Digestive and Liver Disease
Volume 42, Issue 5 , Pages 320-330 , May 2010

From the metabolic syndrome to NAFLD or vice versa?

  • Ester Vanni

      Affiliations

    • Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, C. so Bramante 88, 10126 Turin, Italy
  • ,
  • Elisabetta Bugianesi

      Affiliations

    • Division of Gastro-Hepatology, San Giovanni Battista Hospital, University of Turin, C. so Bramante 88, 10126 Turin, Italy
    • Corresponding Author InformationCorresponding author. Fax: +39 011 6335927.
  • ,
  • Anna Kotronen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
  • ,
  • Samuele De Minicis

      Affiliations

    • Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
  • ,
  • Hannele Yki-Järvinen

      Affiliations

    • Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
    • Minerva Medical Research Institute, Helsinki, Finland
  • ,
  • Gianluca Svegliati-Baroni

      Affiliations

    • Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy

Received 5 January 2010 ,Accepted 17 January 2010.

References 

  1. Alberti KG, Zimmet P, Shaw J IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059–1062
  2. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology. 2003;37(5):1202–1219
  3. Kotronen A, Westerbacka J, Bergholm R, et al. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92(9):3490–3497
  4. Yki-Jarvinen H. Action of insulin on glucose metabolism in vivo. Baillieres Clin Endocrinol Metab. 1993;7(4):903–927
  5. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87(7):3023–3028
  6. Bugianesi E, Gastaldelli A, Vanni E, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48(4):634–642
  7. Juurinen L, Tiikkainen M, Hakkinen AM, et al. Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292(3):E829–E835
  8. Vollenweider P, Randin D, Tappy L, et al. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. J Clin Invest. 1994;93(6):2365–2371
  9. Ferrari P, Weidmann P. Insulin, insulin sensitivity and hypertension. J Hypertens. 1990;8(6):491–500
  10. Lewis GF, Uffelman KD, Szeto LW, et al. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes. 1993;42(6):833–842
  11. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49(4):755–765
  12. Fabbrini E, Mohammed BS, Magkos F, et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134(2):424–431
  13. Adiels M, Westerbacka J, Soro-Paavonen A, et al. Acute suppression of VLDL(1) secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia. 2007;50(11):2356–2365
  14. Taskinen MR. Type 2 diabetes as a lipid disorder. Curr Mol Med. 2005;5(3):297–308
  15. Rashid S, Watanabe T, Sakaue T, et al. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem. 2003;36(6):421–429
  16. Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29(7):777–822
  17. Schindhelm RK, Dekker JM, Nijpels G, et al. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the hoorn study. Atherosclerosis. 2006;
  18. Meisinger C, Doring A, Schneider A, et al. Serum gamma-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population. Atherosclerosis. 2006;189(2):297–302
  19. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13(10):1579–1584
  20. Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;
  21. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the united states. Am J Gastroenterol. 2003;98(5):960–967
  22. Kotronen A, Yki-Jarvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(1):27–38
  23. Sattar N, McConnachie A, Ford I, et al. Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: Specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor. Diabetes. 2007;56(4):984–991
  24. Kotronen A, Juurinen L, Hakkarainen A, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31(1):165–169
  25. Kotronen A, Juurinen L, Tiikkainen M, et al. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 2008;135(1):122–130
  26. Kotronen A, Vehkavaara S, Seppala-Lindroos A, et al. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293(6):E1709–E1715
  27. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351
  28. Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med. 2005;37(5):347–356
  29. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26(3):439–451
  30. Westerbacka J, Kolak M, Kiviluoto T, et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes. 2007;56(11):2759–2765
  31. Makkonen J, Westerbacka J, Kolak M, et al. Increased expression of the macrophage markers and of 11beta-HSD-1 in subcutaneous adipose tissue, but not in cultured monocyte-derived macrophages, is associated with liver fat in human obesity. Int J Obes (Lond). 2007;
  32. Kolak M, Westerbacka J, Velagapudi VR, et al. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes. 2007;56(8):1960–1968
  33. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007;5(3):167–179
  34. Schmitz-Peiffer C, Craig DL, Biden TJ. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem. 1999;274(34):24202–24210
  35. Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9(2):139–150
  36. Hannun YA, Obeid LM. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem. 2002;277(29):25847–25850
  37. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006;45(1):42–72
  38. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97–105
  39. Aarsland A, Wolfe RR. Hepatic secretion of VLDL fatty acids during stimulated lipogenesis in men. J Lipid Res. 1998;39(6):1280–1286
  40. Korchak HM. Regulation of hepatic lipogenesis. Tufts Folia Med. 1962;8:134–143
  41. Higuchi N, Kato M, Shundo Y, et al. Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res. 2008;38(11):1122–1129
  42. Kotronen A, Seppanen-Laakso T, Westerbacka J, et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes. 2009;58(1):203–208
  43. Hannah VC, Ou J, Luong A, et al. Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem. 2001;276(6):4365–4372
  44. Xu J, Nakamura MT, Cho HP, et al. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem. 1999;274(33):23577–23583
  45. Lehner R, Kuksis A. Biosynthesis of triacylglycerols. Prog Lipid Res. 1996;35(2):169–201
  46. Shmueli E, Alberti KG, Record CO. Diacylglycerol/protein kinase C signalling: a mechanism for insulin resistance?. J Intern Med. 1993;234(4):397–400
  47. Tiikkainen M, Bergholm R, Vehkavaara S, et al. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes. 2003;52(3):701–707
  48. Larson-Meyer DE, Heilbronn LK, Redman LM, et al. Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabetes Care. 2006;29(6):1337–1344
  49. Kechagias S, Ernersson A, Dahlqvist O, et al. Fast food based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008;
  50. Pietilainen KH, Rissanen A, Kaprio J, et al. Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins. Am J Physiol Endocrinol Metab. 2005;288(4):E768–E774
  51. Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37(4):909–916
  52. Cortez-Pinto H, Jesus L, Barros HL, et al. How different is the dietary pattern in non-alcoholic steatohepatitis patients?. Clin Nutr. 2006;25(5):816–823
  53. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;
  54. Valtuena S, Pellegrini N, Ardigo D, et al. Dietary glycemic index and liver steatosis. Am J Clin Nutr. 2006;84(1):136–142[quiz 268–9]
  55. Bathum L, Petersen HC, Rosholm JU, et al. Evidence for a substantial genetic influence on biochemical liver function tests: results from a population-based Danish twin study. Clin Chem. 2001;47(1):81–87
  56. Makkonen J, Pietilainen KH, Rissanen A, Kaprio J, Yki-Jarvinen H. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monosygotic and dizygotic twins. J Hepatol. 2009;50(5):1035–1042
  57. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–1465
  58. Day CP. Natural history of NAFLD: remarkably benign in the absence of cirrhosis. Gastroenterology. 2005;129:375–378
  59. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–2047
  60. Day CP, James OF. Steatohepatitis: a tale of “two hits”. Gastroenterology. 1998;114:842–845
  61. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  62. Westerbacka J, Lammi K, Häkkinen AM, et al. Dietary fat content modifies liver fat in overweight nondiabetic subjects. J Clin Endocrinol Metab. 2005;90:2804–2806
  63. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133:496–506
  64. Sanjal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192
  65. Chalasani N, Deeq MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1497–1502
  66. Leclercq IA, Farrell GC, Field J, et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000;105:1067–1075
  67. Pérez-Carreras M, Del Hoyo P, Martìn MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38:999–1007
  68. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–1374
  69. Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis. 2008;28:360–369
  70. Malhi H, Bronk SF, Werneburg NW, et al. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–12101
  71. Feldstein AE, Canbay A, Guicciardi ME, et al. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol. 2003;39:978–983
  72. Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185–194
  73. Li Z, Berk M, McIntyre TM, et al. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology. 2008;47:1495–1503
  74. Bugianesi E, Pagotto U, Manini R, et al. Plasma adiponectin in nonalcoholic fatty liver disease is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab. 2005;90:3498–3504
  75. Hui JM, Hodge A, Farrell GC, et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?. Hepatology. 2004;40:46–54
  76. Musso G, Gambino R, Biroli G, et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2005;100:2438–2446
  77. Bajaj M, Suraamornkul S, Hardies LJ, et al. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients. Int J Obes Relat Metab Disord. 2004;28:783–789
  78. Pagano C, Soardo G, Pilon C, 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;91:1081–1086
  79. Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?. Hepatology. 2002;36:403–409
  80. Diehl AM. Lessons from animal models of NASH. Hepatol Res. 2005;33:138–144
  81. Leclercq IA, Farrell GC, Schriemer R, et al. Leptin is essential for hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002;37:206–213
  82. Ogawa W, Kasuga M. Fat stress and insulin resistance. Science. 2008;322:1483–1484
  83. Paradis V, Perlemuter G, Bonvoust F, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738–744
  84. Ota T, Takamura T, Kurita S, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132:282–293
  85. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854
  86. Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–460
  87. Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005;353:604–615
  88. Browning J, Horton J. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152
  89. Wagner M, Zollner G, Trauner M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology. 2008;48:1383–1386
  90. Zollner G, Marschall HU, Wagner M, et al. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm. 2006;3:231–251
  91. Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett. 2008;582:10–18[Epub November 20, 2007]
  92. Modica S, Moschetta A. Nuclear bile acid receptor FXR as pharmacological target: are we there yet?. FEBS Lett. 2006;580:5492–5499[Epub August 8, 2006]
  93. Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–1418
  94. Zhang Y, Castellani LW, Sinal CJ, et al. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev. 2004;18:157–169
  95. Lee FY, Lee H, Hubbert ML, et al. FXR, a multipurpose nuclear receptor. Trends Biochem Sci. 2006;31:572–580[Epub August 14, 2006]
  96. Pineda Torra I, Claudel T, Duval C, et al. Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol. 2003;17:259–272
  97. Sinal CJ, Tohkin M, Miyata M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–744
  98. Lambert G, Amar MJ, Guo G, et al. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J Biol Chem. 2003;278:2563–2570
  99. Cariou B, van Harmelen K, Duran-Sandoval D, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006;281:11039–11049
  100. Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA. 2006;103:1006–1011
  101. Ma K, Saha PK, Chan L, et al. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116:1102–1109
  102. Duran-Sandoval D, Cariou B, Percevault F, et al. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem. 2005;280:29971–29979
  103. Stojakovic T, Putz-Bankuti C, Fauler G, et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology. 2007;46:776–784
  104. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778
  105. Svegliati-Baroni G, Ridolfi F, Hannivoort R, et al. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor. Gastroenterology. 2005;128:1042–1055
  106. Michalik L, Wahli W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest. 2006;116:598–606
  107. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–650
  108. Akiyama TE, Nicol CJ, Fievet C, et al. Peroxisome proliferator-activated receptor-alpha regulates lipid homeostasis, but is not associated with obesity: studies with congenic mouse lines. J Biol Chem. 2001;276:39088–39093
  109. Stienstra R, Mandard S, Patsouris D, et al. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology. 2007;148:2753–2763
  110. Svegliati-Baroni G, Candelaresi C, Saccomanno S, 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;169:846–860
  111. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454:470–477
  112. Capanni M, Calella F, Centenaro G, et al. Prolonged n-3 PUFA dietary supplementation improves fatty liver in patients with NAFLD. J Hepatol. 2004;40:A168
  113. Uno M, Kurita S, Misu H, et al. Tranilast, an antifibrogenic agent, ameliorates a dietary rat model of nonalcoholic steatohepatitis. Hepatology. 2008;48:109–118
  114. Beraza N, Malato Y, Vander Borght S, et al. Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis. Gut. 2008;57:655–663
  115. Wunderlich FT, Luedde T, Singer S, et al. Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA. 2008;105:1297–1302
  116. Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128:334–342
  117. Tanaka N, Moriya K, Kiyosawa K, et al. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest. 2008;118:683–694
  118. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351:1106–1118
  119. Semple RK, Chatterjee VK, O’Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest. 2006;116:581–589
  120. Miyazaki Y, Glass L, Triplitt C, et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in type II diabetic patients. Diabetologia. 2001;44:2210–2219
  121. Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28:551–558
  122. Galli A, Crabb DW, Ceni E, et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology. 2002;122:1924–1940
  123. Marra F, DeFranco R, Robino G, et al. Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis. World J Gastroenterol. 2005;11:4931–4938
  124. Marra F, Efsen E, Romanelli RG, et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology. 2000;119:466–478
  125. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307
  126. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–1184
  127. Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135:100–110
  128. Reilly SM, Lee CH. PPAR delta as a therapeutic target in metabolic disease. FEBS Lett. 2008;582:26–31
  129. Lee CH, Olson P, Hevener A, et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA. 2006;103:3444–3449
  130. Nagasawa T, Inada Y, Nakano S, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol. 2006;536:182–191

PII: S1590-8658(10)00020-4

doi: 10.1016/j.dld.2010.01.016

Digestive and Liver Disease
Volume 42, Issue 5 , Pages 320-330 , May 2010