Journal of Gastroenterology

, Volume 47, Issue 3, pp 215–225 | Cite as

Inflammation and fibrogenesis in steatohepatitis

  • Hideki Fujii
  • Norifumi Kawada


Nonalcoholic fatty liver disease consists of a range of disorders characterized by excess accumulation of triglyceride within the liver. Whereas simple steatosis is clinically benign, nonalcoholic steatohepatitis (NASH) often progresses to cirrhosis. Inflammation and fibrogenesis are closely inter-related and are major targets of NASH research. Experimental data have shown that inflammation in NASH is caused by insulin resistance, systemic lipotoxicity due to overnutrition, lipid metabolites, the production of proinflammatory cytokines and adipokines by visceral adipose tissue, gut-derived bacteria, and oxidative stress. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is recognized as the hepatic stellate cell. Although the fibrotic mechanisms underlying NASH are largely similar to those observed in other chronic liver diseases, the altered patterns of circulating adipokines, the generation of oxidative stress, and the hormonal profile associated with the metabolic syndrome might play unique roles in the fibrogenesis associated with the disease. Information on the basic pathogenesis of NASH with a focus on the generation of inflammation and fibrosis will be discussed.


Insulin resistance Lipotoxicity Adipokine Oxidative stress Stellate cell 



Cytochrome P450 2E1


Free fatty acids


Farnesoid X receptor


Hepatic stellate cells




Nonalcoholic fatty liver disease


Nonalcoholic steatohepatitis


Nuclear factor kappa B


NADPH oxidase


Peroxisome proliferator-activated receptor


Reactive oxygen species


Transforming growth factor-β1


Toll-like receptors


Tumor necrosis factor



This work was supported by a grant from the Ministry of Health, Labor and Welfare of Japan to N. Kawada (2008–2010), and by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science through grant 23790806 to H. Fujii (2011).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:511–31.PubMedCrossRefGoogle Scholar
  2. 2.
    Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.PubMedCrossRefGoogle Scholar
  3. 3.
    Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.PubMedCrossRefGoogle Scholar
  7. 7.
    Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol. 2004;40:578–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Day CP, James OF. Hepatic steatosis: innocent bystander or guilty party? Hepatology. 1998;27:1463–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol. 2003;163:1301–11.PubMedCrossRefGoogle Scholar
  15. 15.
    Jou J, Choi SS, Diehl AM. Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:370–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Arrese M. Burning hepatic fat: therapeutic potential for liver-specific thyromimetics in the treatment of nonalcoholic fatty liver disease. Hepatology. 2009;49:348–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.PubMedCrossRefGoogle Scholar
  18. 18.
    Bugianesi E, Moscatiello S, Ciaravella MF, Marchesini G. Insulin resistance in nonalcoholic fatty liver disease. Curr Pharm Des. 2010;16:1941–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Stefan N, Kantartzis K, Haring HU. Causes and metabolic consequences of fatty liver. Endocr Rev. 2008;29:939–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Ota T, Takamura T, Kurita S, Matsuzawa N, Kita Y, Uno M, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132:282–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Bugianesi E, Marchesini G, Gentilcore E, Cua IH, Vanni E, Rizzetto M, et al. Fibrosis in genotype 3 chronic hepatitis C and nonalcoholic fatty liver disease: role of insulin resistance and hepatic steatosis. Hepatology. 2006;44:1648–55.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA. 1994;91:10878–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev. 2008;60:311–57.PubMedCrossRefGoogle Scholar
  25. 25.
    Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.PubMedCrossRefGoogle Scholar
  27. 27.
    Nieto N. Ethanol and fish oil induce NFkappaB transactivation of the collagen alpha2(I) promoter through lipid peroxidation-driven activation of the PKC-PI3K-Akt pathway. Hepatology 2007;45:1433–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125–72.PubMedCrossRefGoogle Scholar
  29. 29.
    Kawada N. Evolution of hepatic fibrosis research. Hepatol Res. 2011;41:199–208.PubMedCrossRefGoogle Scholar
  30. 30.
    Ikejima K, Okumura K, Kon K, Takei Y, Sato N. Role of adipocytokines in hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22(Suppl 1):S87–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol. 2008;22:1023–31.PubMedCrossRefGoogle Scholar
  32. 32.
    De Minicis S, Svegliati-Baroni G. Fibrogenesis in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:179–87.PubMedCrossRefGoogle Scholar
  33. 33.
    Ogawa W, Kasuga M. Cell signaling. Fat stress and liver resistance. Science. 2008;322:1483–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Su GL. Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol. 2002;283:G256–65.PubMedGoogle Scholar
  36. 36.
    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. 2003;39:978–83.PubMedCrossRefGoogle Scholar
  37. 37.
    Tomita K, Tamiya G, Ando S, Ohsumi K, Chiyo T, Mizutani A, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut. 2006;55:415–24.PubMedCrossRefGoogle Scholar
  38. 38.
    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;37:343–50.PubMedCrossRefGoogle Scholar
  39. 39.
    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;27:412–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Manco M, Marcellini M, Giannone G, Nobili V. Correlation of serum TNF-alpha levels and histologic liver injury scores in pediatric nonalcoholic fatty liver disease. Am J Clin Pathol. 2007;127:954–60.PubMedCrossRefGoogle Scholar
  41. 41.
    Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34:1158–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1946–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54:1610–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–3.PubMedCrossRefGoogle Scholar
  45. 45.
    van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48:449–57.PubMedCrossRefGoogle Scholar
  46. 46.
    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11:183–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med. 1999;130:671–80.PubMedGoogle Scholar
  48. 48.
    Lord G. Role of leptin in immunology. Nutr Rev. 2002;60:S35–8. discussion S68–84, 5–7.Google Scholar
  49. 49.
    Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol. 2005;174:3137–42.PubMedGoogle Scholar
  50. 50.
    Leclercq IA, Farrell GC, Schriemer R, Robertson GR. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002;37:206–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Potter JJ, Rennie-Tankesley L, Mezey E. Influence of leptin in the development of hepatic fibrosis produced in mice by Schistosoma mansoni infection and by chronic carbon tetrachloride administration. J Hepatol 2003;38:281–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology. 2002;122:1399–410.PubMedCrossRefGoogle Scholar
  53. 53.
    Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, et al. Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. FASEB J. 2004;18:1612–4.PubMedGoogle Scholar
  54. 54.
    De Minicis S, Seki E, Oesterreicher C, Schnabl B, Schwabe RF, Brenner DA. Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology. 2008;48:2016–26.PubMedCrossRefGoogle Scholar
  55. 55.
    Testa R, Franceschini R, Giannini E, Cataldi A, Botta F, Fasoli A, et al. Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis. J Hepatol. 2000;33:33–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang YY, Lin SY. Leptin in relation to hepatocellular carcinoma in patients with liver cirrhosis. Horm Res. 2003;60:185–90.PubMedCrossRefGoogle Scholar
  57. 57.
    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;41:943–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology. 2002;36:403–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol. 2003;98:2771–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun. 1996;221:286–9.PubMedCrossRefGoogle Scholar
  61. 61.
    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;116:1784–92.PubMedCrossRefGoogle Scholar
  62. 62.
    Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112:91–100.PubMedGoogle Scholar
  63. 63.
    Asano T, Watanabe K, Kubota N, Gunji T, Omata M, Kadowaki T, et al. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol. 2009;24:1669–76.PubMedCrossRefGoogle Scholar
  64. 64.
    Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007;47:556–64.PubMedCrossRefGoogle Scholar
  65. 65.
    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;54:117–21.PubMedCrossRefGoogle Scholar
  66. 66.
    Louthan MV, Barve S, McClain CJ, Joshi-Barve S. Decreased serum adiponectin: an early event in pediatric nonalcoholic fatty liver disease. J Pediatr. 2005;147:835–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Aller R, de Luis DA, Fernandez L, Calle F, Velayos B, Olcoz JL, et al. Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease. Dig Dis Sci. 2008;53:1088–92.PubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–12.PubMedCrossRefGoogle Scholar
  70. 70.
    Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, et al. Regulation of fasted blood glucose by resistin. Science. 2004;303:1195–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Sato N, Kobayashi K, Inoguchi T, Sonoda N, Imamura M, Sekiguchi N, et al. Adenovirus-mediated high expression of resistin causes dyslipidemia in mice. Endocrinology. 2005;146:273–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes. 2001;50:2199–202.PubMedCrossRefGoogle Scholar
  73. 73.
    Curat CA, Wegner V, Sengenes C, Miranville A, Tonus C, Busse R, et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia. 2006;49:744–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Bertolani C, Sancho-Bru P, Failli P, Bataller R, Aleffi S, DeFranco R, et al. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol. 2006;169:2042–53.PubMedCrossRefGoogle Scholar
  75. 75.
    Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab. 2006;91:1081–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1135–9.PubMedGoogle Scholar
  77. 77.
    Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1497–502.PubMedCrossRefGoogle Scholar
  78. 78.
    Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, et al. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:850–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol. 2002;37:56–62.PubMedCrossRefGoogle Scholar
  80. 80.
    Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, et al. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology. 2005;41:1272–81.PubMedCrossRefGoogle Scholar
  81. 81.
    Mizrahi A, Molshanski-Mor S, Weinbaum C, Zheng Y, Hirshberg M, Pick E. Activation of the phagocyte NADPH oxidase by Rac Guanine nucleotide exchange factors in conjunction with ATP and nucleoside diphosphate kinase. J Biol Chem. 2005;280:3802–11.PubMedCrossRefGoogle Scholar
  82. 82.
    Wheeler MD, Kono H, Yin M, Nakagami M, Uesugi T, Arteel GE, et al. The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med. 2001;31:1544–9.PubMedCrossRefGoogle Scholar
  83. 83.
    De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys. 2007;462:266–72.PubMedCrossRefGoogle Scholar
  84. 84.
    Reinehr R, Becker S, Eberle A, Grether-Beck S, Haussinger D. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem. 2005;280:27179–94.PubMedCrossRefGoogle Scholar
  85. 85.
    De Minicis S, Bataller R, Brenner DA. NADPH oxidase in the liver: defensive, offensive, or fibrogenic? Gastroenterology. 2006;131:272–5.PubMedCrossRefGoogle Scholar
  86. 86.
    De Minicis S, Seki E, Paik YH, Osterreicher CH, Kodama Y, Kluwe J, et al. Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. Hepatology. 2010;52:1420–30.PubMedCrossRefGoogle Scholar
  87. 87.
    Serviddio G, Bellanti F, Vendemiale G, Altomare E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5:233–44.PubMedCrossRefGoogle Scholar
  88. 88.
    Petta S, Muratore C, Craxi A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis. 2009;41:615–25.PubMedCrossRefGoogle Scholar
  89. 89.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.PubMedCrossRefGoogle Scholar
  90. 90.
    Perez-Carreras M, Del Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38:999–1007.PubMedGoogle Scholar
  91. 91.
    St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127:397–408.PubMedCrossRefGoogle Scholar
  92. 92.
    Reddy JK, Mannaerts GP. Peroxisomal lipid metabolism. Annu Rev Nutr. 1994;14:343–70.PubMedCrossRefGoogle Scholar
  93. 93.
    Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B, Hall SD, et al. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology. 2003;37:544–50.PubMedCrossRefGoogle Scholar
  94. 94.
    Bartlett K, Eaton S. Mitochondrial beta-oxidation. Eur J Biochem. 2004;271:462–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Weltman MD, Farrell GC, Liddle C. Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation. Gastroenterology. 1996;111:1645–53.PubMedCrossRefGoogle Scholar
  96. 96.
    Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology. 1998;27:128–33.PubMedCrossRefGoogle Scholar
  97. 97.
    Kathirvel E, Morgan K, French SW, Morgan TR. Overexpression of liver-specific cytochrome P4502E1 impairs hepatic insulin signaling in a transgenic mouse model of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2009;21:973–83.PubMedCrossRefGoogle Scholar
  98. 98.
    Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol. 2011;5:201–12.PubMedCrossRefGoogle Scholar
  99. 99.
    Barreyro FJ, Kobayashi S, Bronk SF, Werneburg NW, Malhi H, Gores GJ. Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis. J Biol Chem. 2007;282:27141–54.PubMedCrossRefGoogle Scholar
  100. 100.
    Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–98.PubMedCrossRefGoogle Scholar
  101. 101.
    Cazanave SC, Gores GJ. Mechanisms and clinical implications of hepatocyte lipoapoptosis. Clin Lipidol. 2010;5:71–85.PubMedCrossRefGoogle Scholar
  102. 102.
    Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA, Agboola KM, et al. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology. 2009;50:1421–30.PubMedCrossRefGoogle Scholar
  103. 103.
    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. 2006;44:27–33.PubMedCrossRefGoogle Scholar
  104. 104.
    Younossi ZM, Jarrar M, Nugent C, Randhawa M, Afendy M, Stepanova M, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg. 2008;18:1430–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Anty R, Iannelli A, Patouraux S, Bonnafous S, Lavallard VJ, Senni-Buratti M, et al. A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients. Aliment Pharmacol Ther. 2010;32:1315–22.PubMedCrossRefGoogle Scholar
  106. 106.
    Musso G, Gambino R, Durazzo M, Cassader M. Noninvasive assessment of liver disease severity with liver fat score and CK-18 in NAFLD: prognostic value of liver fat equation goes beyond hepatic fat estimation. Hepatology. 2010;51:715–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Bataller R, Sancho-Bru P, Gines P, Brenner DA. Liver fibrogenesis: a new role for the renin–angiotensin system. Antioxid Redox Signal. 2005;7:1346–55.PubMedCrossRefGoogle Scholar
  108. 108.
    Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, et al. Activated human hepatic stellate cells express the renin–angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125:117–25.PubMedCrossRefGoogle Scholar
  109. 109.
    Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000;118:1149–56.PubMedCrossRefGoogle Scholar
  110. 110.
    Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112:1383–94.PubMedGoogle Scholar
  111. 111.
    Moreno M, Bataller R. Cytokines and renin–angiotensin system signaling in hepatic fibrosis. Clin Liver Dis. 2008;12:825–52, ix.Google Scholar
  112. 112.
    Kamada Y, Tamura S, Kiso S, Fukui K, Doi Y, Ito N, et al. Angiotensin II stimulates the nuclear translocation of Smad2 and induces PAI-1 mRNA in rat hepatic stellate cells. Hepatol Res. 2003;25:296–305.Google Scholar
  113. 113.
    Kanno K, Tazuma S, Nishioka T, Hyogo H, Chayama K. Angiotensin II participates in hepatic inflammation and fibrosis through MCP-1 expression. Dig Dis Sci. 2005;50:942–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Yang L, Bataller R, Dulyx J, Coffman TM, Gines P, Rippe RA, et al. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005;43:317–23.PubMedCrossRefGoogle Scholar
  115. 115.
    Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol. 2009;15:942–54.PubMedCrossRefGoogle Scholar
  116. 116.
    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;94:2557–62.PubMedCrossRefGoogle Scholar
  117. 117.
    Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 2007;13:1324–32.PubMedCrossRefGoogle Scholar
  118. 118.
    Brun P, Castagliuolo I, Pinzani M, Palu G, Martines D. Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2005;289:G571–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–35.PubMedCrossRefGoogle Scholar
  120. 120.
    Elfaki DA, Bjornsson E, Lindor KD. Review article: nuclear receptors and liver disease–current understanding and new therapeutic implications. Aliment Pharmacol Ther. 2009;30:816–25.PubMedCrossRefGoogle Scholar
  121. 121.
    Trauner M, Halilbasic E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology. 2011;140:1120–5.PubMedCrossRefGoogle Scholar
  122. 122.
    Svegliati-Baroni G, Candelaresi C, Saccomanno S, Ferretti G, Bachetti T, Marzioni M, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol. 2006;169:846–60.PubMedCrossRefGoogle Scholar
  123. 123.
    Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol. 2008;14:6395–400.PubMedCrossRefGoogle Scholar
  124. 124.
    Cussons AJ, Watts GF, Mori TA, Stuckey BG. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab. 2009;94:3842–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28:551–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology. 2002;122:1924–40.PubMedCrossRefGoogle Scholar
  127. 127.
    Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology. 2000;119:466–78.PubMedCrossRefGoogle Scholar
  128. 128.
    Ratziu V, Caldwell S, Neuschwander-Tetri BA. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology. 2010;52:2206–15.PubMedCrossRefGoogle Scholar
  129. 129.
    Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem. 2001;276:28857–65.PubMedCrossRefGoogle Scholar
  130. 130.
    Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002;277:2908–15.PubMedCrossRefGoogle Scholar
  131. 131.
    Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45:3569–72.PubMedCrossRefGoogle Scholar
  132. 132.
    Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17:259–72.Google Scholar
  133. 133.
    Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116:1102–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312:233–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Batkai S, Kunos G. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension. 2008;52:601–7.PubMedCrossRefGoogle Scholar
  136. 136.
    Teixeira-Clerc F, Julien B, Grenard P, Tran Van Nhieu J, Deveaux V, Li L, et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med. 2006;12:671–6.PubMedCrossRefGoogle Scholar
  137. 137.
    Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 2005;128:742–55.PubMedCrossRefGoogle Scholar
  138. 138.
    Van Gaal LF, Scheen AJ, Rissanen AM, Rossner S, Hanotin C, Ziegler O. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur Heart J. 2008;29:1761–71.PubMedCrossRefGoogle Scholar
  139. 139.
    Janero DR, Makriyannis A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin Emerg Drugs. 2009;14:43–65.PubMedCrossRefGoogle Scholar
  140. 140.
    Daly AK, Ballestri S, Carulli L, Loria P, Day CP. Genetic determinants of susceptibility and severity in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol. 2011;5:253–63.PubMedCrossRefGoogle Scholar
  141. 141.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.PubMedCrossRefGoogle Scholar
  142. 142.
    Qiao A, Liang J, Ke Y, Li C, Cui Y, Shen L, et al. Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis. Hepatology. 2011;54:509–21.PubMedCrossRefGoogle Scholar
  143. 143.
    Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148 M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1209–17.PubMedCrossRefGoogle Scholar
  144. 144.
    Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, et al. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC Med Genet. 2010;11:172.PubMedCrossRefGoogle Scholar
  145. 145.
    Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology. 2010;139:1567–76.PubMedCrossRefGoogle Scholar
  146. 146.
    Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 2011;7:e1001324.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Department of Hepatology, Graduate School of MedicineOsaka City UniversityOsakaJapan

Personalised recommendations