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  • Review Article
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Pharmacological agents for NASH

Nature Reviews Gastroenterology & Hepatology volume 10, pages 676–685 (2013)Cite this article

Subjects

Abstract

NASH is a common liver disease that increases liver-related mortality and reduces survival. The need for optimal management of NASH is therefore a priority for today's practicing hepatologist. The rationale for specific pharmacological therapy for NASH is based on the potential for disease progression and the difficulties that many patients have successfully implementing, in the long term, diet and lifestyle changes. Even in those that succeed, limited evidence exists that severe liver injury in patients with NASH can be reversed by diet and lifestyle measures alone. This Review provides a personal and critical assessment of the histological efficacy and safety of agents tested in randomized trials in patients with NASH.

Key Points

  • NASH is a well-described liver disease that increases liver-related mortality and reduces survival; the prevalence of NASH is increasing

  • Pharmacological treatment for NASH is needed when diet and lifestyle measures cannot be implemented sustainably, or when the disease is already advanced (clinically significant; that is, bridging fibrosis)

  • Currently, 'glitazones' have the best evidence-based data for NASH treatment; pioglitazone can be used for the treatment of NASH in the short-term, but long-term adverse effects are, however, a serious issue

  • No proof of efficacy on hepatic histology exists for metformin

  • Vitamin E might be recommended as first-line therapy for adults with NASH who do not have diabetes, but confirmation of efficacy is needed and concerns remain about long-term safety

  • Innovative pharmacological agents designed for the treatment of NASH are currently in development and need to be tested in large, placebo-controlled trials

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References

  1. Kleiner, D. & Brunt, E. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin. Liver Dis. 32, 3–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the american association for the study of liver diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55, 2005–2023 (2012).

    Article  PubMed  Google Scholar 

  3. Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865–873 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Younossi, Z. M. et al. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology 53, 1874–1882 (2011).

    Article  PubMed  Google Scholar 

  5. Soderberg, C. et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 51, 595–602 (2010).

    Article  PubMed  Google Scholar 

  6. Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. P. & Marchesini, G. A position paper on NAFLD/NASH based on the EASL 2009 Special Conference. J. Hepatol. 53, 372–384 (2010).

    Article  PubMed  Google Scholar 

  7. Vuppalanchi, R. & Chalasani, N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 49, 306–317 (2009).

    Article  PubMed  Google Scholar 

  8. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Charlotte, F., Naour, G. L., Bernhardt, C., Poynard, T. & Ratziu, V. A comparison of the fibrotic potential of nonalcoholic fatty liver disease and chronic hepatitis C. Hum. Pathol. 41, 1178–1185 (2010).

    Article  PubMed  Google Scholar 

  10. Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54, 344–353 (2011).

    Article  PubMed  Google Scholar 

  11. Kallwitz, E. R., McLachlan, A. & Cotler, S. J. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J. Gastroenterol. 14, 22–28 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu, Z., Bucher, N. L. & Farmer, S. R. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell Biol. 16, 4128–4136 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fajas, L., Fruchart, J. C. & Auwerx, J. Transcriptional control of adipogenesis. Curr. Opin. Cell Biol. 10, 165–173 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Kim, J. B. & Spiegelman, B. M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 10, 1096–1107 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Schoonjans, K. et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 15, 5336–5348 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Frohnert, B. I., Hui, T. Y. & Bernlohr, D. A. Identification of a functional peroxisome proliferator-responsive element in the murine fatty acid transport protein gene. J. Biol. Chem. 274, 3970–3977 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Yu, J. G. et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51, 2968–2974 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Xu, A. et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Invest. 112, 91–100 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Saha, A. K. et al. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem. Biophys. Res. Commun. 314, 580–585 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Fryer, L. G., Parbu-Patel, A. & Carling, D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J. Biol. Chem. 277, 25226–25232 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Wu, Z., Xie, Y., Morrison, R. F., Bucher, N. L. & Farmer, S. R. PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes. J. Clin. Invest. 101, 22–32 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Galli, A. et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122, 1924–1940 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Leclercq, I. A., Sempoux, C., Starkel, P. & Horsmans, Y. Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut 55, 1020–1029 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Marra, F. et al. Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119, 466–478 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Betteridge, D. J. Effects of pioglitazone on lipid and lipoprotein metabolism. Diabetes Obes. Metab. 9, 640–647 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Musso, G., Gambino, R., Cassader, M. & Pagano, G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52, 79–104 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Boettcher, E., Csako, G., Pucino, F., Wesley, R. & Loomba, R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 35, 66–75 (2012).

    Article  CAS  PubMed  Google Scholar 

  28. Mahady, S. E., Webster, A. C., Walker, S., Sanyal, A. & George, J. The role of thiazolidinediones in non-alcoholic steatohepatitis—a systematic review and meta analysis. J. Hepatol. 55, 1383–1390 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Musso, G., Cassader, M., Rosina, F. & Gambino, R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55, 885–904 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Rakoski, M. O., Singal, A. G., Rogers, M. A. & Conjeevaram, H. Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 32, 1211–1221 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Shyangdan, D. et al. Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Health Technol. Assess 15, 1–110 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ratziu, V. et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51, 445–453 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135, 100–110 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Suzuki, A., Lymp, J., Sauver, J. S., Angulo, P. & Lindor, K. Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis. Liver Int. 26, 1209–1216 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Leuschner, U. F. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52, 472–479 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176–1184 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Petersen, K. F. et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54, 603–608 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Tiikkainen, M. 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 52, 701–707 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Lutchman, G. et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 46, 424–429 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Gastaldelli, A. et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50, 1087–1093 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Bell, L. N. et al. Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. Hepatology 56, 1311–1318 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Balas, B. et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J. Hepatol 47, 565–570 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Ratziu, V., Caldwell, S. & Neuschwander-Tetri, B. A. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology 52, 2206–2215 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Lincoff, A. M., Wolski, K., Nicholls, S. J. & Nissen, S. E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298, 1180–1188 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Loke, Y. K., Singh, S. & Furberg, C. D. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180, 32–39 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Neumann, A. et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia 55, 1953–1962 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hickman, I. & Macdonald, G. Is vitamin E beneficial in chronic liver disease? Hepatology 46, 288–290 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Zingg, J. M. Vitamin E: an overview of major research directions. Mol. Aspects Med. 28, 400–422 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Paolisso, G. et al. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am. J. Clin. Nutr. 57, 650–656 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Ohrvall, M., Tengblad, S. & Vessby, B. Lower tocopherol serum levels in subjects with abdominal adiposity. J. Intern. Med. 234, 53–60 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Soden, J. S. et al. Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis. Hepatology 46, 485–495 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Sokol, R. J. et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology 114, 164–174 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Azzi, A. et al. Vitamin E mediates cell signaling and regulation of gene expression. Ann. NY Acad. Sci. 1031, 86–95 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Morante, M. et al. Vitamin E deficiency induces liver nuclear factor-κB DNA-binding activity and changes in related genes. Free Radic. Res. 39, 1127–1138 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Sanyal, A. J. et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 2, 1107–1115 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Dufour, J. F. et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol 4, 1537–1543 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Harrison, S. A., Torgerson, S., Hayashi, P., Ward, J. & Schenker, S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am. J. Gastroenterol. 98, 2485–2490 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Nobili, V. et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48, 119–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Lavine, J. E. et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305, 1659–1668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huang, H. Y. & Appel, L. J. Supplementation of diets with α-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J. Nutr. 133, 3137–3140 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Sen, C. K., Khanna, S. & Roy, S. Tocotrienols: vitamin E beyond tocopherols. Life Sci. 78, 2088–2098 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bowry, V. W., Ingold, K. U. & Stocker, R. Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem. J. 288, 341–344 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bowry, V. W., Mohr, D., Cleary, J. & Stocker, R. Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J. Biol. Chem. 270, 5756–5763 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Bowry, V. W. & Stocker, R. Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J. Am. Chem. Soc. 115, 6029–6044 (1993).

    Article  CAS  Google Scholar 

  67. Abudu, N., Miller, J. J., Attaelmannan, M. & Levinson, S. S. Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin. Chim. Acta 339, 11–25 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Isanaka, S. et al. Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial. JAMA 308, 1535–1544 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Singal, A. K., Jampana, S. C. & Weinman, S. A. Antioxidants as therapeutic agents for liver disease. Liver Int. 31, 1432–1448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kuper, H. et al. Diet and hepatocellular carcinoma: a case-control study in Greece. Nutr. Cancer 38, 6–12 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Polesel, J. et al. Nutrients intake and the risk of hepatocellular carcinoma in Italy. Eur. J. Cancer 43, 2381–2387 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Zhang, W. et al. Vitamin intake and liver cancer risk: a report from two cohort studies in China. J. Natl Cancer Inst. 104, 1173–1181 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database of Systematic Reviews, Issue 3, Art. No.: CD007176 http://dx.doi.org/10.1002/14651858.CD007176.pub2.

  74. Myung, S. K. et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 346, f10 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bjelakovic, G. et al. C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297, 842–857 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Miller, E. R. 3rd et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142, 37–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 306, 1549–1556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schurks, M., Glynn, R. J., Rist, P. M., Tzourio, C. & Kurth, T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 341, c5702 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ratziu, V. Treatment of NASH with ursodeoxycholic acid: pro. Clin. Res. Hepatol. Gastroenterol. 36 (Suppl. 1), S41–S45 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Laurin, J. et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23, 1464–1467 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Lindor, K. D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39, 770–778 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Ratziu, V. et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J. Hepatol. 54, 1011–1019 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Lee, S., Gura, K. M. & Puder, M. Omega-3 fatty acids and liver disease. Hepatology 45, 841–845 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Zelber-Sagi, S. et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J. Hepatol. 47, 711–717 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. El-Badry, A. M., Graf, R. & Clavien, P.-A. Omega 3–Omega 6: What is right for the liver? J. Hepatol. 47, 718–725 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Pachikian, B. D. et al. Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets. PLoS ONE 6, e23365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang, Y., Yang, X., Shi, H., Dong, L. & Bai, J. Effect of α-linolenic acid on endoplasmic reticulum stress-mediated apoptosis of palmitic acid lipotoxicity in primary rat hepatocytes. Lipids Health Dis. 10, 122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kromhout, D., Giltay, E. J. & Geleijnse, J. M. n-3 fatty acids and cardiovascular events after myocardial infarction. N. Engl. J. Med. 363, 2015–2026 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Roncaglioni, M. C. et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N. Engl. J. Med. 368, 1800–1808 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Capanni, M. et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment. Pharmacol. Ther. 23, 1143–1151 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Parker, H. M. et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J. Hepatol 56, 944–951 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Sawada, N. et al. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology 142, 1468–1475 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Leon, H. et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ 337, a2931 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Mozaffarian, D. & Rimm, E. B. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 296, 1885–1899 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. McKenney, J. M. & Sica, D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 27, 715–728 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Dastidar, S. G., Rajagopal, D. & Ray, A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr. Opin. Investig. Drugs 8, 364–372 (2007).

    CAS  PubMed  Google Scholar 

  97. Strieter, R. M. et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun. 155, 1230–1236 (1988).

    Article  CAS  PubMed  Google Scholar 

  98. Bhat, V. B. & Madyastha, K. M. Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline. Biochem. Biophys. Res. Commun. 288, 1212–1217 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Koppe, S. W., Sahai, A., Malladi, P., Whitington, P. F. & Green, R. M. Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J. Hepatol. 41, 592–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Zein, C. O. et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54, 1610–1619 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Zein, C. O. et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 56, 1291–1299 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Lebrec, D. et al. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology 138, 1755–1762.e2 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Rebouche, C. J. & Seim, H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu. Rev. Nutr. 18, 39–61 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Malaguarnera, M. et al. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis—a randomized and controlled clinical trial. Am. J. Gastroenterol. 105, 1338–1345 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lin, H. Z. et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med. 6, 998–1003 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Marchesini, G. et al. Metformin in nonalcoholic steatohepatitis. Lancet 358, 893–894 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Bugianesi, E. et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am. J. Gastroenterol. 100, 1082–1090 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Haukeland, J. W. et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand. J. Gastroenterol. 44, 853–860 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Loomba, R. et al. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther. 29, 172–182 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Tiikkainen, M. et al. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 53, 2169–2176 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, H. P. et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut 62, 606–615 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Bhalla, K. et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev. Res. (Phila) 5, 544–552 (2012).

    Article  CAS  Google Scholar 

  114. Zhang, Z. J. et al. Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 97, 2347–2353 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Ekstedt, M. et al. Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study. J. Hepatol. 47, 135–141 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Lewis, J. H. et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 46, 1453–1463 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Athyros, V. G. et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 376, 1916–1922 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Trauner, M. & Halilbasic, E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 140, 1120–1125 e1–12 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Ma, K., Saha, P. K., Chan, L. & Moore, D. D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Watanabe, M. et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113, 1408–1418 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Yang, F. et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 67, 863–867 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940–946 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Wagner, M., Zollner, G. & Trauner, M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology 48, 1383–1386 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology 48, 1632–1643 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. McMahan, R. H. et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 288, 11761–11770 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang, S., Wang, J., Liu, Q. & Harnish, D. C. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J. Hepatol. 51, 380–388 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Adorini, L., Pruzanski, M. & Shapiro, D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov. Today 17, 988–997 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Hambruch, E. et al. Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor−/− mice. J. Pharmacol. Exp. Ther. 343, 556–567 (2012).

    Article  CAS  PubMed  Google Scholar 

  131. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  132. Abel, U. et al. Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists. Bioorg. Med. Chem. Lett. 20, 4911–4917 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Barish, G. D., Narkar, V. A. & Evans, R. M. PPARδ: a dagger in the heart of the metabolic syndrome. J. Clin. Invest. 116, 590–597 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bojic, L. A. & Huff, M. W. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr. Opin. Lipidol. 24, 171–177 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Qin, X. et al. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 48, 432–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Shan, W. et al. Ligand activation of peroxisome proliferator–activated receptor β/δ (PPARβ/δ) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol. Sci. 105, 418–428 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu, S. et al. Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation. J. Biol. Chem. 286, 1237–1247 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc. Natl Acad. Sci. USA 109, E1369–E1376 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Staels, B. et al. Hepato-protective effects of the dual PPARα/δ agonist GFT505 in rodent models of NAFLD/NASH. Hepatology http://dx.doi.org/10.1002/hep.26461.

  140. Cariou, B., Zair, Y., Staels, B. & Bruckert, E. Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34, 2008–2014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cariou, B. et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923–2930 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  143. Kagan, H. M. & Li, W. Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J. Cell. Biochem. 88, 660–672 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Payne, S. L., Hendrix, M. J. C. & Kirschmann, D. A. Paradoxical roles for lysyl oxidases in cancer—a prospect. J. Cell. Biochem. 101, 1338–1354 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).

    Article  CAS  PubMed  Google Scholar 

  146. Mahady, S. E., Wong, G., Craig, J. C. & George, J. Pioglitazone and vitamin E for nonalcoholic steatohepatitis: A cost utility analysis. Hepatology 56, 2172–2179 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Caldwell, S. H. et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 519–525 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Neuschwander-Tetri, B. A., Brunt, E. M., Wehmeier, K. R., Oliver, D. & Bacon, B. R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-γ ligand rosiglitazone. Hepatology 38, 1008–1017 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Promrat, K. et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39, 188–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  150. Harrison, S. A., Schenker, S. & Cusi, K. Insulin sensitizers in nonalcoholic steatohepatitis. Hepatology 53, 1404–1405 (2011).

    Article  PubMed  Google Scholar 

  151. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  152. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  153. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

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Acknowledgements

V. Ratziu would like to acknowledge support from European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no HEALTH-F2-2009-241,762 for the project FLIP (Fatty liver inhibition of progression).

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  1. Department of Hepatology and Gastroenterology, Hôpital Pitié Salpêtrière, 47-83 Boulevard de l'Hôpital, CdR Saint-Antoine, Paris, 75651, France

    Vlad Ratziu

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V. Ratziu has acted as a consultant for the following companies: Abbott, Astellas, Axcan, Enterome, Galmed, Genfit, Gilead, Intercept, Phenex, Roche–Genentech.

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Ratziu, V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 10, 676–685 (2013). https://doi.org/10.1038/nrgastro.2013.193

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