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Hepatology International
Published in: Hepatology International 3/2007

01-09-2007 | Original Paper

Current and novel therapies for the treatment of nonalcoholic steatohepatitis

Authors: David van der Poorten, Jacob George

Published in: Hepatology International | Issue 3/2007

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Abstract

The worldwide epidemic of obesity and the metabolic syndrome has made nonalcoholic fatty liver disease (NAFLD), one of the most important liver diseases of our time. NAFLD is now the commonest cause of abnormal liver test results in industrialized countries and its incidence is rising. The current treatment of nonalcoholic steatohepatitis (NASH) has focused on lifestyle modification to achieve weight loss and modification of risk factors, such as insulin resistance, dyslipidemia, and hyperglycemia associated with the metabolic syndrome. With our increasing understanding of the pathogenesis of NASH, have come a plethora of new pharmacologic options with great potential to modify the natural history of NAFLD and NASH. This article focuses on a number of novel molecular targets for the treatment of NASH as well as the evidence for currently available therapy. It should be noted, however, that in part because of the long natural history of NASH and NAFLD, no therapy to date has been shown to unequivocally alter liver-related morbidity and mortality in these patients.
Literature
1.
Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–95PubMed
2.
Riley P, O’Donohue J, Crook M. A growing burden: the pathogenesis, investigation and management of non-alcoholic fatty liver disease. Clin Pathol 2007 [Epub ahead of print]
3.
Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:17–26PubMed
4.
Chitturi S, Farrell GC, George J. Non-alcoholic steatohepatitis in the Asia-Pacific region: future shock? J Gastroenterol Hepatol 2004;19:368–74PubMed
5.
Loguercio C, De Simone T, D’Auria MV, de Sio I, Federico A, Tuccillo C, et al. Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the study of the liver. Dig Liver Dis 2004;36:398–405PubMed
6.
Ayata G, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL, et al. Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Hum Pathol 2002;33:1098–104PubMed
7.
Hui J, Kench J, Chitturi S, Sud A, Farrell G, Byth K, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420–7PubMed
8.
Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379PubMed
9.
Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450–455PubMed
10.
Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103–9PubMed
11.
Fan J-G, Zhu J, Li X-J, Chen L, Li L, Dai F, et al. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 2005;43:508–14PubMed
12.
Carulli N. Metabolic syndrome—cardiovascular disease risk and more. Aliment Pharmacol Ther 2005;22(Suppl 2):1–2PubMed
13.
Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42:987–1000PubMed
14.
Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842–5PubMed
15.
Bugianesi E, Zannoni C, Vanni E, Marzocchi R, Marchesini G. Non-alcoholic fatty liver and insulin resistance: a cause-effect relationship? Dig Liver Dis 2004;36:165–73PubMed
16.
Albano E, Mottaran E, Occhino G, Reale E, Vidali M. Review article: role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther 2005;22(Suppl 2):71–3PubMed
17.
Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:1008–17PubMed
18.
Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297–307PubMed
19.
Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004;2:1107–15PubMed
20.
Laurin J, Lindor KD, Crippin JS, Gossard A, Gores GJ, Ludwig J, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464–7PubMed
21.
Yokohama S, Yoneda M, Haneda M, Okamoto S, Okada M, Aso K, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004;40:1222–5PubMed
22.
Despres JP, Golay A, Sjostrom L. Rimonabant in obesity—Lipids Study G. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005;353:2121–34PubMed
23.
Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006;23:1643–1647PubMed
24.
Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193–6PubMed
25.
Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537–44PubMed
26.
Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082–90PubMed
27.
Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001;15:1667–72PubMed
28.
Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485–90PubMed
29.
Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006;4:1537–43PubMed
30.
Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001;96:2711–7PubMed
31.
Loguercio C, Federico A, Trappoliere M, Tuccillo C, Sio ID, Leva AD, et al. The effect of a silybin-vitamin E-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. Epub 2007
32.
Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770–8. PubMed
33.
Merat S, Malekzadeh R, Sohrabi MR, Sotoudeh M, Rakhshani N, Sohrabpour AA, et al. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003;38:414–8PubMed
34.
Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol 2003;12:189–92PubMed
35.
Hussein O, Grosovski M, Schlesinger S, Szvalb S, Assy N. Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH). Dig Dis Sci. Epub 2007
36.
Pamuk GE, Sonsuz A. N-Acetylcysteine in the treatment of non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2003;18:1220–1PubMed
37.
Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365–8PubMed
38.
Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2007;22:634–8PubMed
39.
Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 2002;22:717–26PubMed
40.
Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70:341–67PubMed
41.
Dubois M, Pattou F, Kerr-Conte J, Gmyr V, Vandewalle B, Desreumaux P, et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in normal human pancreatic islet cells. Diabetologia 2000;43:1165–9PubMed
42.
Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia 2001;44:2210–9PubMed
43.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 1994;331:1188–93PubMed
44.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8:731–7PubMed
45.
Kipnes MS, Krosnick A, Rendell MS, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001;111:10–7PubMed
46.
Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S. Efficacy and safety of pioglitazone in type 2 diabetes: a randomized, placebo-controlled study in patients receiving stable insulin therapy. Int J Clin Pract 2002;56:251–7PubMed
47.
Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, et al. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002;10:1008–15PubMedCrossRef
48.
Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;87:2784–91PubMed
49.
Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:519–25PubMed
50.
Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL. Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol 2000;95:272–6PubMed
51.
Vella A, de Groen PC, Dinneen SF. Fatal hepatotoxicity associated with troglitazone. Ann Intern Med 1998;129:1080PubMed
52.
Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43:527–50PubMed
53.
Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997;94:4312–17PubMed
54.
Tobin JF, Freedman LP. Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. Trends Endocrinol Metab 2006;17:284–90PubMed
55.
Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006;116:571–580PubMed
56.
de Gottardi A, Pazienza V, Pugnale P, Bruttin F, Rubbia-Brandt L, Juge-Aubry CE, et al. Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment Pharmacol Ther 2006;23:107–14PubMed
57.
Yeon JE, Choi KM, Baik SH, Kim KO, Lim HJ, Park KH, et al. Reduced expression of peroxisome proliferator-activated receptor-alpha may have an important role in the development of non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2004;19:799–804PubMed
58.
Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999;31:384PubMed
59.
Ogawa Y, Murata Y, Saibara T, Nishioka A, Kariya S, Yoshida S. Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate. Oncol Rep 2003;10:1473–8PubMed
60.
Nagasawa T, Inada Y, Nakano S, Tamura T, Takahashi T, Maruyama K, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 2006;536:182–91PubMed
61.
Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists: are they opening Pandora’s box? Pharmacol Res 2007 [Epub ahead of print]
62.
Etgen GJ, Oldham BA, Johnson WT, Broderick CL, Montrose CR, Brozinick JT, et al. A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models. Diabetes 2002;51:1083–7PubMed
63.
Fievet C, Fruchart JC, Staels B. PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Curr Opin Pharmacol 2006;6:606–14PubMed
64.
Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study. Diabetes Care 2006;29:1016–23PubMed
65.
Carmona MC, Louche K, Nibbelink M, Prunet B, Bross A, Desbazeille M, et al. Fenofibrate prevents rosiglitazone-induced body weight gain in ob/ob mice. Int J Obes (Lond) 2005;29:864–71
66.
67.
Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590–7PubMed
68.
Peter Nagy ZSKL. Immunohistochemical detection of transforming growth factor-beta in fibrotic liver diseases. Hepatology 1991;14:269–73
69.
Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, et al. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995;273:509–15PubMed
70.
Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 2001;34:745–50PubMed
71.
Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001;121:148–55PubMed
72.
Ueki M, Koda M, Yamamoto S, Matsunaga Y, Murawaki Y. Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats. J Gastroenterol 2006;41:996–1004PubMed
73.
Yokohama S, Tokusashi Y, Nakamura K, Tamaki Y, Okamoto S, Okada M, et al. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol 2006;12:322–6PubMed
74.
Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002;40:609–11PubMed
75.
Sugimoto K, Qi NR, Kazdova L, Pravenec M, Ogihara T, Kurtz TW. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension 2006;47:1003–9PubMed
76.
Moriuchi A, Yamasaki H, Shimamura M, Kita A, Kuwahara H, Fujishima K, et al. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-gamma activation. Biochem Biophys Res Commun 2007;356:1024–30PubMed
77.
Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 2006;30(Suppl 1):S13–8. Review
78.
Kumar RN, Chambers WA, Pertwee RG. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 2001;56:1059–68PubMed
79.
Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 2003;111:43–50PubMed
80.
Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001;7:827–32PubMed
81.
Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, Karsak M, et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 2005;128(3):742–55PubMed
82.
Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005;115:1298–305PubMed
83.
Teixeira-Clerc F, Julien B, Grenard P, Tran Van Nhieu J, Deveaux V, Li L, et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 2006;12:671–6PubMed
84.
Hezode C, Roudot-Thoraval F, Nguyen S, Grenard P, Julien B, Zafrani ES, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005;42:63–71PubMed
85.
Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors. Lancet 2005;365:1363–4PubMed
86.
Bensaid M, Gary-Bobo M, Esclangon A, Maffrand JP, Le Fur G, Oury-Donat F, et al. The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells. Mol Pharmacol 2003;63:908–14PubMed
87.
Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 2003;278:9073–85PubMed
88.
Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 2003;278:40352–63PubMed
89.
Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762–9PubMed
90.
Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003;52:1655–63PubMed
91.
Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 2000;102:1296–301PubMed
92.
Beltowski J. Adiponectin and resistin—new hormones of white adipose tissue. Med Sci Monit 2003;9:RA55–61PubMed
93.
Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004;40:46–54PubMed
94.
Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 2003;125:1796–807PubMed
95.
Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology 2004;40:177–84PubMed
96.
Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112:91–100PubMed
97.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–52PubMed
98.
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472–80PubMed
99.
Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006;101:2629–40PubMed
100.
Mantzoros CS. The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med 1999;130:671–80PubMed
101.
Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y, et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001;34:288–97PubMed
102.
Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 2005;42:1339–48PubMed
103.
Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol 2004;41:943–49PubMed
104.
Chalasani N, Crabb DW, Cummings OW, Kwo PY, Asghar A, Pandya PK, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? Am J Gastroenterol 2003;98:2771–6PubMed
105.
Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002;36:403–9PubMed
106.
Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996;81:4059–67PubMed
107.
DeFronzo RA, Barzilai N, Simonson DC. Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 1991;73:1294–301PubMedCrossRef
108.
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550–4PubMed
109.
Lenhard JM, Kliewer SA, Paulik MA, Plunket KD, Lehmann JM, Weiel JE. Effects of troglitazone and metformin on glucose and lipid metabolism: alterations of two distinct molecular pathways. Biochem Pharmacol 1997;54:801–808PubMed
110.
Argaud D, Roth H, Wiernsperger N, Leverve XM. Metformin decreases gluconeogenesis by enhancing the pyruvate kinase flux in isolated rat hepatocytes. Eur J Biochem 1993;213:1341–8PubMed
111.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–74PubMed
112.
Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000;6:998–1003PubMed
113.
Nair S, Diehl AM, Wiseman M, Farr GH, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther 2004;20:23–8PubMed
114.
Farmer JA, Torre-Amione G. Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Safety 2000;23:197–213PubMed
115.
de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 2004;24:584–91PubMed
116.
Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126:1287–92PubMed
117.
Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005;329:62–5PubMed
118.
Horlander JC KP, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120:A544
119.
Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis 2006;184:233–4PubMed
120.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696–1705PubMed
121.
Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J, Group NNS. Five weeks of treatment with the GLP-1 analogue liraglutide improves glycemic control and lowers body weight in subjects with type 2 diabetes. Exp Clin Endocrin Diab 2006;114:417–23
122.
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28:1092–100PubMed
123.
Riddle MC, Henry RR, Poon TH, Zhang B, Mac SM, Holcombe JH, et al. Exenatide elicits sustained glycemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabet Metab Res Rev 2006;22:483–91
124.
Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46 PubMed
Metadata
Title
Current and novel therapies for the treatment of nonalcoholic steatohepatitis
Authors
David van der Poorten
Jacob George
Publication date
01-09-2007
Publisher
Springer-Verlag
Published in
Hepatology International / Issue 3/2007
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-007-9011-8

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