1932

Abstract

Nonalcoholic fatty liver disease remains a major cause of liver-related morbidity and mortality worldwide. It is a complex disease associated with obesity, diabetes, and dyslipidemia but is increasingly recognized in normal-weight individuals. Its progressive inflammatory phenotype, nonalcoholic steatohepatitis (NASH), currently has no effective treatment apart from lifestyle interventions. Multiple pathogenic pathways are involved in disease progression, and targets for intervention have been identified. These targets mediate glucose, lipid, and bile acid metabolism; inflammation; apoptosis; and fibrosis. Novel therapeutic agents are being developed in each of these pathways, and several have shown promise in early phase testing. Given the complexity of the disease, intervention trials are large and long and require histologic confirmation as a primary endpoint for disease improvement or regression. We highlight active Phase 2 and 3 therapeutic trials for NASH as this field rapidly expands in development.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010617-052545
2018-01-06
2024-06-19
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/58/1/annurev-pharmtox-010617-052545.html?itemId=/content/journals/10.1146/annurev-pharmtox-010617-052545&mimeType=html&fmt=ahah

Literature Cited

  1. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES. 1.  et al. 2015. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149:2389–97.e10 [Google Scholar]
  2. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD. 2.  et al. 2004. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40:61387–95 [Google Scholar]
  3. Patton HM, Sirlin C, Behling C, Middleton M, Schwimmer JB. 3.  2006. Pediatric nonalcoholic fatty liver disease: a critical appraisal of current data and implications for future research. J. Pediatr. Gastroenterol. Nutr. 43:4413–27 [Google Scholar]
  4. Denzer C, Thiere D, Muche R, Koenig W, Mayer H. 4.  et al. 2009. Gender-specific prevalences of fatty liver in obese children and adolescents: roles of body fat distribution, sex steroids, and insulin resistance. J. Clin. Endocrinol. Metab. 94:103872–81 [Google Scholar]
  5. Vernon G, Baranova A, Younossi ZM. 5.  2011. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34:3274–85 [Google Scholar]
  6. Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A. 6.  et al. 2010. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 52:3913–24 [Google Scholar]
  7. Schattenberg JM, Schuppan D. 7.  2011. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Curr. Opin. Lipidol. 22:6479–88 [Google Scholar]
  8. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM. 8.  et al. 2012. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55:62005–23 [Google Scholar]
  9. Musso G, Gambino R, Cassader M, Pagano G. 9.  2011. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann. Med. 43:8617–49 [Google Scholar]
  10. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. 10.  2015. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases–U.S. Food and Drug Administration Joint Workshop. Hepatology 61:41392–405 [Google Scholar]
  11. Wattacheril J, Sanyal AJ. 11.  2016. Lean NAFLD: an underrecognized outlier. Curr. Hepatol. Rep. 15:2134–39 [Google Scholar]
  12. Neuschwander-Tetri BA. 12.  2017. Non-alcoholic fatty liver disease. BMC Med 15:145 [Google Scholar]
  13. Petta S, Gastaldelli A, Rebelos E, Bugianesi E, Messa P. 13.  et al. 2016. Pathophysiology of non alcoholic fatty liver disease. Int. J. Mol. Sci. 17:122082 [Google Scholar]
  14. Mells JE, Anania FA. 14.  2013. The role of gastrointestinal hormones in hepatic lipid metabolism. Semin. Liver Dis. 33:4343–57 [Google Scholar]
  15. Brandl K, Schnabl B. 15.  2017. Intestinal microbiota and nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 33:3128–33 [Google Scholar]
  16. Sookoian S, Pirola CJ. 16.  2017. Genetic predisposition in nonalcoholic fatty liver disease. Clin. Mol. Hepatol. 23:11–12 [Google Scholar]
  17. Ratziu V. 17.  2017. Non-pharmacological interventions in non-alcoholic fatty liver disease patients. Liver Int 37:Suppl. 190–96 [Google Scholar]
  18. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M. 18.  et al. 2010. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51:1121–29 [Google Scholar]
  19. Keating SE, Hackett DA, Parker HM, O'Connor HT, Gerofi JA. 19.  et al. 2015. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J. Hepatol. 63:1174–82 [Google Scholar]
  20. Satapathy SK, Sanyal AJ. 20.  2015. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin. Liver Dis. 35:3221–35 [Google Scholar]
  21. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A. 21.  et al. 2008. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) trial. Gastroenterology 135:1100–10 [Google Scholar]
  22. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM. 22.  et al. 2010. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362:181675–85 [Google Scholar]
  23. Staels B, Fruchart JC. 23.  2005. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54:82460–70 [Google Scholar]
  24. Perazzo H, Dufour JF. 24.  2016. The therapeutic landscape of non-alcoholic steatohepatitis. Liver Int 37:5634–47 [Google Scholar]
  25. Pawlak M, Lefebvre P, Staels B. 25.  2015. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 62:3720–33 [Google Scholar]
  26. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P. 26.  et al. 2016. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:51147–59.e5 [Google Scholar]
  27. Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J. 27.  et al. 2009. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp. Clin. Trials 30:188–96 [Google Scholar]
  28. Chen Z, Vigueira PA, Chambers KT, Hall AM, Mitra MS. 28.  et al. 2012. Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione. J. Biol. Chem. 287:2823537–48 [Google Scholar]
  29. Colca JR, VanderLugt JT, Adams WJ, Shashlo A, McDonald WG. 29.  et al. 2013. Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. Clin. Pharmacol. Ther. 93:4352–59 [Google Scholar]
  30. Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G. 30.  et al. 2017. Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66:2324–34 [Google Scholar]
  31. Williamson RM, Price JF, Glancy S, Perry E, Nee LD. 31.  et al. 2011. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 34:51139–44 [Google Scholar]
  32. Portillo-Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D. 32.  et al. 2014. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J. Clin. Endocrinol. Metab. 100:62231–38 [Google Scholar]
  33. Campbell JE, Drucker DJ. 33.  2013. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab 17:6819–37 [Google Scholar]
  34. Ding X, Saxena NK, Lin S, Gupta NA, Anania FA. 34.  2006. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43:1173–81 [Google Scholar]
  35. Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J. 35.  et al. 2010. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51:51584–92 [Google Scholar]
  36. Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S. 36.  et al. 2011. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int 31:91285–97 [Google Scholar]
  37. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D. 37.  et al. 2016. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387:10019679–90 [Google Scholar]
  38. Ohki T, Isogawa A, Iwamoto M, Ohsugi M, Yoshida H. 38.  et al. 2012. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. Sci. World J. 2012:496453 [Google Scholar]
  39. Fukuhara T, Hyogo H, Ochi H, Fujino H, Kan H. 39.  et al. 2014. Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus. Hepatogastroenterology 61:130323–28 [Google Scholar]
  40. Macauley M, Hollingsworth KG, Smith FE, Thelwall PE, Al-Mrabeh A. 40.  et al. 2015. Effect of vildagliptin on hepatic steatosis. J. Clin. Endocrinol. Metab. 100:41578–85 [Google Scholar]
  41. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU. 41.  et al. 2013. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145:3574–82.e1 [Google Scholar]
  42. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G. 42.  et al. 2002. 6α-Ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45:173569–72 [Google Scholar]
  43. Ali AH, Carey EJ, Lindor KD. 43.  2015. Recent advances in the development of farnesoid X receptor agonists. Ann. Transl. Med. 3:15 [Google Scholar]
  44. Min HK, Kapoor A, Fuchs M, Mirshahi F, Zhou H. 44.  et al. 2012. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab 15:5665–74 [Google Scholar]
  45. Ozcan L, Tabas I. 45.  2012. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annu. Rev. Med. 63:317–28 [Google Scholar]
  46. Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M. 46.  et al. 2016. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLOS ONE 11:6e0158156 [Google Scholar]
  47. Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M. 47.  et al. 2016. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp. Clin. Trials 47:356–65 [Google Scholar]
  48. Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA. 48.  et al. 2009. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50:51421–30 [Google Scholar]
  49. Shiffman M, Freilich B, Vuppalanchi R, Watt K, Burgess G. 49.  et al. 2015. A placebo-controlled, multicenter, double-blind, randomised trial of emricasan (IDN-6556) in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases Presented at Intl. Liver Congr. 2015, 50th Annu. Meet. Eur. Assoc. Study Liver, April 22–26 Vienna: [Google Scholar]
  50. Yang RY, Rabinovich GA, Liu FT. 50.  2008. Galectins: structure, function and therapeutic potential. Expert Rev. Mol. Med. 10:e17 [Google Scholar]
  51. Di Lella S, Sundblad V, Cerliani JP, Guardia CM, Estrin DA. 51.  et al. 2011. When galectins recognize glycans: from biochemistry to physiology and back again. Biochemistry 50:377842–57 [Google Scholar]
  52. Henderson NC, Sethi T. 52.  2009. The regulation of inflammation by galectin-3. Immunol. Rev. 230:1160–71 [Google Scholar]
  53. Traber PG, Zomer E. 53.  2013. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLOS ONE 8:12e83481 [Google Scholar]
  54. Traber PG, Chou H, Zomer E, Hong F, Klyosov A. 54.  et al. 2013. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLOS ONE 8:10e75361 [Google Scholar]
  55. Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM. 55.  et al. 2010. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16:91009–17 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010617-052545
Loading
/content/journals/10.1146/annurev-pharmtox-010617-052545
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error