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Current and Emerging Therapies for Non-alcoholic Fatty Liver Disease

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Abstract

Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the developed world and commonly associated with metabolic comorbidities such as diabetes mellitus, hypertension, dyslipidemia, and obesity. Non-alcoholic steatohepatitis is an aggressive form of non-alcoholic fatty liver disease, associated with an increased risk of liver and non-liver-related mortality. Currently there are no approved therapies for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and standard-of-care lifestyle advice is rarely effective. This has spurned intense drug development efforts and several agents are in clinical trials to address this major gap in non-alcoholic fatty liver disease. Drug development efforts have focused on pathogenic mechanisms including pathways involving lipid metabolism, inflammation, and fibrosis. This review presents the overview of the trials and agents in the pipeline of emerging therapies for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

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References

  1. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9:524–30 (quiz e60).

    PubMed  Google Scholar 

  2. Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, Younossi Y, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–86.

    PubMed  Google Scholar 

  3. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.

    PubMed  Google Scholar 

  4. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    PubMed  Google Scholar 

  5. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.

    CAS  PubMed  Google Scholar 

  6. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–21.

    PubMed  Google Scholar 

  7. Stepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58:3017–23.

    CAS  PubMed  Google Scholar 

  8. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367.e5–378.e5 (quiz e14–15).

    Google Scholar 

  9. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–88 (quiz e15–16).

    PubMed  Google Scholar 

  10. Dudekula A, Rachakonda V, Shaik B, Behari J. Weight loss in nonalcoholic fatty liver disease patients in an ambulatory care setting is largely unsuccessful but correlates with frequency of clinic visits. PLoS ONE. 2014;9:e111808.

    PubMed  PubMed Central  Google Scholar 

  11. Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148:547–55.

    PubMed  Google Scholar 

  12. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 Eng J Med. 2006;355:2297–307.

    CAS  Google Scholar 

  14. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology. 2008;135:100–10.

    CAS  PubMed  Google Scholar 

  15. Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–82.

    PubMed  Google Scholar 

  16. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(389–97):e10.

    Google Scholar 

  17. Hagstrom H, Nasr P, Ekstedt M, Hammar U, Stal P, Hultcrantz R, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265–73.

    PubMed  Google Scholar 

  18. Younossi ZM. Long-term outcomes of nonalcoholic fatty liver disease: from nonalcoholic steatohepatitis to nonalcoholic steatofibrosis. Clin Gastroenterol Hepatol. 2017;15:1144–7.

    PubMed  Google Scholar 

  19. Ratziu V, Harrison S, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(1147–59):e5.

    Google Scholar 

  20. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65.

    CAS  PubMed  Google Scholar 

  21. Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–53.

    PubMed  Google Scholar 

  22. Kim D, Kim WR, Kim HJ, Therneau TM. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013;57:1357–65.

    CAS  PubMed  Google Scholar 

  23. Wong VW-S, Wong GL-H, Yip GW-K, Lo AO-S, Lim J, Chu WC-W, et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut. 2011;60:1721–7.

    CAS  PubMed  Google Scholar 

  24. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with monalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165:305.

    PubMed  Google Scholar 

  25. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–90.

    CAS  PubMed  Google Scholar 

  26. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67:1754–67.

    CAS  PubMed  Google Scholar 

  27. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

    PubMed  Google Scholar 

  28. Keating SE, Hackett DA, Parker HM, O’Connor HT, Gerofi JA, Sainsbury A, et al. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol. 2015;63:174–82.

    PubMed  Google Scholar 

  29. Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA. 1999;281:235–42.

    CAS  PubMed  Google Scholar 

  30. Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009;49:80–6.

    CAS  PubMed  Google Scholar 

  31. Després J-P, Ross R, Boka G, Alméras N, Lemieux I, ADAGIO-Lipids Investigators. Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-Lipids trial. Arterioscler Thromb Vasc Biol. 2009;29:416–23.

    PubMed  Google Scholar 

  32. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007;370:1706–13.

    CAS  PubMed  Google Scholar 

  33. 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;12:189–92.

    PubMed  Google Scholar 

  34. James WPT, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905–17.

    CAS  PubMed  Google Scholar 

  35. 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;35:373–9.

    CAS  PubMed  Google Scholar 

  36. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.

    CAS  PubMed  Google Scholar 

  37. Siddiqui MS, Cheang KL, Luketic VA, Boyett S, Idowu MO, Patidar K, et al. Nonalcoholic steatohepatitis (NASH) is associated with a decline in pancreatic beta cell (β-cell) function. Dig Dis Sci. 2015;60:2529–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–4.

    CAS  PubMed  Google Scholar 

  39. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29:172–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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;100:1082–90.

    CAS  PubMed  Google Scholar 

  41. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, 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. 2011;305:1659–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vidal-Puig AJ, Considine RV, Jimenez-Liñan M, Werman A, Pories WJ, Caro JF, et al. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 1997;99:2416–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the Fatty Liver Improvement by Rosiglitazone Therapy (FLIRT 2) extension trial. Hepatology. 2010;51:445–53.

    CAS  PubMed  Google Scholar 

  44. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.

    CAS  PubMed  Google Scholar 

  45. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu I-C, et al. Response to pioglitazone in patients with nonalcoholic steatohepatitis with vs without type 2 diabetes. Clin Gastroenterol Hepatol. 2018;16(558–66):e2.

    Google Scholar 

  47. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik B, Feingold KR, et al. Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab. 2006;91:3349–54.

    CAS  PubMed  Google Scholar 

  48. Murphy CE, Rodgers PT. Effects of thiazolidinediones on bone loss and fracture. Ann Pharmacother. 2007;41:2014–8.

    CAS  PubMed  Google Scholar 

  49. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–8.

    CAS  PubMed  Google Scholar 

  50. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 2004;43:993–1002.

    CAS  PubMed  Google Scholar 

  51. Alam S, Kabir J, Mustafa G, Gupta U, Hasan SKMN, Alam AKMK. Effect of telmisartan on histological activity and fibrosis of non-alcoholic steatohepatitis: a 1-year randomized control trial. Saudi J Gastroenterol. 2016;22:69–76.

    PubMed  PubMed Central  Google Scholar 

  52. Hirata T, Tomita K, Kawai T, Yokoyama H, Shimada A, Kikuchi M, et al. Effect of telmisartan or losartan for treatment of nonalcoholic fatty liver disease: fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY). Int J Endocrinol. 2013;2013:587140.

    PubMed  PubMed Central  Google Scholar 

  53. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–4.

    CAS  PubMed  Google Scholar 

  54. Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50:609–13.

    PubMed  Google Scholar 

  55. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin versus placebo in the treatment of nonalcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65:369–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, 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;58:1941–52.

    CAS  PubMed  Google Scholar 

  57. Poulsen LI, Siersbæk M, Mandrup S. PPARs: fatty acid sensors controlling metabolism. Semin Cell Dev Biol. 2012;23:631–9.

    PubMed  Google Scholar 

  58. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–44.

    CAS  PubMed  Google Scholar 

  59. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, Kasmi KE, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem. 2013;288:11761–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun. 2017;1:1024–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018;391:1174–85.

    CAS  PubMed  Google Scholar 

  63. 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;2:1107–15.

    CAS  PubMed  Google Scholar 

  64. Bell LN, Wang J, Muralidharan S, Chalasani S, Fullenkamp AM, Wilson LA, 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. 2012;56:1311–8.

    CAS  PubMed  Google Scholar 

  65. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–65.

    CAS  PubMed  Google Scholar 

  66. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.

    PubMed  PubMed Central  Google Scholar 

  67. Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306:1549–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Miller ER, 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.

    CAS  PubMed  Google Scholar 

  69. Beilfuss A, Sowa J-P, Sydor S, Beste M, Bechmann LP, Schlattjan M, et al. Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently. Gut. 2015;64:791–9.

    CAS  PubMed  Google Scholar 

  70. Barchetta I, Carotti S, Labbadia G, Gentilucci UV, Muda AO, Angelico F, et al. Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus. Hepatology. 2012;56:2180–7.

    CAS  PubMed  Google Scholar 

  71. 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;98:2485–90.

    CAS  PubMed  Google Scholar 

  72. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, 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. 2010;105:1338–45.

    CAS  PubMed  Google Scholar 

  73. Spadaro L, Magliocco O, Spampinato D, Piro S, Oliveri C, Alagona C, et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Digest Liver Dis. 2008;40:194–9.

    CAS  Google Scholar 

  74. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J Hepatol. 2009;50:1102–11.

    CAS  PubMed  Google Scholar 

  75. Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F. Silymarin in non alcoholic fatty liver disease. World J Hepatol. 2013;5:109–13.

    PubMed  PubMed Central  Google Scholar 

  76. Farsi F, Mohammadshahi M, Alavinejad P, Rezazadeh A, Zarei M, Engali KA. Functions of coenzyme Q10 supplementation on liver enzymes, markers of systemic inflammation, and adipokines in patients affected by nonalcoholic fatty liver disease: a double-blind, placebo-controlled, randomized clinical trial. J Am Coll Nutr. 2016;35:346–53.

    CAS  PubMed  Google Scholar 

  77. Chang X, Wang Z, Zhang J, Yan H, Bian H, Xia M, et al. Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease. J Transl Med. 2016;14:266.

    PubMed  PubMed Central  Google Scholar 

  78. Bertola A, Bonnafous S, Anty R, Patouraux S, Saint-Paul M-C, Iannelli A, et al. Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients. PLoS One. 2010;5:e13577.

    PubMed  PubMed Central  Google Scholar 

  79. Seki E, De Minicis S, Inokuchi S, Taura K, Miyai K, Van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50:185–97.

    CAS  PubMed  Google Scholar 

  80. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11:e0158156.

    PubMed  PubMed Central  Google Scholar 

  81. Yamamoto E, Dong Y-F, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, et al. Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension. 2008;52:573–80.

    CAS  PubMed  Google Scholar 

  82. Wang P-X, Ji Y-X, Zhang X-J, Zhao L-P, Yan Z-Z, Zhang P, et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med. 2017;23:439–49.

    CAS  PubMed  Google Scholar 

  83. Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D, et al. PS070: reduction of liver seatosis and fibrosis with an Ask1 inhibitor in a murine model of Nash is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64:S170.

    Google Scholar 

  84. Reilly SM, Chiang S-H, Decker SJ, Chang L, Uhm M, Larsen MJ, et al. An inhibitor of the protein kinases TBK1/IKKε improves obesity-related metabolic dysfunctions. Nat Med. 2013;19:313–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2017. https://doi.org/10.1002/hep.29514 (Epub ahead of print).

    Article  PubMed  Google Scholar 

  86. Patel SS, Guzman L, Lin F-P, Pence T, Reichman T, John B, et al. Utilization of aspirin and statin in mnagement of coronary artery disease in patients with cirrhosis undergoing liver transplant evaluation. Liver Transpl. 2018;24(7):872–80.

    PubMed  Google Scholar 

  87. Kamal S, Khan MA, Seth A, Cholankeril G, Gupta D, Singh U, et al. Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112:1495–505.

    CAS  PubMed  Google Scholar 

  88. Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metab, Clin Exp. 2008;57:1711–8.

    CAS  Google Scholar 

  89. Kargiotis K, Athyros VG, Giouleme O, Katsiki N, Katsiki E, Anagnostis P, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol. 2015;21:7860–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–4.

    CAS  PubMed  Google Scholar 

  91. Mauro VF, Tuckerman CE. Ezetimibe for management of hypercholesterolemia. Ann Pharmacother. 2003;37:839–48.

    CAS  PubMed  Google Scholar 

  92. Deushi M, Nomura M, Kawakami A, Haraguchi M, Ito M, Okazaki M, et al. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett. 2007;581:5664–70.

    CAS  PubMed  Google Scholar 

  93. Park H, Shima T, Yamaguchi K, Mitsuyoshi H, Minami M, Yasui K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:101–7.

    CAS  PubMed  Google Scholar 

  94. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R, Salotti J, et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology. 2015;61:1239–50.

    CAS  PubMed  Google Scholar 

  95. Zhang MJ, Spite M. Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids. Annu Rev Nutr. 2012;32:203–27.

    CAS  PubMed  Google Scholar 

  96. Schmitz G, Ecker J. The opposing effects of n − 3 and n − 6 fatty acids. Prog Lipid Res. 2008;47:147–55.

    CAS  PubMed  Google Scholar 

  97. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology. 2014;147(377–84):e1.

    Google Scholar 

  98. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–87.

    CAS  PubMed  Google Scholar 

  99. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol. 2016;13:412–25.

    CAS  PubMed  Google Scholar 

  100. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142(1100–1):e2.

    Google Scholar 

  102. Adar T, Ben Ya'acov A, Lalazar G, Lichtenstein Y, Nahman D, Mizrahi M, et al. Oral administration of immunoglobulin G-enhanced colostrum alleviates insulin resistance and liver injury and is associated with alterations in natural killer T cells. Clin Exp Immunol. 2012;167:252–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Mizrahi M, Shabat Y, Ya’acov BA, Lalazar G, Adar T, Wong V, et al. Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH. J Inflamm Res. 2012;5:141–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, et al. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12(2085–91):e1.

    Google Scholar 

  105. ClinicalTrials.gov. Phase 2a, dose-ranging study with PF-05221304 in nonalcoholic fatty liver disease (NAFLD). https://clinicaltrials.gov/ct2/show/NCT03248882.. Accessed 3 Sep 2018

  106. ClinicalTrials.gov. GS-0976 in adults with nonalcoholic steatohepatitis. https://clinicaltrials.gov/ct2/show/NCT02856555.. Accessed 3 Sep 2018

  107. Kim C-W, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, et al. Acetyl coA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation. Cell Metab. 2017;26(394–406):e6.

    Google Scholar 

  108. Shiffman M, Freilich B, Vuppalanchi R, Watt K, Burgess G, Morris M, et al. LP37: a placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J Hepatol. 2015;62:S282.

    Google Scholar 

  109. Linton SD, Aja T, Armstrong RA, Bai X, Chen L-S, Chen N, et al. First-in-class pan caspase inhibitor developed for the treatment of liver disease. J Med Chem. 2005;48:6779–82.

    CAS  PubMed  Google Scholar 

  110. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35:953–66.

    CAS  PubMed  Google Scholar 

  111. Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, et al. Emricasan improves liver function in patients with cirrhosis and high model for end-stage liver disease scores compared with placebo. Clin Gastroenterol Hepatol. 2018;18:432. https://doi.org/10.1016/j.cgh.2018.06.012 (Epub ahead of print).

    Article  CAS  Google Scholar 

  112. ClinicalTrials.gov. Emricasan, a caspase inhibitor, for treatment of subjects with decompensated NASH cirrhosis. https://clinicaltrials.gov/ct2/show/NCT03205345.. Accessed 3 Sep 2018.

  113. ClinicalTrials.gov. Emricasan, an oral caspase inhibitor, in subjects with non-alcoholic steatohepatitis (NASH) cirrhosis and severe portal hypertension. https://clinicaltrials.gov/ct2/show/NCT02960204.. Accessed 3 Sep 2018.

  114. Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci USA. 2006;103:5060–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel M-I, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013;8:e75361.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Harrison SA, Marri SR, Chalasani N, Kohli R, Aronstein W, Thompson GA, et al. Randomised clinical study. Aliment Pharmacol Ther. 2016;44:1183–98.

    CAS  PubMed  Google Scholar 

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Correspondence to Mohammad Shadab Siddiqui.

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Samarth S. Patel and Mohammad Shadab Siddiqui have no conflicts of interest that are directly relevant to the contents of this article.

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Patel, S.S., Siddiqui, M.S. Current and Emerging Therapies for Non-alcoholic Fatty Liver Disease. Drugs 79, 75–84 (2019). https://doi.org/10.1007/s40265-018-1040-1

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