Journal of Hepatology
Volume 51, Issue 1 , Pages 212-223 , July 2009

Kupffer cells in non-alcoholic fatty liver disease: The emerging view

References 

  1. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40:S17–S29
  2. Ioannou GN. Implications of elevated serum alanine aminotransferase levels: think outside the liver. Gastroenterology. 2008;135:1935–1944
  3. Cheung O, Sanyal AJ. Hepatitis C infection and nonalcoholic fatty liver disease. Clin Liver Dis. 2008;12:573–585
  4. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology. 2002;36:1349–1354
  5. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438
  6. Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Prog Liver Dis. 1986;8:283–298
  7. Day CP, James OF. Steatohepatitis: a tale of two hits?. Gastroenterology. 1998;114:842–845
  8. Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party?. Hepatology. 1998;27:1463–1466
  9. Bouwens L, Baekeland M, De Zanger R, Wisse E. Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver. Hepatology. 1986;6:718–722
  10. Smedsrod B, De Bleser PJ, Braet F, Lovisetti P, Vanderkerken K, Wisse E, et al. Cell biology of liver endothelial and Kupffer cells. Gut. 1994;35:1509–1516
  11. Decker K. Biologically active products of stimulated liver macrophages (Kupffer cells). Eur J Biochem. 1990;192:245–261
  12. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43:S54–S62
  13. Burgio VL, Ballardini G, Artini M, Caratozzolo M, Bianchi FB, Levrero M. Expression of co-stimulatory molecules by Kupffer cells in chronic hepatitis of hepatitis C virus etiology. Hepatology. 1998;27:1600–1606
  14. Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008;47:729–736
  15. Maher JJ, Leon P, Ryan JC. Beyond insulin resistance: innate immunity in nonalcoholic steatohepatitis. Hepatology. 2008;48:670–678
  16. MacPhee PJ, Schmidt EE, Groom AC. Evidence for Kupffer cell migration along liver sinusoids, from high-resolution in vivo microscopy. Am J Physiol. 1992;263:G17–G23
  17. Sleyster EC, Knook DL. Relation between localization and function of rat liver Kupffer cells. Lab Invest. 1982;47:484–490
  18. Laskin DL, Weinberger B, Laskin JD. Functional heterogeneity in liver and lung macrophages. J Leukoc Biol. 2001;70:163–170
  19. Fabriek BO, Dijkstra CD, van den Berg TK. The macrophage scavenger receptor CD163. Immunobiology. 2005;210:153–160
  20. Armbrust T, Ramadori G. Functional characterization of two different Kupffer cell populations of normal rat liver. J Hepatol. 1996;25:518–528
  21. Park JW, Jeong G, Kim SJ, Kim MK, Park SM. Predictors reflecting the pathological severity of non-alcoholic fatty liver disease: comprehensive study of clinical and immunohistochemical findings in younger Asian patients. J Gastroenterol Hepatol. 2007;22:491–497
  22. Lefkowitch JH, Haythe JH, Regent N. Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol. 2002;15:699–704
  23. Husztik E, Lazar G, Parducz A. Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol. 1980;61:624–630
  24. Hardonk MJ, Dijkhuis FW, Hulstaert CE, Koudstaal J. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J Leukoc Biol. 1992;52:296–302
  25. Andres D, Sanchez-Reus I, Bautista M, Cascales M. Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity, expression of metallothionein and HSP70. Biochem Pharmacol. 2003;66:917–926
  26. Muriel P, Escobar Y. Kupffer cells are responsible for liver cirrhosis induced by carbon tetrachloride. J Appl Toxicol. 2003;23:103–108
  27. Zhong Z, Connor HD, Mason RP, Qu W, Gao W, Lemasters JJ, et al. Role of Kupffer cells in reperfusion injury in fat-loaded livers from ethanol-treated rats. J Pharmacol Exp Ther. 1995;275:1512–1517
  28. Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH, et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. J Immunol. 2005;175:7661–7668
  29. Bautista AP, Skrepnik N, Niesman MR, Bagby GJ. Elimination of macrophages by liposome-encapsulated dichloromethylene diphosphonate suppresses the endotoxin-induced priming of Kupffer cells. J Leukoc Biol. 1994;55:321–327
  30. Hatano M, Sasaki S, Ohata S, Shiratsuchi Y, Yamazaki T, Nagata K, et al. Effects of Kupffer cell-depletion on Concanavalin A-induced hepatitis. Cell Immunol. 2008;251:25–30
  31. Goldin RD, Ratnayaka ID, Brown IN, Wickramasinghe SN. The effect of Kupffer cell elimination on ethanol-induced liver damage in mice. Int J Exp Pathol. 1995;76:353–359
  32. Goldin RD, Ratnayaka ID, Breach CS, Brown IN, Wickramasinghe SN. Role of macrophages in acetaminophen (paracetamol)-induced hepatotoxicity. J Pathol. 1996;179:432–435
  33. 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;47:571–579
  34. Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007;56:16–23
  35. Tsujimoto T, Kawaratani H, Kitazawa T, Hirai T, Ohishi H, Kitade M, et al. Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model. World J Gastroenterol. 2008;14:6036–6043
  36. Tonan T, Fujimoto K, Morita Y, Hirota N, Azuma S, Ono N, et al. Kupffer cell function in NASH patients: correlation between SPIO-MRI and histopathological findings. Hepatology. 2008;48:993A
  37. Rai RM, Zhang JX, Clemens MG, Diehl AM. Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro- and anti-inflammatory cytokines. Shock. 1996;6:243–247
  38. Rai RM, Loffreda S, Karp CL, Yang SQ, Lin HZ, Diehl AM. Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver. Hepatology. 1997;25:889–895
  39. Meijer C, Wiezer MJ, Diehl AM, Schouten HJ, Meijer S, van Rooijen N, et al. Kupffer cell depletion by CI2MDP-liposomes alters hepatic cytokine expression and delays liver regeneration after partial hepatectomy. Liver. 2000;20:66–77
  40. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–335
  41. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5
  42. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–145
  43. Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology. 2006;44:287–298
  44. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–364
  45. Kagan JC, Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell. 2006;125:943–955
  46. Fitzgerald KA, Chen ZJ. Sorting out Toll signals. Cell. 2006;125:834–836
  47. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008;48:1224–1231
  48. Szabo G, Hritz I, Velayudham A, Nath B, Catalano D, Petrasek J, et al. A novel critical role of interferon regulatory factor 3 in alcoholic liver disease. Hepatology. 2008;48:373A
  49. Zhai Y, Shen XD, O’Connell R, Gao F, Lassman C, Busuttil RW, et al. Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol. 2004;173:7115–7119
  50. Kendrick S, Leathart JB, Henderson E, De Alvis N, Stewart S, Burt AD, et al. A ‘loss-of-function’ mutation in TIRAP, the gene encoding the Toll-like receptor adapter molecule Mal protects against fibrosis in NAFLD but not ALD. Hepatology. 2008;48:334A
  51. Selvarajoo K, Takada Y, Gohda J, Helmy M, Akira S, Tomita M, et al. Signaling flux redistribution at toll-like receptor pathway junctions. PLoS ONE. 2008;3:e3430
  52. Faggioni R, Fantuzzi G, Gabay C, Moser A, Dinarello CA, Feingold KR, et al. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol. 1999;276:R136–R142
  53. 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. 1997;94:2557–2562
  54. Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Konigsrainer A, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr. 2008;138:1452–1455
  55. Mathurin P, Deng QG, Keshavarzian A, Choudhary S, Holmes EW, Tsukamoto H. Exacerbation of alcoholic liver injury by enteral endotoxin in rats. Hepatology. 2000;32:1008–1017
  56. Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008;48:983–992
  57. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37:343–350
  58. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol. 2005;39:540–543
  59. Terpstra V, van Amersfoort ES, van Velzen AG, Kuiper J, van Berkel TJ. Hepatic and extrahepatic scavenger receptors: function in relation to disease. Arterioscler Thromb Vasc Biol. 2000;20:1860–1872
  60. Ono K, Nishitani C, Mitsuzawa H, Shimizu T, Sano H, Suzuki H, et al. Mannose-binding lectin augments the uptake of lipid A, Staphylococcus aureus, and Escherichia coli by Kupffer cells through increased cell surface expression of scavenger receptor A. J Immunol. 2006;177:5517–5523
  61. Vishnyakova TG, Bocharov AV, Baranova IN, Chen Z, Remaley AT, Csako G, et al. Binding and internalization of lipopolysaccharide by Cla-1, a human orthologue of rodent scavenger receptor B1. J Biol Chem. 2003;278:22771–22780
  62. Cai L, Ji A, de Beer FC, Tannock LR, van der Westhuyzen DR. SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance. J Clin Invest. 2008;118:364–375
  63. Scott MJ, Billiar TR. Beta2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes. J Biol Chem. 2008;283:29433–29446
  64. O’Neill LA. When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction. Immunity. 2008;29:12–20
  65. Fan H, Cook JA. Molecular mechanisms of endotoxin tolerance. J Endotoxin Res. 2004;10:71–84
  66. Fujihara M, Muroi M, Tanamoto K, Suzuki T, Azuma H, Ikeda H. Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol Ther. 2003;100:171–194
  67. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4:920–927
  68. Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006;7:1074–1081
  69. Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA, Oravecz T. Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 2006;176:1899–1907
  70. Xu H, An H, Hou J, Han C, Wang P, Yu Y, et al. Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Mol Immunol. 2008;45:3545–3552
  71. An H, Hou J, Zhou J, Zhao W, Xu H, Zheng Y, et al. Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat Immunol. 2008;9:542–550
  72. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7:454–465
  73. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol. 2006;7:148–155
  74. Hagey L, Baman L, Oliver DL, Barakat F, Petcharaporn L, Karlen N, et al. Characterization of lipids in human liver biopsies of patients with severe statosis (NAFLD) using mass spectrometry. Hepatology. 2008;48:839A
  75. Shimada M, Yoshida S, Kitamura Y, Yoshino M, Yamada M, Tsuchishima M, et al. Relationship between fatty acid fractions in liver tissue and the progression of pathology in NASH. Hepatology. 2008;48:802A
  76. Farrell GC, Teoh NC, McCuskey RS. Hepatic microcirculation in fatty liver disease. Anat Rec (Hoboken). 2008;291:684–692
  77. Kim JK. Fat uses a TOLL-road to connect inflammation and diabetes. Cell Metab. 2006;4:417–419
  78. Lee JY, Hwang DH. The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors. Mol Cells. 2006;21:174–185
  79. Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 2006;4:185–198
  80. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116:3015–3025
  81. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, et al. Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem. 2003;278:37041–37051
  82. Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lutjohann D, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology. 2008;48:474–486
  83. Shiri-Sverdlov R, Wouters K, van Gorp PJ, Gijbels MJ, Noel B, Buffat L, et al. Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J Hepatol. 2006;44:732–741
  84. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35
  85. Li Z, Soloski MJ, Diehl AM. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease. Hepatology. 2005;42:880–885
  86. Guebre-Xabier M, Yang S, Lin HZ, Schwenk R, Krzych U, Diehl AM. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology. 2000;31:633–640
  87. Kremer M, Hines IN, Milton RJ, Wheeler MD. Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis. Hepatology. 2006;44:216–227
  88. Xu CF, Yu CH, Li YM, Xu L, Du J, Shen Z. Association of the frequency of peripheral natural killer T cells with nonalcoholic fatty liver disease. World J Gastroenterol. 2007;13:4504–4508
  89. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–839
  90. Sugden MC, Holness MJ. Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance. Biochem Soc Trans. 2008;36:891–900
  91. Younossi ZM. Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28:2–12
  92. Rigamonti E, Chinetti-Gbaguidi G, Staels B. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol. 2008;28:1050–1059
  93. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 2006;4:13–24
  94. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116–1120
  95. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7:496–507
  96. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, et al. Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab. 2008;7:485–495
  97. Reiman RM, Thompson RW, Feng CG, Hari D, Knight R, Cheever AW, et al. Interleukin-5 (IL-5) augments the progression of liver fibrosis by regulating IL-13 activity. Infect Immun. 2006;74:1471–1479
  98. Ikejima K, Okumura K, Kon K, Takei Y, Sato N. Role of adipocytokines in hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22:S87–S92
  99. Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol. 2008;22:1023–1031
  100. Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412–421
  101. Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60:S1–S14
  102. La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol. 2004;4:371–379
  103. Shen J, Sakaida I, Uchida K, Terai S, Okita K. Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells. Life Sci. 2005;77:1502–1515
  104. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42:1339–1348
  105. 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. 2004;41:943–949
  106. Lee TS, Lin CY, Tsai JY, Wu YL, Su KH, Lu KY, et al. Resistin increases lipid accumulation by affecting class A scavenger receptor, CD36 and ATP-binding cassette transporter-A1 in macrophages. Life Sci. 2009;84:97–104
  107. Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H, et al. Visfatin, an adipocytokine with proinflammatory and immunomodulating properties. J Immunol. 2007;178:1748–1758
  108. 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. 2006;116:1784–1792
  109. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54:117–121
  110. Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S, et al. Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem. 2004;279:30817–30822
  111. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?. Hepatology. 2004;40:46–54
  112. Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood. 2000;96:1723–1732
  113. Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem Biophys Res Commun. 2004;316:924–929
  114. Park PH, Huang H, McMullen MR, Mandal P, Sun L, Nagy LE. Suppression of lipopolysaccharide-stimulated tumor necrosis factor-alpha production by adiponectin is mediated by transcriptional and post-transcriptional mechanisms. J Biol Chem. 2008;283:26850–26858
  115. Thakur V, Pritchard MT, McMullen MR, Nagy LE. Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2006;290:G998–G1007
  116. Huang H, Park PH, McMullen MR, Nagy LE. Mechanisms for the anti-inflammatory effects of adiponectin in macrophages. J Gastroenterol Hepatol. 2008;23:S50–S53
  117. Kuga S, Otsuka T, Niiro H, Nunoi H, Nemoto Y, Nakano T, et al. Suppression of superoxide anion production by interleukin-10 is accompanied by a downregulation of the genes for subunit proteins of NADPH oxidase. Exp Hematol. 1996;24:151–157
  118. Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol. 2003;15:247–254
  119. Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973;134:707–716
  120. Forman HJ, Torres M. Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. Am J Respir Crit Care Med. 2002;166:S4–S8
  121. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4:181–189
  122. Forman HJ, Torres M, Fukuto J. Redox signaling. Mol Cell Biochem. 2002;234–235:49–62
  123. Lambeth JD. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med. 2007;43:332–347
  124. Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet. 1995;9:202–209
  125. Forman HJ, Torres M. Redox signaling in macrophages. Mol Aspects Med. 2001;22:189–216
  126. Kono H, Rusyn I, Yin M, Gabele E, Yamashina S, Dikalova A, et al. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest. 2000;106:867–872
  127. Teufelhofer O, Parzefall W, Kainzbauer E, Ferk F, Freiler C, Knasmuller S, et al. Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice. Carcinogenesis. 2005;26:319–329
  128. James LP, McCullough SS, Knight TR, Jaeschke H, Hinson JA. Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res. 2003;37:1289–1297
  129. dela Pena A, Leclercq IA, Williams J, Farrell GC. NADPH oxidase is not an essential mediator of oxidative stress or liver injury in murine MCD diet-induced steatohepatitis. J Hepatol. 2007;46:304–313
  130. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003;552:335–344
  131. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001;52:159–164
  132. Nicholls DG, Ferguson SJ. Bioenergetics: an introduction to the chemiosmotic theory. 2 ed.. New York: Academic Press; 1992;
  133. Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med. 2004;37:755–767
  134. Brand MD, Esteves TC. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2005;2:85–93
  135. Nubel T, Ricquier D. Respiration under control of uncoupling proteins: clinical perspective. Horm Res. 2006;65:300–310
  136. Mattiasson G, Sullivan PG. The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid Redox Signal. 2006;8:1–38
  137. Ryu JW, Hong KH, Maeng JH, Kim JB, Ko J, Park JY, et al. Overexpression of uncoupling protein 2 in THP1 monocytes inhibits beta2 integrin-mediated firm adhesion and transendothelial migration. Arterioscler Thromb Vasc Biol. 2004;24:864–870
  138. Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, et al. Protective role of uncoupling protein 2 in atherosclerosis. Circulation. 2003;107:388–390
  139. Kizaki T, Suzuki K, Hitomi Y, Taniguchi N, Saitoh D, Watanabe K, et al. Uncoupling protein 2 plays an important role in nitric oxide production of lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci USA. 2002;99:9392–9397
  140. Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 1999;11:809–815
  141. Arsenijevic D, Onuma H, Pecqueur C, Raimbault S, Manning BS, Miroux B, et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000;26:435–439
  142. Bai Y, Onuma H, Bai X, Medvedev AV, Misukonis M, Weinberg JB, et al. Persistent NF-kappa B activation in Ucp2−/− mice leads to enhanced nitric oxide and inflammatory cytokine production. J Biol Chem. 2005;280:19062–19069
  143. Maemura K, Zheng Q, Wada T, Ozaki M, Takao S, Aikou T, et al. Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells. Immunol Cell Biol. 2005;83:336–343
  144. Luckey SW, Petersen DR. Metabolism of 4-hydroxynonenal by rat Kupffer cells. Arch Biochem Biophys. 2001;389:77–83
  145. Baffy G. Uncoupling protein-2 and non-alcoholic fatty liver disease. Front Biosci. 2005;10:2082–2096
  146. Larrouy D, Laharrague P, Carrera G, Viguerie-Bascands N, Levi-Meyrueis C, Fleury C, et al. Kupffer cells are a dominant site of uncoupling protein 2 expression in rat liver. Biochem Biophys Res Commun. 1998;235:760–764
  147. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem. 1999;274:5692–5700
  148. Lee FY, Li Y, Yang EK, Yang SQ, Lin HZ, Trush MA, et al. Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. Am J Physiol. 1999;276:C386–C394
  149. Fulop P, Derdak Z, Sheets A, Sabo E, Berthiaume EP, Resnick MB, et al. Lack of UCP2 reduces Fas-mediated liver injury in ob/ob mice and reveals importance of cell-specific UCP2 expression. Hepatology. 2006;44:592–601
  150. Evans ZP, Ellett JD, Schmidt MG, Schnellmann RG, Chavin KD. Mitochondrial uncoupling protein-2 mediates steatotic liver injury following ischemia/reperfusion. J Biol Chem. 2007;283:8573–8579
  151. Wan CD, Wang CY, Liu T, Cheng R, Wang HB. Alleviation of ischemia/reperfusion injury in ob/ob mice by inhibiting UCP-2 expression in fatty liver. World J Gastroenterol. 2008;14:590–594
  152. Emre Y, Hurtaud C, Nubel T, Criscuolo F, Ricquier D, Cassard-Doulcier AM. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem J. 2007;402:271–278
  153. Jin X, Yu CH, Lv GC, Li YM. Increased intestinal permeability in pathogenesis and progress of nonalcoholic steatohepatitis in rats. World J Gastroenterol. 2007;13:1732–1736
  154. Zhou M, Xu A, Tam PK, Lam KS, Chan L, Hoo RL, et al. Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology. 2008;48:1087–1096
  155. James AM, Cocheme HM, Smith RA, Murphy MP. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem. 2005;280:21295–21312
  156. Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279:34682–34690
  157. Szeto HH. Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J. 2006;8:E277–E283
  158. Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci. 2008;1147:395–412
  159. Henriksen JH, Holst JJ, Moller S, Brinch K, Bendtsen F. Increased circulating leptin in alcoholic cirrhosis: relation to release and disposal. Hepatology. 1999;29:1818–1824

 The author declared that he does not have anything to disclose regarding conflict of interest with respect to this manuscript. This work was partly funded by a NIH grant DK 61890.

PII: S0168-8278(09)00170-6

doi: 10.1016/j.jhep.2009.03.008

Journal of Hepatology
Volume 51, Issue 1 , Pages 212-223 , July 2009