Kleiner, D. & Brunt, E. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin. Liver Dis.32, 3–13 (2012). ArticleCASPubMed Google Scholar
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. Hepatology55, 2005–2023 (2012). ArticlePubMed Google Scholar
Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology44, 865–873 (2006). ArticleCASPubMed Google Scholar
Younossi, Z. M. et al. Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver-related mortality. Hepatology53, 1874–1882 (2011). ArticlePubMed Google Scholar
Soderberg, C. et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology51, 595–602 (2010). ArticlePubMed Google Scholar
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). ArticlePubMed Google Scholar
Vuppalanchi, R. & Chalasani, N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology49, 306–317 (2009). ArticlePubMed Google Scholar
Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology51, 121–129 (2010). ArticleCASPubMed Google Scholar
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). ArticlePubMed Google Scholar
Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology54, 344–353 (2011). ArticlePubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Fajas, L., Fruchart, J. C. & Auwerx, J. Transcriptional control of adipogenesis. Curr. Opin. Cell Biol.10, 165–173 (1998). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Yu, J. G. et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes51, 2968–2974 (2002). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Galli, A. et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology122, 1924–1940 (2002). ArticleCASPubMed Google Scholar
Leclercq, I. A., Sempoux, C., Starkel, P. & Horsmans, Y. Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut55, 1020–1029 (2006). ArticleCASPubMedPubMed Central Google Scholar
Marra, F. et al. Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology119, 466–478 (2000). ArticleCASPubMed Google Scholar
Betteridge, D. J. Effects of pioglitazone on lipid and lipoprotein metabolism. Diabetes Obes. Metab.9, 640–647 (2007). ArticleCASPubMed Google Scholar
Musso, G., Gambino, R., Cassader, M. & Pagano, G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology52, 79–104 (2010). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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. Diabetologia55, 885–904 (2012). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Shyangdan, D. et al. Insulin sensitisers in the treatment of non-alcoholic fatty liver disease: a systematic review. Health Technol. Assess15, 1–110 (2011). CASPubMedPubMed Central Google Scholar
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. Hepatology51, 445–453 (2010). ArticleCASPubMed Google Scholar
Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med.355, 2297–2307 (2006). ArticleCASPubMed Google Scholar
Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology135, 100–110 (2008). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Leuschner, U. F. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology52, 472–479 (2010). ArticleCASPubMed Google Scholar
Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology135, 1176–1184 (2008). ArticleCASPubMed Google Scholar
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. Diabetes54, 603–608 (2005). ArticleCASPubMed Google Scholar
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. Diabetes52, 701–707 (2003). ArticleCASPubMed Google Scholar
Lutchman, G. et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology46, 424–429 (2007). ArticleCASPubMed Google Scholar
Gastaldelli, A. et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology50, 1087–1093 (2009). ArticleCASPubMed Google Scholar
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. Hepatology56, 1311–1318 (2012). ArticleCASPubMed Google Scholar
Balas, B. et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J. Hepatol47, 565–570 (2007). ArticleCASPubMed Google Scholar
Ratziu, V., Caldwell, S. & Neuschwander-Tetri, B. A. Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues. Hepatology52, 2206–2215 (2010). ArticleCASPubMed Google Scholar
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. JAMA298, 1180–1188 (2007). ArticleCASPubMed Google Scholar
Loke, Y. K., Singh, S. & Furberg, C. D. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ180, 32–39 (2009). ArticlePubMedPubMed Central Google Scholar
Neumann, A. et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia55, 1953–1962 (2012). ArticleCASPubMedPubMed Central Google Scholar
Hickman, I. & Macdonald, G. Is vitamin E beneficial in chronic liver disease? Hepatology46, 288–290 (2007). ArticleCASPubMed Google Scholar
Zingg, J. M. Vitamin E: an overview of major research directions. Mol. Aspects Med.28, 400–422 (2007). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Ohrvall, M., Tengblad, S. & Vessby, B. Lower tocopherol serum levels in subjects with abdominal adiposity. J. Intern. Med.234, 53–60 (1993). ArticleCASPubMed Google Scholar
Soden, J. S. et al. Subcutaneous vitamin E ameliorates liver injury in an in vivo model of steatocholestasis. Hepatology46, 485–495 (2007). ArticleCASPubMed Google Scholar
Sokol, R. J. et al. Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat. Gastroenterology114, 164–174 (1998). ArticleCASPubMed Google Scholar
Azzi, A. et al. Vitamin E mediates cell signaling and regulation of gene expression. Ann. NY Acad. Sci.1031, 86–95 (2004). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Dufour, J. F. et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol4, 1537–1543 (2006). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Nobili, V. et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology48, 119–128 (2008). ArticleCASPubMed Google Scholar
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. JAMA305, 1659–1668 (2011). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCAS Google Scholar
Abudu, N., Miller, J. J., Attaelmannan, M. & Levinson, S. S. Vitamins in human arteriosclerosis with emphasis on vitamin C and vitamin E. Clin. Chim. Acta339, 11–25 (2004). ArticleCASPubMed Google Scholar
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. JAMA308, 1535–1544 (2012). ArticleCASPubMed Google Scholar
Kuper, H. et al. Diet and hepatocellular carcinoma: a case-control study in Greece. Nutr. Cancer38, 6–12 (2000). ArticleCASPubMed Google Scholar
Polesel, J. et al. Nutrients intake and the risk of hepatocellular carcinoma in Italy. Eur. J. Cancer43, 2381–2387 (2007). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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.
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. BMJ346, f10 (2013). ArticleCASPubMedPubMed Central Google Scholar
Bjelakovic, G. et al. C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA297, 842–857 (2007). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Klein, E. A. et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA306, 1549–1556 (2011). ArticleCASPubMedPubMed Central Google Scholar
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. BMJ341, c5702 (2010). ArticlePubMedPubMed Central Google Scholar
Ratziu, V. Treatment of NASH with ursodeoxycholic acid: pro. Clin. Res. Hepatol. Gastroenterol.36 (Suppl. 1), S41–S45 (2012). ArticleCASPubMed Google Scholar
Laurin, J. et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology23, 1464–1467 (1996). ArticleCASPubMed Google Scholar
Lindor, K. D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology39, 770–778 (2004). ArticleCASPubMed Google Scholar
Ratziu, V. et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J. Hepatol.54, 1011–1019 (2011). ArticleCASPubMed Google Scholar
Lee, S., Gura, K. M. & Puder, M. Omega-3 fatty acids and liver disease. Hepatology45, 841–845 (2007). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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 ONE6, e23365 (2011). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Roncaglioni, M. C. et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N. Engl. J. Med.368, 1800–1808 (2013). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Parker, H. M. et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J. Hepatol56, 944–951 (2012). ArticleCASPubMed Google Scholar
Sawada, N. et al. Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma. Gastroenterology142, 1468–1475 (2012). ArticleCASPubMed Google Scholar
Mozaffarian, D. & Rimm, E. B. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA296, 1885–1899 (2006). ArticleCASPubMed Google Scholar
McKenney, J. M. & Sica, D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy27, 715–728 (2007). ArticleCASPubMed Google Scholar
Dastidar, S. G., Rajagopal, D. & Ray, A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr. Opin. Investig. Drugs8, 364–372 (2007). CASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Zein, C. O. et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology54, 1610–1619 (2011). ArticleCASPubMed Google Scholar
Zein, C. O. et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology56, 1291–1299 (2012). ArticleCASPubMed Google Scholar
Lebrec, D. et al. Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology138, 1755–1762.e2 (2010). ArticleCASPubMed Google Scholar
Rebouche, C. J. & Seim, H. Carnitine metabolism and its regulation in microorganisms and mammals. Annu. Rev. Nutr.18, 39–61 (1998). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med.19, 576–585 (2013). ArticleCASPubMedPubMed Central Google Scholar
Lin, H. Z. et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat. Med.6, 998–1003 (2000). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Loomba, R. et al. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment. Pharmacol. Ther.29, 172–182 (2008). ArticleCASPubMed Google Scholar
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. Diabetes53, 2169–2176 (2004). ArticleCASPubMed Google Scholar
Chen, H. P. et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut62, 606–615 (2012). ArticleCASPubMed Google Scholar
Bhalla, K. et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev. Res. (Phila)5, 544–552 (2012). ArticleCAS Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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. Hepatology46, 1453–1463 (2007). ArticleCASPubMed Google Scholar
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. Lancet376, 1916–1922 (2010). ArticleCASPubMed Google Scholar
Trauner, M. & Halilbasic, E. Nuclear receptors as new perspective for the management of liver diseases. Gastroenterology140, 1120–1125 e1–12 (2011). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell102, 731–744 (2000). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis28, 940–946 (2007). ArticleCASPubMed Google Scholar
Wagner, M., Zollner, G. & Trauner, M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology48, 1383–1386 (2008). ArticleCASPubMed Google Scholar
Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology48, 1632–1643 (2008). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
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). ArticleCASPubMed Google Scholar
Adorini, L., Pruzanski, M. & Shapiro, D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov. Today17, 988–997 (2012). ArticleCASPubMed Google Scholar
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. Gastroenterology145, 574–582 (2013). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Bojic, L. A. & Huff, M. W. Peroxisome proliferator-activated receptor delta: a multifaceted metabolic player. Curr. Opin. Lipidol.24, 171–177 (2013). ArticleCASPubMed Google Scholar
Qin, X. et al. Peroxisome proliferator-activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology48, 432–441 (2008). ArticleCASPubMed Google Scholar
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). ArticleCASPubMedPubMed Central Google Scholar
Liu, S. et al. Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation. J. Biol. Chem.286, 1237–1247 (2011). ArticleCASPubMed Google Scholar
Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc. Natl Acad. Sci. USA109, E1369–E1376 (2012). ArticleCASPubMedPubMed Central Google Scholar
Staels, B. et al. Hepato-protective effects of the dual PPARα/δ agonist GFT505 in rodent models of NAFLD/NASH. Hepatologyhttp://dx.doi.org/10.1002/hep.26461.
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 Care34, 2008–2014 (2011). ArticleCASPubMedPubMed Central Google Scholar
Cariou, B. et al. Dual peroxisome proliferator-activated receptor α/δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care36, 2923–2930 (2013). ArticleCASPubMedPubMed Central Google Scholar
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
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). ArticleCASPubMed Google Scholar
Mahady, S. E., Wong, G., Craig, J. C. & George, J. Pioglitazone and vitamin E for nonalcoholic steatohepatitis: A cost utility analysis. Hepatology56, 2172–2179 (2012). ArticleCASPubMed Google Scholar
Caldwell, S. H. et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am. J. Gastroenterol.96, 519–525 (2001). ArticleCASPubMed Google Scholar
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. Hepatology38, 1008–1017 (2003). ArticleCASPubMed Google Scholar
Promrat, K. et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology39, 188–196 (2004). ArticleCASPubMed Google Scholar
Harrison, S. A., Schenker, S. & Cusi, K. Insulin sensitizers in nonalcoholic steatohepatitis. Hepatology53, 1404–1405 (2011). ArticlePubMed Google Scholar
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
US National Library of Medicine. ClinicalTrials.gov[online], (2013).