T. E. Graham, N. Mody et al., “Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes,” Nature, vol. 436, no. 7049, pp. 356–362, 2005. View at Publisher · View at Google Scholar · View at PubMed
  64. T. E. Graham, Q. Yang, M. Blüher et al., “Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects,” The New England Journal of Medicine, vol. 354, no. 24, pp. 2552–2563, 2006. View at Publisher · View at Google Scholar · View at PubMed
  65. N. Klöting, T. E. Graham, J. Berndt et al., “Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass,” Cell Metabolism, vol. 6, no. 1, pp. 79–87, 2007. View at Publisher · View at Google Scholar · View at PubMed
  66. P. Balagopal, T. E. Graham, B. B. Kahn, A. Altomare, V. Funanage, and D. George, “Reduction of elevated serum retinol binding protein in obese children by lifestyle intervention: association with subclinical inflammation,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 5, pp. 1971–1974, 2007. View at Publisher · View at Google Scholar · View at PubMed
  67. A. Yao-Borengasser, V. Varma, A. M. Bodles et al., “Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 7, pp. 2590–2597, 2007. View at Publisher · View at Google Scholar · View at PubMed
  68. A. Fukuhara, M. Matsuda, M. Nishizawa et al., “Visfatin: a protein secreted by visceral fat that Mimics the effects of insulin,” Science, vol. 307, no. 5708, pp. 426–430, 2005. View at Publisher · View at Google Scholar · View at PubMed
  69. S. Chitturi, G. Farrell, L. Frost et al., “Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?,” Hepatology, vol. 36, no. 2, pp. 403–409, 2002. View at Publisher · View at Google Scholar · View at PubMed
  70. P. Angulo, L. M. Alba, L. M. Petrovic, L. A. Adams, K. D. Lindor, and M. D. Jensen, “Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease,” Journal of Hepatology, vol. 41, no. 6, pp. 943–949, 2004. View at Publisher · View at Google Scholar · View at PubMed
  71. N. Chalasani, D. W. Crabb, O. W. Cummings et al., “Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis?,” The American Journal of Gastroenterology, vol. 98, no. 12, pp. 2771–2776, 2003. View at Publisher · View at Google Scholar · View at PubMed
  72. G. Musso, R. Gambino, M. Durazzo et al., “Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease,” Hepatology, vol. 42, no. 5, pp. 1175–1183, 2005. View at Publisher · View at Google Scholar · View at PubMed
  73. E. Tsochatzis, G. V. Papatheodoridis, E. Hadziyannis et al., “Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity,” Scandinavian Journal of Gastroenterology, vol. 43, no. 9, pp. 1128–1136, 2008. View at Publisher · View at Google Scholar · View at PubMed
  74. A. Uygun, A. Kadayifci, Z. Yesilova et al., “Serum leptin levels in patients with nonalcoholic steatohepatitis,” The American Journal of Gastroenterology, vol. 95, no. 12, pp. 3584–3589, 2000. View at Publisher · View at Google Scholar
  75. E. Bugianesi, U. Pagotto, R. Manini et al., “Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity,” The Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 6, pp. 3498–3504, 2005. View at Publisher · View at Google Scholar · View at PubMed
  76. J. M. Hui, A. Hodge, G. C. Farrell, J. G. Kench, A. Kriketos, and J. George, “Beyond insulin resistance in NASH: TNF-α or adiponectin?,” Hepatology, vol. 40, no. 1, pp. 46–54, 2004. View at Publisher · View at Google Scholar · View at PubMed
  77. M. Shimada, H. Kawahara, K. Ozaki et al., “Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis,” The American Journal of Gastroenterology, vol. 102, no. 9, pp. 1931–1938, 2007. View at Publisher · View at Google Scholar · View at PubMed
  78. Z. M. Younossi, M. Jarrar, C. Nugent et al., “A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH),” Obesity Surgery, vol. 18, no. 11, pp. 1430–1437, 2008. View at Publisher · View at Google Scholar · View at PubMed
  79. A. Y.-H. Wang, I. J. Hickman, A. A. Richards, J. P. Whitehead, J. B. Prins, and G. A. MacDonald, “High molecular weight adiponectin correlates with insulin sensitivity in patients with hepatitis C genotype 3, but not genotype 1 infection,” The American Journal of Gastroenterology, vol. 100, no. 12, pp. 2717–2723, 2005. View at Publisher · View at Google Scholar · View at PubMed
  80. M. Nannipieri, F. Cecchetti, M. Anselmino et al., “Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis,” Obesity Surgery, vol. 19, no. 4, pp. 467–474, 2009. View at Publisher · View at Google Scholar · View at PubMed
  81. H. Ma, V. Gomez, L. Lu, X. Yang, X. Wu, and S.-Y. Xiao, “Expression of adiponectin and its receptors in livers of morbidly obese patients with non-alcoholic fatty liver disease,” Journal of Gastroenterology and Hepatology, vol. 24, no. 2, pp. 233–237, 2009. View at Publisher · View at Google Scholar · View at PubMed
  82. S. Kaser, A. Maschen, A. Cayon et al., “Adiponectin and its receptors in non-alcoholic steatohepatitis,” Gut, vol. 54, no. 1, pp. 117–121, 2005. View at Publisher · View at Google Scholar · View at PubMed
  83. G. Musso, R. Gambino, F. De Michieli, M. Durazzo, G. Pagano, and M. Cassader, “Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH,” Hepatology, vol. 47, no. 4, pp. 1167–1177, 2008. View at Publisher · View at Google Scholar · View at PubMed
  84. S. Abiru, K. Migita, Y. Maeda et al., “Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis,” Liver International, vol. 26, no. 1, pp. 39–45, 2006. View at Publisher · View at Google Scholar · View at PubMed
  85. V. W. Wong, A. Y. Hui, S. W. Tsang et al., “Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease,” Clinical Gastroenterology and Hepatology, vol. 4, no. 9, pp. 1154–1161, 2006. View at Publisher · View at Google Scholar · View at PubMed
  86. M. H. Jarrar, A. Baranova, R. Collantes et al., “Adipokines and cytokines in non-alcoholic fatty liver disease,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 5, pp. 412–421, 2008. View at Publisher · View at Google Scholar · View at PubMed
  87. C. Pagano, G. Soardo, C. Pilon et al., “Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 3, pp. 1081–1086, 2006. View at Google Scholar
  88. A. Wieckowska, B. G. Papouchado, Z. Li, R. Lopez, N. N. Zein, and A. E. Feldstein, “Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis,” The American Journal of Gastroenterology, vol. 103, no. 6, pp. 1372–1379, 2008. View at Publisher · View at Google Scholar · View at PubMed
  89. D. García-Galiano, M. A. Sánchez-Garrido, I. Espejo et al., “IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients,” Obesity Surgery, vol. 17, no. 4, pp. 493–503, 2007. View at Publisher · View at Google Scholar · View at PubMed
  90. J. W. Haukeland, J. K. Damås, Z. Konopski et al., “Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2,” Journal of Hepatology, vol. 44, no. 6, pp. 1167–1174, 2006. View at Publisher · View at Google Scholar · View at PubMed
  91. J. A. Seo, N. H. Kim, S. Y. Park et al., “Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease,” Clinical Endocrinology, vol. 68, no. 4, pp. 555–560, 2008. View at Publisher · View at Google Scholar · View at PubMed
  92. R. Aller, D. A. de Luis, O. Izaola et al., “Influence of visfatin on histopathological changes of non-alcoholic fatty liver disease,” to appear in Digestive Diseases and Sciences. View at Publisher · View at Google Scholar · View at PubMed
  93. L. A. Adams, C. O. Zein, P. Angulo, and K. D. Lindor, “A pilot trial of pentoxifylline in nonalcoholic steatohepatitis,” The American Journal of Gastroenterology, vol. 99, no. 12, pp. 2365–2368, 2004. View at Publisher · View at Google Scholar · View at PubMed
  94. S. K. Satapathy, P. Sakhuja, V. Malhotra, B. C. Sharma, and S. K. Sarin, “Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis,” Journal of Gastroenterology and Hepatology, vol. 22, no. 5, pp. 634–638, 2007. View at Publisher · View at Google Scholar · View at PubMed
  95. S. S. Koca, I. H. Bahcecioglu, O. K. Poyrazoglu, I. H. Ozercan, K. Sahin, and B. Ustundag, “The treatment with antibody of TNF-α reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet,” Inflammation, vol. 31, no. 2, pp. 91–98, 2008. View at Publisher · View at Google Scholar · View at PubMed
  96. S. Naveau, S. Chollet-Martin, S. Dharancy et al., “A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis,” Hepatology, vol. 39, no. 5, pp. 1390–1397, 2004. View at Publisher · View at Google Scholar · View at PubMed
  97. R. Belfort, S. A. Harrison, K. Brown et al., “A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis,” The New England Journal of Medicine, vol. 355, no. 22, pp. 2297–2307, 2006. View at Publisher · View at Google Scholar · View at PubMed
  98. J. S. Smolen, A. Beaulieu, A. Rubbert-Roth et al., “Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial,” The Lancet, vol. 371, no. 9617, pp. 987–997, 2008. View at Publisher · View at Google Scholar · View at PubMed