Evolving therapies for non-alcoholic steatohepatitis

Expert Opinion on Drug Discovery

Volumn 9, Issue 6, 2014, Pages 687-696

  Tilg, Herbert ^a   Moschen, Alexander R ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

Author keywords

Adiponectin; Farnesoid X receptor; Inflammation; Insulin resistance; Peroxisome proliferator activated receptor

Indexed keywords

ADIPONECTIN; ADIPONECTIN RECEPTOR; ALPHA TOCOPHEROL; AMLEXANOX; FARNESOID X RECEPTOR; I KAPPA B; I KAPPA B KINASE ALPHA; I KAPPA B KINASE BETA; I KAPPA B KINASE EPSILON; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN; INTERLEUKIN 1; INTERLEUKIN 6; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA AGONIST; PIOGLITAZONE; PREBIOTIC AGENT; TANK BINDING KINASE 1; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; CELL RECEPTOR; FARNESOID X-ACTIVATED RECEPTOR; GLUCOSE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR;

ANTIINFLAMMATORY ACTIVITY; DIET; FATTY LIVER; GLUCOSE METABOLISM; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTESTINE FLORA; LIFESTYLE MODIFICATION; LIPID METABOLISM; LIVER FIBROSIS; LONG TERM CARE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; REVIEW; AGONISTS; ANIMAL; DRUG DESIGN; DRUG EFFECTS; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOPHYSIOLOGY;

ANIMALS; DRUG DESIGN; GLUCOSE; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; RECEPTORS, ADIPONECTIN; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 84901288519     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2014.911283     Document Type: Review

References (86)

1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013;10(11):686-90
2. Wree A, Broderick L, Canbay A, et al. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013;10(11):627-36
3. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10(11):656-65
4. Gerner RR, Wieser V, Moschen AR, Tilg H. Metabolic inflammation: Role of cytokines in the crosstalk between adipose tissue and liver. Can J Physiol Pharmacol 2013;91(11):867-72
5. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011;29:415-45
6. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 2013;339(6116):172-7
7. Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell 2013;152(4):673-84
8. Kau AL, Ahern PP, Griffin NW, et al. Human nutrition, the gut microbiome and the immune system. Nature 2011;474(7351):327-36
9. Moschen AR, Kaser S, Tilg H. Non-Alcoholic steatohepatitis: A microbiota-driven disease. Trends Endocrinol Metab 2013;24(11):537-45
10. Mouzaki M, Comelli EM, Arendt BM, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013;58(1):120-7
11. Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-Alcoholic fatty liver disease in mice. Gut 2013;62(12):1787-94
12. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-85
13. Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013;10(11):676-85
14. Yoneda M, Mawatari H, Fujita K, et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol 2007;42(7):573-82 (Pubitemid 47190075
15. Pihlajamaki J, Kuulasmaa T, Kaminska D, et al. Serum interleukin 1 receptor antagonist as an independent marker of non-Alcoholic steatohepatitis in humans. J Hepatol 2012;56(3):663-70
16. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 2010;52(5):1836-46
17. Samuel VT, Shulman GI. Mechanisms for insulin resistance: Common threads and missing links. Cell 2012;148(5):852-71
18. Wieser V, Moschen AR, Tilg H. Inflammation, cytokines and insulin resistance: A clinical perspective. Arch Immunol Ther Exp (Warsz) 2013;61(2):119-25
19. Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 2012;15(5):635-45
20. Wen H, Gris D, Lei Y, et al. Fatty acidinduced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 2011;12(5):408-15
21. Lee YS, Li P, Huh JY, et al. Inflammation is necessary for long-Term but not short-Term high-fat diet-induced insulin resistance. Diabetes 2011;60(10):2474-83
22. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012;489(7415):242-9
23. Sun Z, Lazar MA. Dissociating fatty liver and diabetes. Trends Endocrinol Metab 2013;24(1):4-12
24. Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000;343(20):1467-76
25. Moschen AR, Molnar C, Geiger S, et al. Anti-inflammatory effects of excessive weight loss: Potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut 2010;59(9):1259-64
26. Le KA, Mahurkar S, Alderete TL, et al. Subcutaneous adipose tissue macrophage infiltration is associated with hepatic and visceral fat deposition, hyperinsulinemia, and stimulation of NF-kappaB stress pathway. Diabetes 2011;60(11):2802-9
27. Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity-And dietinduced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293(5535):1673-7 (Pubitemid 32807849
28. Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005;11(2):183-90 (Pubitemid 40321354
29. Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005;11(2):191-8 (Pubitemid 40321355
30. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activator of nuclear factor-kappaB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 2013;19(3):358-63
31. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: Rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162(4):597-605
32. Chiang SH, Bazuine M, Lumeng CN, et al. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 2009;138(5):961-75
33. Reilly SM, Chiang SH, Decker SJ, et al. An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice. Nat Med 2013;19(3):313-21
34. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 2012;142(5):1100-1; e2
35. Imajo K, Fujita K, Yoneda M, et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptinmediated signaling. Cell Metab 2012;16(1):44-54
36. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study. Lancet 2013;381(9865):468-75
37. Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010;16(9):1009-17
38. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270(45):26746-9
39. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules: Adipocyte-derived plasma protein adiponectin. Circulation 1999;100(25):2473-6 (Pubitemid 30005109
40. Yokota T, Oritani K, Takahashi I, et al. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000;96(5):1723-32 (Pubitemid 30661055
41. Maeda N, Shimomura I, Kishida K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002;8(7):731-7 (Pubitemid 34778727
42. Wolf AM, Wolf D, Rumpold H, et al. Adiponectin induces the antiinflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun 2004;323(2):630-5 (Pubitemid 39221142
43. Mandal P, Park PH, McMullen MR, et al. The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology 2010;51(4):1420-9
44. Mandal P, Roychowdhury S, Park PH, et al. Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure. J Immunol 2010;185(8):4928-37
45. Ye R, Scherer PE. Adiponectin, driver or passenger on the road to insulin sensitivity? Mol Metab 2013;2(3):133-41
46. Bruun JM, Lihn AS, Verdich C, et al. Regulation of adiponectin by adipose tissue-derived cytokines: In vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003;285(3):E527-E33
47. Iwaki M, Matsuda M, Maeda N, et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003;52(7):1655-63 (Pubitemid 36792453
48. Turer AT, Scherer PE. Adiponectin: Mechanistic insights and clinical implications. Diabetologia 2012;55(9):2319-26
49. Polyzos SA, Toulis KA, Goulis DG, et al. Serum total adiponectin in nonalcoholic fatty liver disease: A systematic review and meta-Analysis. Metabolism 2011;60(3):313-26
50. Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112(1):91-100 (Pubitemid 38056380
51. Masaki T, Chiba S, Tatsukawa H, et al. Adiponectin protects LPS-induced liver injury through modulation of TNF-Alpha in KK-Ay obese mice. Hepatology 2004;40(1):177-84 (Pubitemid 38868936
52. Wolf AM, Wolf D, Avila MA, et al. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol 2006;44(3):537-43 (Pubitemid 43227878
53. Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6(10):772-83 (Pubitemid 44453463
54. Kim JY, Van De Wall E, Laplante M, et al. Obesity-Associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007;117(9):2621-37 (Pubitemid 47494363
55. Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423(6941):762-9 (Pubitemid 36735700
56. Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13(3):332-9 (Pubitemid 46376688
57. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 2008;454(7203):463-9
58. Kaser S, Moschen A, Cayon A, et al. Adiponectin and its receptors in non-Alcoholic steatohepatitis. Gut 2005;54(1):117-21 (Pubitemid 40007229
59. Okada-Iwabu M, Yamauchi T, Iwabu M, et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013;503(7477):493-9
60. Wei W, Dutchak PA, Wang X, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-Activated receptor gamma. Proc Natl Acad Sci USA 2012;109(8):3143-8
61. Thomas C, Pellicciari R, Pruzanski M, et al. Targeting bile-Acid signalling for metabolic diseases. Nat Rev Drug Discov 2008;7(8):678-93
62. Hollman DA, Milona A, van Erpecum KJ, van Mil SW. Anti-inflammatory and metabolic actions of FXR: Insights into molecular mechanisms. Biochim Biophys Acta 2012;1821(11):1443-52
63. Pols TW, Noriega LG, Nomura M, et al. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011;54(6):1263-72
64. Fuchs C, Claudel T, Trauner M. Bile acid-mediated control of liver triglycerides. Semin Liver Dis 2013;33(4):330-42
65. Li F, Jiang C, Krausz KW, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013;4:2384
66. Cariou B, van Harmelen K, Duran-Sandoval D, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006;281(16):11039-49 (Pubitemid 43855527
67. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 2006;116(4):1102-9
68. McMahan RH, Wang XX, Cheng LL, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013;288(17):11761-70
69. Zhang Y, Ge X, Heemstra LA, et al. Loss of FXR protects against dietinduced obesity and accelerates liver carcinogenesis in ob/ob mice. Mol Endocrinol 2012;26(2):272-80
70. Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA 2006;103(4):1006-11 (Pubitemid 43212212
71. Maneschi E, Vignozzi L, Morelli A, et al. FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. J Endocrinol 2013;218(2):215-31
72. Verbeke L, Farre R, Trebicka J, et al. Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2013. [Epub ahead of print]
73. Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl- chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002;45(17):3569-72 (Pubitemid 34856095
74. Wang YD, Chen WD, Wang M, et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008;48(5):1632-43
75. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012;17(17-18):988-97
76. Mudaliar S, Henry RR, Sanyal AJ, 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 2013;145(3):574-82; e1
77. The Farnesoid X Receptor (FXR) Ligand Obeticholic Acis in Nonalcoholic Steatohepatitis (NAS) Treatment Trial (FLINT). National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). US National Library of Medicine. ClinicalTrials.gov [online]. 2013. Available from: Http://clinicaltrials. gov/show/NCT0126549 [Last accessed 28 March 2014]
78. Qin X, Xie X, Fan Y, et al. Peroxisome proliferator-Activated receptor-delta induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice. Hepatology 2008;48(2):432-41
79. Liu S, Hatano B, Zhao M, et al. Role of peroxisome proliferator-Activated receptor{delta}/{beta} in hepatic metabolic regulation. J Biol Chem 2011;286(2):1237-47
80. Iwaisako K, Haimerl M, Paik YH, et al. Protection from liver fibrosis by a peroxisome proliferator-Activated receptor delta agonist. Proc Natl Acad Sci USA 2012;109(21):E1369-76
81. Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-Activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis. Hepatology 2013;58(6):1941-52
82. Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011;34(9):2008-14
83. Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferatoractivated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013;36(10):2923-30
84. A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety, and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase-Like Molecule 2 (LOXL2) in Subjects With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH). Gilead Sciences. US National Library of Medicine. ClinicalTrials.gov [online]. 2013. Available from: Http://clinicaltrials. gov/ct2/show/NCT01672866? term=NCT01672866&rank=1 [Last accessed 28 March 2014]
85. A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase-Like 2 (LOXL2), in Subjects With Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH). Gilead Sciences. US National Library of Medicine. ClinicalTrials.gov [online]. 2013. Available from: Http://clinicaltrials. gov/ct2/show/NCT01672879? term=NCT01672879&rank=1 [Last accessed 28 March 2014]
86. A Multicentre, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GFT505 Once Daily on Steatohepatitis in Patients With Non-Alcoholic Steatohepatitis (NASH). Genfit. US National Library of Medicine. ClinicalTrials.gov [online]. 2013. Available from: Http://clinicaltrials. gov/ct2/show/NCT01694849? term=NCT01694849&rank=1 [Last accessed 28 March 2014]