Pharmacological agents for NASH

Nature Reviews Gastroenterology and Hepatology

Volumn 10, Issue 11, 2013, Pages 676-685

  Ratziu, Vlad ^a  

^a PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALANINE AMINOTRANSFERASE; ALPHA TOCOPHEROL; CARNITINE; FARNESOID X RECEPTOR; GFT 505; METFORMIN; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY LOXL2; OBETICHOLIC ACID; OMEGA 3 FATTY ACID; PENTOXIFYLLINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; TROGLITAZONE; UNCLASSIFIED DRUG; URSODEOXYCHOLIC ACID;

ANTIINFLAMMATORY ACTIVITY; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; HUMAN; LIVER PROTECTION; LOW DRUG DOSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT DURATION;

DRUG THERAPY; FATTY LIVER; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; THIAZOLIDINEDIONES; TREATMENT OUTCOME;

EID: 84887316663     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2013.193     Document Type: Review

References (153)

1. Kleiner, D. & Brunt, E. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin. Liver Dis. 32, 3-13 (2012).
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).
3. Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865-873 (2006).
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).
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).
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).
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).
8. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121-129 (2010).
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).
10. Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54, 344-353 (2011).
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).
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).
13. Fajas, L., Fruchart, J. C. & Auwerx, J. Transcriptional control of adipogenesis. Curr. Opin. Cell Biol. 10, 165-173 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
24. Marra, F. et al. Ligands of peroxisome proliferator-activated receptor ? modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119, 466-478 (2000).
25. Betteridge, D. J. Effects of pioglitazone on lipid and lipoprotein metabolism. Diabetes Obes. Metab. 9, 640-647 (2007).
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).
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).
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).
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).
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).
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).
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).
33. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675-1685 (2010).
34. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297-2307 (2006).
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).
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).
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).
38. Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176-1184 (2008).
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).
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).
41. Lutchman, G. et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology 46, 424-429 (2007).
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).
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).
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).
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).
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).
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).
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).
49. Hickman, I. & Macdonald, G. Is vitamin E beneficial in chronic liver disease? Hepatology 46, 288-290 (2007).
50. Zingg, J. M. Vitamin E: an overview of major research directions. Mol. Aspects Med. 28, 400-422 (2007).
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).
52. Ohrvall, M., Tengblad, S. & Vessby, B. Lower tocopherol serum levels in subjects with abdominal adiposity. J. Intern. Med. 234, 53-60 (1993).
53. Soden, J. S. et al. Subcutaneous vitamin E ameliorates liver injury in anin vivo model of steatocholestasis. Hepatology 46, 485-495 (2007).
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).
55. Azzi, A. et al. Vitamin E mediates cell signaling and regulation of gene expression. Ann. NY Acad. Sci. 1031, 86-95 (2004).
56. Morante, M. et al. Vitamin E deficiency induces liver nuclear factor-?B DNA-binding activity and changes in related genes. Free Radic. Res. 39, 1127-1138 (2005).
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).
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).
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).
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).
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).
62. Huang, H. Y. & Appel, L. J. Supplementation of diets with ?-tocopherol reduces serum concentrations of gamma-and delta-tocopherol in humans. J. Nutr. 133, 3137-3140 (2003).
63. Sen, C. K., Khanna, S. & Roy, S. Tocotrienols: vitamin E beyond tocopherols. Life Sci. 78, 2088-2098 (2006).
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).
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).
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).
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).
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).
69. Singal, A. K., Jampana, S. C. & Weinman, S. A. Antioxidants as therapeutic agents for liver disease. Liver Int. 31, 1432-1448 (2011).
70. Kuper, H. et al. Diet and hepatocellular carcinoma: a case-control study in Greece. Nutr. Cancer 38, 6-12 (2000).
71. Polesel, J. et al. Nutrients intake and the risk of hepatocellular carcinoma in Italy. Eur. J. Cancer 43, 2381-2387 (2007).
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).
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).
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).
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).
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).
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).
79. Ratziu, V. Treatment of NASH with ursodeoxycholic acid: pro. Clin. Res. Hepatol. Gastroenterol. 36 (Suppl. 1), S41-S45 (2012).
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).
81. Lindor, K. D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39, 770-778 (2004).
82. Ratziu, V. et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J. Hepatol. 54, 1011-1019 (2011).
83. Lee, S., Gura, K. M. & Puder, M. Omega?3 fatty acids and liver disease. Hepatology 45, 841-845 (2007).
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).
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).
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).
87. Zhang, Y., Yang, X., Shi, H., Dong, L. & Bai, J. Effect of ?-linolenic acid on endoplasmic reticulum stress-mediated apoptosis of palmitic acid lipotoxicity in primary rat hepatocytes. Lipids Health Dis. 10, 122 (2011).
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).
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).
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).
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).
92. Sawada, N. et al. Consumption of n?3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology 142, 1468-1475 (2012).
93. Leon, H. et al. Effect of fish oil on arrhythmias and mortality: systematic review. BMJ 337, a2931 (2008).
94. Mozaffarian, D. & Rimm, E. B. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA 296, 1885-1899 (2006).
95. McKenney, J. M. & Sica, D. Role of prescription omega?3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 27, 715-728 (2007).
96. Dastidar, S. G., Rajagopal, D. & Ray, A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr. Opin. Investig. Drugs 8, 364-372 (2007).
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).
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).
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).
100. Zein, C. O. et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54, 1610-1619 (2011).
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).
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).
103. Rebouche, C. J. & Seim, H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu. Rev. Nutr. 18, 39-61 (1998).
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).
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).
106. Lin, H. Z. et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med. 6, 998-1003 (2000).
107. Marchesini, G. et al. Metformin in nonalcoholic steatohepatitis. Lancet 358, 893-894 (2001).
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).
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).
110. Loomba, R. et al. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther. 29, 172-182 (2008).
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).
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).
113. Bhalla, K. et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev. Res. (Phila) 5, 544-552 (2012).
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).
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).
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).
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).
118. Trauner, M. & Halilbasic, E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology 140, 1120-1125 e1-12 (2011).
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).
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).
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).
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).
123. Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940-946 (2007).
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).
125. Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor ?B in hepatic inflammatory response. Hepatology 48, 1632-1643 (2008).
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).
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).
128. Adorini, L., Pruzanski, M. & Shapiro, D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov. Today 17, 988-997 (2012).
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).
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).
131. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/show/NCT01265498 (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).
133. Barish, G. D., Narkar, V. A. & Evans, R. M. PPAR?: a dagger in the heart of the metabolic syndrome. J. Clin. Invest. 116, 590-597 (2006).
134. Bojic, L. A. & Huff, M. W. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr. Opin. Lipidol. 24, 171-177 (2013).
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).
136. Shan, W. et al. Ligand activation of peroxisome proliferator-activated receptor ?/? (PPAR?/?) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol. Sci. 105, 418-428 (2008).
137. Liu, S. et al. Role of peroxisome proliferator-activated receptor ?/? in hepatic metabolic regulation. J. Biol. Chem. 286, 1237-1247 (2011).
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).
139. Staels, B. et al. Hepato-protective effects of the dual PPAR?/? 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 ?/? agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34, 2008-2014 (2011).
141. Cariou, B. et al. Dual peroxisome proliferator-activated receptor ?/? agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923-2930 (2013).
142. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01694849?term=NCT01694849&rank=1 (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).
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).
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).
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).
147. Caldwell, S. H. et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am. J. Gastroenterol. 96, 519-525 (2001).
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-? ligand rosiglitazone. Hepatology 38, 1008-1017 (2003).
149. Promrat, K. et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39, 188-196 (2004).
150. Harrison, S. A., Schenker, S. & Cusi, K. Insulin sensitizers in nonalcoholic steatohepatitis. Hepatology 53, 1404-1405 (2011).
151. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01154985?term=NCT01154985&rank=1 (2013).
152. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01672866?term=NCT01672866&rank=1 (2013).
153. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01672879?term=NCT01672879&rank=1 (2013).