The Korean Journal of Medicine

  • 제79권5호
  • /
  • Pages.461-474
  • /
  • 2010
  • /
  • 1738-9364(pISSN)
  • /
  • 2289-0769(eISSN)
대한내과학회 (The Korean Association of Internal Medicine)
권호 표지

비알코올성 지방간질환의 발병기전에 대한 최신지견

Recent update on pathogenesis of nonalcoholic fatty liver disease

  • 손주현 (한양대학교 의과대학 내과학교실) ;
  • 김태엽 (한양대학교 의과대학 내과학교실)
  • Sohn, Joo-Hyun (Department of Internal Medicine, Hanyang University College of Medicine) ;
  • Kim, Tae-Yeob (Department of Internal Medicine, Hanyang University College of Medicine)
  • 발행 : 2010.11.01
⟨ 이전 논문 다음 논문 ⟩

초록

Recently, the prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in Korean population. NAFLD includes a spectrum of hepatic pathology from simple steatosis in its most benign form, to nonalcoholic steatohepatitis (NASH) and/or cirrhosis. NAFLD has a strong association with type 2 diabetes and obesity, and thus it is now recognized to represent the hepatic manifestation of metabolic syndrome. The pathogenesis of simple steatosis occurrence and its progression to NASH is not entirely elucidated and multi-factorial. Liver fat accumulation is mainly induced by insulin resistance and increased free fatty acids, and then NASH is developed by oxidative stress, lipid peroxidation, mitochondrial dysfunction, gut-derived endotoxin, and cytokine/adipokine interplay. Genetic factors and environmental factors such as exercise and high fat and high fructose diet also participate in the development of NAFLD. This review is focused to summarize the up-to-date understanding of NAFLD pathogenesis.

키워드

참고문헌

  1. Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 21:3-16, 2001 https://doi.org/10.1055/s-2001-12925
  2. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:1387-1395, 2004 https://doi.org/10.1002/hep.20466
  3. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology 129:375-378, 2005 https://doi.org/10.1053/j.gastro.2005.05.041
  4. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44:865-873, 2006 https://doi.org/10.1002/hep.21327
  5. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology 40:820-826, 2004
  6. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129:113-124, 2005 https://doi.org/10.1053/j.gastro.2005.04.014
  7. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116:1413-1419, 1999 https://doi.org/10.1016/S0016-5085(99)70506-8
  8. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 114:842-845, 1998 https://doi.org/10.1016/S0016-5085(98)70599-2
  9. Harrison SA, Kadakia S, Lang KA, Schenker S. Nonalcoholic steatohepatitis: what we know in the new millennium. Am J Gastroenterol 97:2714-2724, 2002
  10. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45:1366-1374, 2007 https://doi.org/10.1002/hep.21655
  11. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40:185-194, 2004 https://doi.org/10.1002/hep.20283
  12. Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 28:370-379, 2008 https://doi.org/10.1055/s-0028-1091981
  13. Gambino R, Cassader M, Pagano G, Durazzo M, Musso G. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 45:1097-1107, 2007 https://doi.org/10.1002/hep.21631
  14. Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: possible pathogenetic role in NASH. Hepatology 47:1167-1177, 2008 https://doi.org/10.1002/hep.22142
  15. Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, Akisawa N, Saibara T, Hiroi M, Enzan H, Onishi S. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 40:781-786, 2004 https://doi.org/10.1016/j.jhep.2004.01.028
  16. Miele L, Beale G, Patman G, Nobili V, Leathart J, Grieco A, Abate M, Friedman SL, Narla G, Bugianesi E, Day CP, Reeves HL. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology 135:282-291, 2008 https://doi.org/10.1053/j.gastro.2008.04.004
  17. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461-1465, 2008 https://doi.org/10.1038/ng.257
  18. Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, Dziura J, Lifton RP, Shulman GI. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 362:1082-1089, 2010 https://doi.org/10.1056/NEJMoa0907295
  19. Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, Faga E, Silli B, Pagano G. Dietary habits and their relations to insulin resistance and postprandial lipemia in non-alcoholic steatohepatitis. Hepatology 37:909-916, 2003 https://doi.org/10.1053/jhep.2003.50132
  20. Toshimitsu K, Matsuura B, Ohkubo I, Niiya T, Furukawa S, Hiasa Y, Kawamura M, Ebihara K, Onji M. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition 23:46-52, 2007 https://doi.org/10.1016/j.nut.2006.09.004
  21. Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 48:983-992, 2008 https://doi.org/10.1016/j.jhep.2008.01.035
  22. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295:G987-G995, 2008 https://doi.org/10.1152/ajpgi.90272.2008
  23. Suzuki A, Lindor K, St Saver J, Lymp J, Mendes F, Muto A, Okada T, Angulo P. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol 43:1060-1066, 2005 https://doi.org/10.1016/j.jhep.2005.06.008
  24. Kechagias S, Ernersson A, Dahlqvist O, Lundberg P, Lindstrom T, Nystrom FH. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut 57:649-654, 2008 https://doi.org/10.1136/gut.2007.131797
  25. Barres R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, Krook A, Zierath JR. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 10:189-198, 2009 https://doi.org/10.1016/j.cmet.2009.07.011
  26. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 42:132-138, 2005
  27. Cheung O, Sanyal AJ. Abnormalities of lipid metabolism in non-alcoholic fatty liver disease. Semin Liver Dis 28:351-359, 2008 https://doi.org/10.1055/s-0028-1091979
  28. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343-1351, 2005
  29. Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46:1081-1090, 2007 https://doi.org/10.1002/hep.21763
  30. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 48:1-26, 2008
  31. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med 10:355-361, 2004 https://doi.org/10.1038/nm1025
  32. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123:134-140, 2002 https://doi.org/10.1053/gast.2002.34168
  33. Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B Jr, Reitman ML, Gonzalez FJ. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 111:737-747, 2003
  34. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125-1131, 2002
  35. Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 101:7281-7286, 2004 https://doi.org/10.1073/pnas.0401516101
  36. Dentin R, Pegorier JP, Benhamed F, Foufelle F, Ferre P, Fauveau V, Magnuson MA, Girard J, Postic C. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J Biol Chem 279:20314-20326, 2004 https://doi.org/10.1074/jbc.M312475200
  37. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, Postic C. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55:2159-2170, 2006 https://doi.org/10.2337/db06-0200
  38. Schreuder TC, Verwer BJ, van Nieuwkerk CM, Mulder CJ. Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol 14:2474-2486, 2008 https://doi.org/10.3748/wjg.14.2474
  39. Semple RK, Chatterjee VK, O'Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest 116:581-589, 2006 https://doi.org/10.1172/JCI28003
  40. Pfutzner A, Hohberg C, Lubben G, Pahler S, Pfutzner AH, Kann P, Forst T. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Horm Metab Res 37:510-515, 2005 https://doi.org/10.1055/s-2005-870320
  41. Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV, Rao MS, Gonzalez FJ, Reddy JK. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem 278:498-505, 2003
  42. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114:147-152, 2004
  43. Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat? J Hepatol 44:253-261, 2006 https://doi.org/10.1016/j.jhep.2005.11.030
  44. Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, Saez E. The nuclear receptor LXR is a glucose sensor. Nature 445:219-223, 2007 https://doi.org/10.1038/nature05449
  45. Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134:556-567, 2008 https://doi.org/10.1053/j.gastro.2007.11.037
  46. Denechaud PD, Dentin R, Girard J, Postic C. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett 582:68-73, 2008 https://doi.org/10.1016/j.febslet.2007.07.084
  47. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434-5446, 2004 https://doi.org/10.1128/MCB.24.12.5434-5446.2004
  48. Tendler D, Lin S, Yancy WS Jr, Mavropoulos J, Sylvestre P, Rockey DC, Westman EC. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci 52:589-593, 2007 https://doi.org/10.1007/s10620-006-9433-5
  49. Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S, Torimura T, Inuzuka S, Sata M, Tanikawa K. Therapeutic effects of restrictra diet and exercise in obese patients with fatty liver. J Hepatol In:103-107, 1997
  50. Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, Bouloumie A. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia 49:744-747, 2006 https://doi.org/10.1007/s00125-006-0173-z
  51. Wang Y, Lam KS, Kraegen EW, Sweeney G, Zhang J, Tso AW, Chow WS, Wat NM, Xu JY, Hoo RL, Xu A. Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans. Clin Chem 53:34-41, 2007
  52. Petta S, Muratore C, Craxi A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis 41:615-625, 2009 https://doi.org/10.1016/j.dld.2009.01.004
  53. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48:449-457, 2008 https://doi.org/10.1002/hep.22350
  54. Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Clin Endocrinol 64:355-365, 2006
  55. Le Roith D, Zick Y. Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care 24:588-597, 2001 https://doi.org/10.2337/diacare.24.3.588
  56. Ferre P, Foufelle F. SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68:72-82, 2007 https://doi.org/10.1159/000100426
  57. Park SH. Nonalcoholic steatohepatitis: pathogenesis and treatment. Korean J Hepatol 14:12-27, 2008 https://doi.org/10.3350/kjhep.2008.14.1.12
  58. Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113:2813-2819, 2000
  59. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98:7522-7527, 2001 https://doi.org/10.1073/pnas.121164498
  60. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183-1192, 2001 https://doi.org/10.1053/gast.2001.23256
  61. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34:738-744, 2001 https://doi.org/10.1053/jhep.2001.28055
  62. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457-461, 2004 https://doi.org/10.1126/science.1103160
  63. Svegliati-Baroni G, Ridolfi F, Di Sario A, Casini A, Marucci L, Gaggiotti G, Orlandoni P, Macarri G, Perego L, Benedetti A, Folli F. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology 29:1743-1751, 1999 https://doi.org/10.1002/hep.510290632
  64. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107:450-455, 1999 https://doi.org/10.1016/S0002-9343(99)00271-5
  65. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784-44790, 2002 https://doi.org/10.1074/jbc.M207217200
  66. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A 97:12222-12226, 2000 https://doi.org/10.1073/pnas.97.22.12222
  67. Perez-Carreras M, Del Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, Colina F, Arenas J, Solis-Herruzo JA. Defective hepatic mitochondrial respiratory chain in patients with non-alcoholic steatohepatitis. Hepatology 38:999-1007, 2003
  68. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int 26:1175-1186, 2006 https://doi.org/10.1111/j.1478-3231.2006.01342.x
  69. Lefkowitch JH, Haythe JH, Regent N. Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol 15:699-704, 2002 https://doi.org/10.1097/01.MP.0000019579.30842.96
  70. Huang H, Liu T, Rose JL, Stevens RL, Hoyt DG. Sensitivity of mice to lipopolysaccharide is increased by a high saturated fat and cholesterol diet. J Inflamm 4:22, 2007 https://doi.org/10.1186/1476-9255-4-22
  71. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343-350, 2003 https://doi.org/10.1053/jhep.2003.50048
  72. Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 49:821-830, 2008 https://doi.org/10.1016/j.jhep.2008.05.025
  73. Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, Szabo G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 49:989-997, 2009 https://doi.org/10.1002/hep.22711
  74. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, Olefsky JM, Brenner DA, Seki E. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 139:323-334, 2010 https://doi.org/10.1053/j.gastro.2010.03.052
  75. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology 50:957-969, 2009 https://doi.org/10.1002/hep.23046
  76. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784-1792, 2006 https://doi.org/10.1172/JCI29126
  77. Wedemeyer I, Bechmann LP, Odenthal M, Jochum C, Marquitan G, Drebber U, Gerken G, Gieseler RK, Dienes HP, Canbay A. Adiponectin inhibits steatotic CD95/Fas up-regulation by hepatocytes: therapeutic implications for hepatitis C. J Hepatol 50:140-149, 2009 https://doi.org/10.1016/j.jhep.2008.08.023
  78. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived horhorhoadiponectin alleviates alcoholic and non-alcoholic fatty liver diseases in mice. J Clin Invest 112:91-100, 2003
  79. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40:46-54, 2004
  80. Bugianesi E, Pagotto U, Manini R, Vanni E, Gastaldelli A, de Iasio R, Gentilcore E, Natale S, Cassader M, Rizzetto M, Pasquali R, Marchesini G. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab 90:3498-3504, 2005 https://doi.org/10.1210/jc.2004-2240
  81. Baranova A, Gowder SJ, Schlauch K, Elariny H, Collantes R, Afendy A, Ong JP, Goodman Z, Chandhoke V, Younossi ZM. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance. Obes Surg 16:1118-1125, 2006 https://doi.org/10.1381/096089206778392149
  82. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut 54:117-121, 2005 https://doi.org/10.1136/gut.2003.037010
  83. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 41:753-760, 2005 https://doi.org/10.1002/hep.20672
  84. Park JH. Insulin resistance in non-alcoholic fatty liver disease. Korean J Hepatol 12:16-30, 2006
  85. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci USA 94:2557-2562, 1997 https://doi.org/10.1073/pnas.94.6.2557
  86. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA. 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, 2007 https://doi.org/10.1158/0008-5472.CAN-06-3075
  87. Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Batkai S, Marsicano G, Lutz B, Buettner C, Kunos G. Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160-3169, 2008 https://doi.org/10.1172/JCI34827
  88. Uygun A, Kadayifci A, Yesilova Z, Erdil A, Yaman H, Saka M, Deveci MS, Bagci S, Gulsen M, Karaeren N, Dagalp K. Serum leptin levels in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 95:3584-3589, 2000 https://doi.org/10.1111/j.1572-0241.2000.03297.x
  89. Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 36:403-409, 2002 https://doi.org/10.1053/jhep.2002.34738
  90. Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, Considine RV. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 98:2771-2776, 2003 https://doi.org/10.1111/j.1572-0241.2003.08767.x
  91. Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol 41:943-949, 2004 https://doi.org/10.1016/j.jhep.2004.08.020
  92. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992-3002, 2008 https://doi.org/10.1172/JCI34260
  93. Tafani M, Schneider TG, Pastorino JG, Farber JL. Cytochrome c-dependent activation of caspase-3 by tumor necrosis factor requires induction of the mitochondrial permeability transition. Am J Pathol 156:2111-2121, 2000 https://doi.org/10.1016/S0002-9440(10)65082-1
  94. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44:27-33, 2006
  95. Shapiro L, Scherer PE. The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8:335-338, 1998 https://doi.org/10.1016/S0960-9822(98)70133-2
  96. Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413-419, 2003
  97. Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, Donnini D, Faggian D, Mussap M, Plebani M, Avellini C, Federspil G, Sechi LA, Vettor R. Increased serum resistin in non-alcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 91:1081-1086, 2006
  98. Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med 14:741-751, 2008
  99. Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab 6:363-375, 2007 https://doi.org/10.1016/j.cmet.2007.09.003
  100. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, Fritsche A, Haring HU. High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans. Diabetes Care 30:1173-1178, 2007 https://doi.org/10.2337/dc06-2342
  101. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 39:978-983, 2003 https://doi.org/10.1016/S0168-8278(03)00460-4
  102. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437-443, 2003 https://doi.org/10.1016/S0016-5085(03)00907-7
  103. McAvoy NC, Ferguson J, Campbell I, Hayes P. Review: Non-alcoholic fatty liver disease: natural history, pathogenesis and treatment. Br J Diabet Vasc Dis 6:251-260, 2006 https://doi.org/10.1177/14746514060060060201