Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors

Nature Reviews Gastroenterology & Hepatology volume 18, pages 24–39 (2021)Cite this article

Subjects

Abstract

The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease.

Key points

  • Nonalcoholic steatohepatitis (NASH) is the fastest growing liver disease worldwide; however, it is often not recognized until advanced disease stages.

  • The management and treatment of NASH, the liver manifestation of the metabolic syndrome, require a holistic approach.

  • Peroxisome proliferator-activated receptors (PPARs) regulate metabolism, inflammation and fibrosis, all of which determine NASH progression.

  • There is an urgent need for medical therapy for patients with NASH.

  • Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH.

  • Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Relationships between NAFLD, T2DM and metabolic syndrome, CVD and HCC.
Fig. 2: The role of PPARs in NASH and fibrosis development.
Fig. 3: PPARs and inflammation.

Similar content being viewed by others

References

  1. Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

    PubMed  Google Scholar 

  2. European Association for the Study of the Liver, European Association for the Study of Diabetes & European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388–1402 (2016).

    Google Scholar 

  3. Chalasani, N. et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67, 328–357 (2018).

    PubMed  Google Scholar 

  4. Angulo, P., Machado, M. V. & Diehl, A. M. Fibrosis in nonalcoholic fatty liver disease: mechanisms and clinical implications. Semin. Liver Dis. 35, 132–145 (2015).

    CAS  PubMed  Google Scholar 

  5. Cholankeril, G. et al. Liver transplantation for nonalcoholic steatohepatitis in the US: temporal trends and outcomes. Dig. Dis. Sci. 62, 2915–2922 (2017).

    PubMed  Google Scholar 

  6. Estes, C. et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J. Hepatol. 69, 896–904 (2018). An important modelling approach emphasizing the global trends in increasing prevalence of NAFLD and its related morbidity and mortality.

    PubMed  Google Scholar 

  7. Byrne, C. D. & Targher, G. NAFLD: a multisystem disease. J. Hepatol. 62 (Suppl. 1), S47–S64 (2015). This review cites the evidence that NAFLD has consequences beyond the liver and specifically increases the risk of T2DM.

    PubMed  Google Scholar 

  8. Francque, S. M., van der Graaff, D. & Kwanten, W. J. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J. Hepatol. 65, 425–443 (2016). This review summarizes the mechanisms that link NAFLD to CVD.

    CAS  PubMed  Google Scholar 

  9. Tilg, H., Moschen, A. R. & Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 14, 32–42 (2017).

    CAS  PubMed  Google Scholar 

  10. Lallukka, S. & Yki-Jarvinen, H. Non-alcoholic fatty liver disease and risk of type 2 diabetes. Best Pract. Res. Clin. Endocrinol. Metab. 30, 385–395 (2016).

    CAS  PubMed  Google Scholar 

  11. Adams, L. A., Anstee, Q. M., Tilg, H. & Targher, G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 66, 1138–1153 (2017).

    PubMed  Google Scholar 

  12. Younossi, Z. M. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71, 793–801 (2019).

    PubMed  Google Scholar 

  13. Targher, G. & Byrne, C. D. A perspective on metabolic syndrome and nonalcoholic fatty liver disease. Metab. Syndr. Relat. Disord. 13, 235–238 (2015).

    CAS  PubMed  Google Scholar 

  14. Francque, S. et al. High prevalence of advanced fibrosis in association with the metabolic syndrome in a Belgian prospective cohort of NAFLD patients with elevated ALT. Results of the Belgian NAFLD registry. Acta Gastroenterol. Belg. 74, 9–16 (2011).

    CAS  PubMed  Google Scholar 

  15. Gastaldelli, A. & Cusi, K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 1, 312–328 (2019). This review describes the crucial role of dysfunctional adipose tissue in the close relationship between diabetes and NAFLD.

    PubMed  PubMed Central  Google Scholar 

  16. Yki-Järvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2, 901–910 (2014).

    PubMed  Google Scholar 

  17. Wainwright, P. & Byrne, C. D. Bidirectional relationships and disconnects between NAFLD and features of the metabolic syndrome. Int. J. Mol. Sci. 17, 367 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. Mantovani, A., Byrne, C. D., Bonora, E. & Targher, G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 41, 372–382 (2018).

    CAS  PubMed  Google Scholar 

  19. Targher, G., Byrne, C. D., Lonardo, A., Zoppini, G. & Barbui, C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J. Hepatol. 65, 589–600 (2016). This meta-analysis cites the evidence that NAFLD is an independent risk factor for incident cardiovascular events.

    PubMed  Google Scholar 

  20. Sattar, N. et al. Age at diagnosis of type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation 139, 2228–2237 (2019).

    PubMed  Google Scholar 

  21. Millett, E. R. C., Peters, S. A. E. & Woodward, M. Sex differences in risk factors for myocardial infarction: cohort study of UK Biobank participants. BMJ 363, k4247 (2018).

    PubMed  PubMed Central  Google Scholar 

  22. Stepanova, M., Rafiq, N. & Younossi, Z. M. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut 59, 1410–1415 (2010).

    PubMed  Google Scholar 

  23. McPherson, S. et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol. 62, 1148–1155 (2015).

    PubMed  Google Scholar 

  24. Tada, T. et al. Type 2 diabetes mellitus: a risk factor for progression of liver fibrosis in middle-aged patients with non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol. 34, 2011–2018 (2019).

    CAS  PubMed  Google Scholar 

  25. Yang, J. D. et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology 71, 907–916 (2020).

    CAS  PubMed  Google Scholar 

  26. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397.e10 (2015).

    PubMed  Google Scholar 

  27. Musso, G., Cassader, M., Paschetta, E. & Gambino, R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern. Med. 177, 633–640 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Armstrong, M. J. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387, 679–690 (2016).

    CAS  PubMed  Google Scholar 

  30. Francque, S. & Vonghia, L. Pharmacological treatment for non-alcoholic fatty liver disease. Adv. Ther. 36, 1052–1074 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Konerman, M. A., Jones, J. C. & Harrison, S. A. Pharmacotherapy for NASH: current and emerging. J. Hepatol. 68, 362–375 (2018).

    CAS  PubMed  Google Scholar 

  32. Derosa, G., Sahebkar, A. & Maffioli, P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J. Cell. Physiol. 233, 153–161 (2018).

    CAS  PubMed  Google Scholar 

  33. Targher, G., Lonardo, A. & Byrne, C. D. Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat. Rev. Endocrinol. 14, 99–114 (2018).

    CAS  PubMed  Google Scholar 

  34. Haas, J. T., Francque, S. & Staels, B. Pathophysiology and mechanisms of nonalcoholic fatty liver disease. Annu. Rev. Physiol. 78, 181–205 (2016).

    CAS  PubMed  Google Scholar 

  35. Mann, J. P., Valenti, L., Scorletti, E., Byrne, C. D. & Nobili, V. Nonalcoholic fatty liver disease in children. Semin. Liver Dis. 38, 1–13 (2018).

    PubMed  Google Scholar 

  36. Fleet, S. E., Lefkowitch, J. H. & Lavine, J. E. Current concepts in pediatric nonalcoholic fatty liver disease. Gastroenterol. Clin. North. Am. 46, 217–231 (2017).

    PubMed  Google Scholar 

  37. Newton, K. P. et al. Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease. JAMA Pediatr. 170, e161971 (2016).

    PubMed  PubMed Central  Google Scholar 

  38. Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J. Hepatol. 73, 202–209 (2020).

    PubMed  Google Scholar 

  39. Rinella, M. E., Tacke, F., Sanyal, A. J., Anstee, Q. M. & Participants of the AASLD/EASL Workshop. Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD. Hepatology 70, 1424–1436 (2019).

    PubMed  Google Scholar 

  40. Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).

    CAS  PubMed  Google Scholar 

  41. Gancheva, S., Jelenik, T., Alvarez-Hernandez, E. & Roden, M. Interorgan metabolic crosstalk in human insulin resistance. Physiol. Rev. 98, 1371–1415 (2018).

    CAS  PubMed  Google Scholar 

  42. Jacome-Sosa, M. M. & Parks, E. J. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr. Opin. Lipidol. 25, 213–220 (2014).

    CAS  PubMed  Google Scholar 

  43. Apostolopoulou, M. et al. Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis. Diabetes Care 41, 1235–1243 (2018).

    CAS  PubMed  Google Scholar 

  44. Bril, F. et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology 65, 1132–1144 (2017).

    CAS  PubMed  Google Scholar 

  45. Dai, W. et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a meta-analysis. Medicine 96, e8179 (2017).

    PubMed  PubMed Central  Google Scholar 

  46. Crewe, C., An, Y. A. & Scherer, P. E. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J. Clin. Invest. 127, 74–82 (2017).

    PubMed  PubMed Central  Google Scholar 

  47. Cusi, K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142, 711–725.e6 (2012). Reviews the key role of adipose tissue and lipotoxicity in the development of muscle and liver insulin resistance and metabolic syndrome and the rationale for PPARγ insulin sensitizers in NASH.

    CAS  PubMed  Google Scholar 

  48. Diehl, A. M. & Day, C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072 (2017).

    CAS  PubMed  Google Scholar 

  49. Neuschwander-Tetri, B. A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52, 774–788 (2010).

    PubMed  Google Scholar 

  50. Bessone, F., Razori, M. V. & Roma, M. G. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol. Life Sci. 76, 99–128 (2019).

    CAS  PubMed  Google Scholar 

  51. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Tamura, S. & Shimomura, I. Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1139–1142 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Roden, M. & Shulman, G. I. The integrative biology of type 2 diabetes. Nature 576, 51–60 (2019). This review summarizes the earliest events leading to insulin resistance, ectopic fat deposition and hyperglycaemia in humans and points to the decisive role of dysfunctional adipose tissue.

    CAS  PubMed  Google Scholar 

  54. Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005). A classic work describing the contribution of adipose tissue to hepatic steatosis and liver insulin resistance in NAFLD.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Bril, F. & Cusi, K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care 40, 419–430 (2017).

    PubMed  Google Scholar 

  56. Liss, K. H. & Finck, B. N. PPARs and nonalcoholic fatty liver disease. Biochimie 136, 65–74 (2017).

    CAS  PubMed  Google Scholar 

  57. Barb, D., Portillo-Sanchez, P. & Cusi, K. Pharmacological management of nonalcoholic fatty liver disease. Metabolism 65, 1183–1195 (2016).

    CAS  PubMed  Google Scholar 

  58. Schuster, S., Cabrera, D., Arrese, M. & Feldstein, A. E. Triggering and resolution of inflammation in NASH. Nat. Rev. Gastroenterol. Hepatol. 15, 349–364 (2018).

    CAS  PubMed  Google Scholar 

  59. Tacke, F. Targeting hepatic macrophages to treat liver diseases. J. Hepatol. 66, 1300–1312 (2017).

    CAS  PubMed  Google Scholar 

  60. Jindal, A. et al. Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Exp. Mol. Pathol. 99, 155–162 (2015).

    CAS  PubMed  Google Scholar 

  61. Zhou, Z. et al. Neutrophil-hepatic stellate cell interactions promote fibrosis in experimental steatohepatitis. Cell Mol. Gastroenterol. Hepatol. 5, 399–413 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Grunhut, J. et al. Macrophages in nonalcoholic steatohepatitis: friend or foe? Eur. Med. J. Hepatol. 6, 100–109 (2018).

    PubMed  PubMed Central  Google Scholar 

  63. Szabo, G. & Csak, T. Role of microRNAs in NAFLD/NASH. Dig. Dis. Sci. 61, 1314–1324 (2016).

    CAS  PubMed  Google Scholar 

  64. Szabo, G. & Csak, T. Inflammasomes in liver diseases. J. Hepatol. 57, 642–654 (2012). Reviews the role of inflammasome activation in chronic inflammation associated with fibrosis and cirrhosis in liver diseases.

    CAS  PubMed  Google Scholar 

  65. Ganz, M. et al. Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. J. Transl. Med. 13, 193 (2015). Describes the development of a murine model consisting of a high fat–cholesterol–sugar diet that mimics liver pathology associated with NAFLD progression in humans and characterizes sterile and microbial danger signals associated with inflammation linked to NAFLD disease progression.

    PubMed  PubMed Central  Google Scholar 

  66. Chu, H., Williams, B. & Schnabl, B. Gut microbiota, fatty liver disease, and hepatocellular carcinoma. Liver Res. 2, 43–51 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. Jayakumar, S. & Loomba, R. Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications. Aliment. Pharmacol. Ther. 50, 144–158 (2019).

    PubMed  PubMed Central  Google Scholar 

  68. Marra, F. & Svegliati-Baroni, G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J. Hepatol. 68, 280–295 (2018).

    CAS  PubMed  Google Scholar 

  69. Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    CAS  PubMed  Google Scholar 

  70. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Krenkel, O. et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 69, 551–563 (2020). This single-cell RNA sequencing analysis of NASH mouse models revealed a striking heterogeneity of myeloid cells and a unique inflammatory polarization of macrophages in NAFLD.

    CAS  PubMed  Google Scholar 

  72. Kazankov, K. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 16, 145–159 (2019). Reviews the role of inflammatory macrophages in disease severity of NASH and highlights studies of potential treatments for patients with NASH that target macrophage recruitment and polarization.

    CAS  PubMed  Google Scholar 

  73. Lefere, S. et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J. Hepatol. 73, 757–770 (2020).

    CAS  PubMed  Google Scholar 

  74. Dreyer, C. et al. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68, 879–887 (1992).

    CAS  PubMed  Google Scholar 

  75. Issemann, I. & Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645–650 (1990).

    CAS  PubMed  Google Scholar 

  76. Wanders, R. J. & Waterham, H. R. Biochemistry of mammalian peroxisomes revisited. Annu. Rev. Biochem. 75, 295–332 (2006).

    CAS  PubMed  Google Scholar 

  77. Michalik, L. et al. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 58, 726–741 (2006).

    CAS  PubMed  Google Scholar 

  78. Fajas, L. et al. The organization, promoter analysis, and expression of the human PPARγ gene. J. Biol. Chem. 272, 18779–18789 (1997).

    CAS  PubMed  Google Scholar 

  79. Tailleux, A., Wouters, K. & Staels, B. Roles of PPARs in NAFLD: potential therapeutic targets. Biochim. Biophys. Acta 1821, 809–818 (2012).

    CAS  PubMed  Google Scholar 

  80. Rakhshandehroo, M., Hooiveld, G., Muller, M. & Kersten, S. Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human. PLoS ONE 4, e6796 (2009).

    PubMed  PubMed Central  Google Scholar 

  81. de la Rosa Rodriguez, M. A. et al. The whole transcriptome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice. BMC Genomics 19, 443 (2018). This paper shows the differences between humans and mice in terms of PPARα activity and target genes.

    PubMed  PubMed Central  Google Scholar 

  82. Roberts, R. A. et al. Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARα. Toxicol. Lett. 112–113, 49–57 (2000).

    PubMed  Google Scholar 

  83. Holden, P. R. & Tugwood, J. D. Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. J. Mol. Endocrinol. 22, 1–8 (1999).

    CAS  PubMed  Google Scholar 

  84. Kersten, S. & Stienstra, R. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver. Biochimie 136, 75–84 (2017).

    CAS  PubMed  Google Scholar 

  85. Cheung, C. et al. Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res. 64, 3849–3854 (2004).

    CAS  PubMed  Google Scholar 

  86. Bell, A. R. et al. Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia. Biochem. J. 332, 689–693 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lawrence, J. W. et al. Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expresson. J. Biol. Chem. 276, 31521–31527 (2001).

    CAS  PubMed  Google Scholar 

  88. Pap, A., Cuaranta-Monroy, I., Peloquin, M. & Nagy, L. Is the mouse a good model of human PPARgamma-related metabolic diseases? Int. J. Mol. Sci. 17, 1236 (2016).

    PubMed Central  Google Scholar 

  89. Su, A. I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl Acad. Sci. USA 101, 6062–6067 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Vidal-Puig, A. et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J. Clin. Invest. 97, 2553–2561 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Francque, S. et al. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. 63, 164–173 (2015).

    CAS  PubMed  Google Scholar 

  92. Kim, S. M. et al. Novel PPARα agonist MHY553 alleviates hepatic steatosis by increasing fatty acid oxidation and decreasing inflammation during aging. Oncotarget 8, 46273–46285 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Chakravarthy, M. V. et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 138, 476–488 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Reid, B. N. et al. Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J. Biol. Chem. 283, 13087–13099 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Xu, H. E. et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc. Natl Acad. Sci. USA 98, 13919–13924 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Braissant, O., Foufelle, F., Scotto, C., Dauca, M. & Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354–366 (1996).

    CAS  PubMed  Google Scholar 

  97. Montagner, A. et al. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 1202–1214 (2016).

    CAS  PubMed  Google Scholar 

  98. Lefebvre, P., Chinetti, G., Fruchart, J. C. & Staels, B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J. Clin. Invest. 116, 571–580 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zardi, E. M. et al. Hepatic PPARs: their role in liver physiology, fibrosis and treatment. Curr. Med. Chem. 20, 3370–3396 (2013).

    CAS  PubMed  Google Scholar 

  100. Chen, L. et al. Oleoylethanolamide, an endogenous PPAR-alpha ligand, attenuates liver fibrosis targeting hepatic stellate cells. Oncotarget 6, 42530–42540 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Wang, Z. et al. Taurine protected As2O3-induced the activation of hepatic stellate cells through inhibiting PPARα-autophagy pathway. Chem. Biol. Interact. 300, 123–130 (2019).

    CAS  PubMed  Google Scholar 

  102. Tardelli, M., Claudel, T., Bruschi, F. V., Moreno-Viedma, V. & Trauner, M. Adiponectin regulates AQP3 via PPARα in human hepatic stellate cells. Biochem. Biophys. Res. Commun. 490, 51–54 (2017).

    CAS  PubMed  Google Scholar 

  103. Bougarne, N. et al. Molecular actions of PPARα in lipid metabolism and inflammation. Endocr. Rev. 39, 760–802 (2018).

    PubMed  Google Scholar 

  104. Pawlak, M. et al. The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice. Hepatology 60, 1593–1606 (2014).

    CAS  PubMed  Google Scholar 

  105. Kersten, S. et al. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Sanderson, L. M., Boekschoten, M. V., Desvergne, B., Muller, M. & Kersten, S. Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiol. Genomics 41, 42–52 (2010).

    CAS  PubMed  Google Scholar 

  107. Lemberger, T. et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J. Biol. Chem. 271, 1764–1769 (1996).

    CAS  PubMed  Google Scholar 

  108. Canaple, L. et al. Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock. Mol. Endocrinol. 20, 1715–1727 (2006).

    CAS  PubMed  Google Scholar 

  109. Guan, D. et al. Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes. Cell 174, 831–842.e12 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Tognini, P. et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab. 26, 523–538.e5 (2017).

    CAS  PubMed  Google Scholar 

  111. Gachon, F. et al. Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity. Proc. Natl Acad. Sci. USA 108, 4794–4799 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Botta, M. et al. PPAR agonists and metabolic syndrome: an established role? Int. J. Mol. Sci. 19, 1197 (2018).

    PubMed Central  Google Scholar 

  113. Pawlak, M., Lefebvre, P. & Staels, B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 62, 720–733 (2015).

    CAS  PubMed  Google Scholar 

  114. Liu, S. et al. Role of peroxisome proliferator-activated receptor δ/β in hepatic metabolic regulation. J. Biol. Chem. 286, 1237–1247 (2011).

    CAS  PubMed  Google Scholar 

  115. Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc. Natl Acad. Sci. USA 109, E1369–E1376 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Dietz, M. et al. Comparative molecular profiling of the PPARα/γ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors. ChemMedChem 7, 1101–1111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ricote, M. & Glass, C. K. PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta 1771, 926–935 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Zizzo, G. & Cohen, P. L. The PPAR-γ antagonist GW9662 elicits differentiation of M2c-like cells and upregulation of the MerTK/Gas6 axis: a key role for PPAR-γ in human macrophage polarization. J. Inflamm. 12, 36 (2015).

    Google Scholar 

  120. Wilding, J. P. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes. Diabetes Obes. Metab. 14, 973–982 (2012).

    CAS  PubMed  Google Scholar 

  121. Han, L., Shen, W. J., Bittner, S., Kraemer, F. B. & Azhar, S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-α. Future Cardiol. 13, 259–278 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Han, L., Shen, W. J., Bittner, S., Kraemer, F. B. & Azhar, S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Future Cardiol. 13, 279–296 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Delerive, P. et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J. Biol. Chem. 274, 32048–32054 (1999).

    CAS  PubMed  Google Scholar 

  124. Hou, X. & Pei, F. Estradiol inhibits cytokine-induced expression of VCAM-1 and ICAM-1 in cultured human endothelial cells via AMPK/PPARα activation. Cell Biochem. Biophys. 72, 709–717 (2015).

    CAS  PubMed  Google Scholar 

  125. Hoekstra, M., Kruijt, J. K., Van Eck, M. & Van Berkel, T. J. Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells. J. Biol. Chem. 278, 25448–25453 (2003).

    CAS  PubMed  Google Scholar 

  126. Girroir, E. E. et al. Quantitative expression patterns of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) protein in mice. Biochem. Biophys. Res. Commun. 371, 456–461 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Auboeuf, D. et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 46, 1319–1327 (1997).

    CAS  PubMed  Google Scholar 

  128. Fan, Y. et al. Suppression of pro-inflammatory adhesion molecules by PPAR-delta in human vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28, 315–321 (2008).

    CAS  PubMed  Google Scholar 

  129. Kilgore, K. S. & Billin, A. N. PPARbeta/delta ligands as modulators of the inflammatory response. Curr. Opin. Investig. Drugs 9, 463–469 (2008).

    CAS  PubMed  Google Scholar 

  130. Liu, Y. et al. The role of PPAR-δ in metabolism, inflammation, and cancer: many characters of a critical transcription factor. Int. J. Mol. Sci. 19, 3339 (2018).

    PubMed Central  Google Scholar 

  131. Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Lanthier, N. et al. Kupffer cell activation is a causal factor for hepatic insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G107–G116 (2010).

    CAS  PubMed  Google Scholar 

  133. Dulai, P. S. et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 65, 1557–1565 (2017).

    CAS  PubMed  Google Scholar 

  134. Hagstrom, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).

    PubMed  Google Scholar 

  135. Weiskirchen, R., Weiskirchen, S. & Tacke, F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Mol. Asp. Med. 65, 2–15 (2019).

    CAS  Google Scholar 

  136. Lefere, S. & Tacke, F. Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep. 1, 30–43 (2019). This is an elegant review on the role of macrophages in NAFLD.

    PubMed  PubMed Central  Google Scholar 

  137. Ritz, T., Krenkel, O. & Tacke, F. Dynamic plasticity of macrophage functions in diseased liver. Cell Immunol. 330, 175–182 (2018).

    CAS  PubMed  Google Scholar 

  138. Ham, S. A. et al. Ligand-activated PPARδ upregulates α-smooth muscle actin expression in human dermal fibroblasts: a potential role for PPARδ in wound healing. J. Dermatol. Sci. 80, 186–195 (2015).

    CAS  PubMed  Google Scholar 

  139. Park, J. R. et al. Effects of peroxisome proliferator-activated receptor-δ agonist on cardiac healing after myocardial infarction. PLoS ONE 11, e0148510 (2016).

    PubMed  PubMed Central  Google Scholar 

  140. Lefebvre, P. et al. Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin. JCI Insight 2, e92264 (2017).

    PubMed Central  Google Scholar 

  141. Kato, A. et al. Identification of fibronectin binding sites in dermatopontin and their biological function. J. Dermatol. Sci. 76, 51–59 (2014).

    CAS  PubMed  Google Scholar 

  142. Soccio, R. E., Chen, E. R. & Lazar, M. A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 20, 573–591 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Ma, X., Wang, D., Zhao, W. & Xu, L. Deciphering the roles of PPARγ in adipocytes via dynamic change of transcription complex. Front. Endocrinol. 9, 473 (2018).

    Google Scholar 

  144. Lumeng, C. & Saltiel, A. Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111–2117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Byrne, C. D. & Targher, G. Ectopic fat, insulin resistance, and nonalcoholic fatty liver disease: implications for cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 34, 1155–1161 (2014).

    CAS  PubMed  Google Scholar 

  146. Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).

    CAS  PubMed  Google Scholar 

  147. Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern. Med. 165, 305–315 (2016). Long-term 3-year study confirming the efficacy of pioglitazone for the treatment of NASH in patients with prediabetes or T2DM.

    PubMed  Google Scholar 

  148. Aithal, G. P. et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135, 1176–1184 (2008).

    CAS  PubMed  Google Scholar 

  149. Lomonaco, R. et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 39, 632–638 (2016). A study that dissects the relative contribution of adipose tissue, hepatic and muscle insulin resistance in patients with and without diabetes and simple steatosis versus NASH.

    PubMed  PubMed Central  Google Scholar 

  150. Larter, C. Z. et al. Peroxisome proliferator-activated receptor-alpha agonist, Wy 14,643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 27, 341–350 (2012).

    CAS  PubMed  Google Scholar 

  151. Belfort, R., Berria, R., Cornell, J. & Cusi, K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab. 95, 829–836 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Fabbrini, E. et al. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 95, 2727–2735 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Palmer, C. N., Hsu, M. H., Griffin, K. J., Raucy, J. L. & Johnson, E. F. Peroxisome proliferator activated receptor-alpha expression in human liver. Mol. Pharmacol. 53, 14–22 (1998).

    CAS  PubMed  Google Scholar 

  154. Fruchart, J. C. et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential: a consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc. Diabetol. 18, 71 (2019).

    PubMed  PubMed Central  Google Scholar 

  155. Basaranoglu, M., Acbay, O. & Sonsuz, A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J. Hepatol. 31, 384 (1999).

    CAS  PubMed  Google Scholar 

  156. Honda, Y. et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci. Rep. 7, 42477 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Araki, E. et al. Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study. Diabetes Obes. Metab. 21, 1737–1744 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Yokote, K. et al. Long-term efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator (SPPARMα), in dyslipidemic patients with renal impairment. Int. J. Mol. Sci. 20, 706 (2019).

    CAS  PubMed Central  Google Scholar 

  159. Maeda, N. et al. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50, 2094–2099 (2001).

    CAS  PubMed  Google Scholar 

  160. Gastaldelli, A. et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment. Pharmacol. Ther. 32, 769–775 (2010).

    CAS  PubMed  Google Scholar 

  161. Ratziu, V. et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135, 100–110 (2008).

    CAS  PubMed  Google Scholar 

  162. 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. Hepatology 51, 445–453 (2010).

    CAS  PubMed  Google Scholar 

  163. Leclercq, I. A., Sempoux, C., Starkel, P. & Horsmans, Y. Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut 55, 1020–1029 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Bril, F. et al. Role of oral vitamin E for the treatment of nonalcoholic steatohepatitis (NASH) in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 42, 1481–1488 (2019).

    CAS  PubMed  Google Scholar 

  165. Sakamoto, J. et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem. Biophys. Res. Commun. 278, 704–711 (2000).

    CAS  PubMed  Google Scholar 

  166. Kalavalapalli, S. et al. Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis. Am. J. Physiol. Endocrinol. Metab. 315, E163–E173 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Ahmadian, M. et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557–566 (2013).

    CAS  PubMed  Google Scholar 

  168. Devchand, P. R., Liu, T., Altman, R. B., FitzGerald, G. A. & Schadt, E. E. The pioglitazone trek via human PPAR gamma: From discovery to a medicine at the FDA and beyond. Front. Pharmacol. 9, 1093 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Jain, M. R. et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 38, 1084–1094 (2018).

    CAS  PubMed  Google Scholar 

  170. Kaul, U. et al. New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence. Cardiovasc. Diabetol. 18, 80 (2019).

    PubMed  PubMed Central  Google Scholar 

  171. Zydus. Zydus announces regulatory filing of Saroglitazar Magnesium for treatment of NASH with DCGI. Zydus Cadila https://zyduscadila.com/public/pdf/pressrelease/Zydus_announces_NDA_filing_of_Saroglitazar_Magnesium_with_DCGI_for_treatment_of_NASH.pdf (2019).

  172. Hong, F., Xu, P. & Zhai, Y. The opportunities and challenges of peroxisome proliferator-activated receptors ligands in clinical drug discovery and development. Int. J. Mol. Sci. 19, 2189 (2018).

    PubMed Central  Google Scholar 

  173. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03061721 (2019).

  174. Haczeyni, F. et al. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol. Commun. 1, 663–674 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Bays HE, E. A. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96, 2889–2897 (2011).

    PubMed  Google Scholar 

  176. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03551522 (2019).

  177. CymaBay Therapeutics. CymaBay Therapeutics reports topline 12-week data from an ongoing phase 2b study of seladelpar in patients with nonalcoholic steatohepatitis. CymaBay https://ir.cymabay.com/press-releases?year=2019&page=2 (2019).

  178. CymaBay Therapeutics. CymaBay Therapeutics halts clinical development of seladelpar. CymaBay https://ir.cymabay.com/press-releases?year=2019&page=1 (2019).

  179. Staels, 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 58, 1941–1952 (2013).

    CAS  PubMed  Google Scholar 

  180. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159.e5 (2016).

    CAS  PubMed  Google Scholar 

  181. Cariou, B. et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36, 2923–2930 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT02704403 (2020).

  183. GENFIT. GENFIT: Announces results from interim analysis of RESOLVE-IT phase 3 trial of elafibranor in adults with NASH and fibrosis. GENFIT https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3 (2020).

  184. McVicker, B. L. & Bennett, R. G. Novel anti-fibrotic therapies. Front. Pharmacol. 8, 318 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. Vallee, A., Vallee, J. N. & Lecarpentier, Y. Metabolic reprogramming in atherosclerosis: Opposed interplay between the canonical WNT/beta-catenin pathway and PPARgamma. J. Mol. Cell Cardiol. 133, 36–46 (2019).

    CAS  PubMed  Google Scholar 

  186. Zhao, N. et al. Enhanced MiR-711 transcription by PPARγ induces endoplasmic reticulum stress-mediated apoptosis targeting calnexin in rat cardiomyocytes after myocardial infarction. J. Mol. Cell Cardiol. 118, 36–45 (2018).

    CAS  PubMed  Google Scholar 

  187. Peymani, M., Ghaedi, K., Irani, S. & Nasr-Esfahani, M. H. Peroxisome proliferator-activated receptor gamma activity is required for appropriate cardiomyocyte differentiation. Cell J. 18, 221–228 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Ortiz-Lopez, C. et al. Prevalence of prediabetes and diabetes and metabolic profile of patients with nonalcoholic fatty liver disease (NAFLD). Diabetes Care 35, 873–878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. DeFronzo, R. A. et al. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 364, 1104–1115 (2011).

    CAS  PubMed  Google Scholar 

  190. Inzucchi, S. E. et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 39, 1684–1692 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).

    CAS  PubMed  Google Scholar 

  192. Chiquette, E., Ramirez, G. & Defronzo, R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch. Intern. Med. 164, 2097–2104 (2004).

    CAS  PubMed  Google Scholar 

  193. Goldberg, R. B. et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28, 1547–1554 (2005).

    CAS  PubMed  Google Scholar 

  194. Mazzone, T. et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 296, 2572–2581 (2006).

    CAS  PubMed  Google Scholar 

  195. Nissen, S. E. et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 299, 1561–1573 (2008).

    CAS  PubMed  Google Scholar 

  196. Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005). Paradigm-changing study on the ability of a diabetes medication and insulin-sensitizer (pioglitazone) to reduce stroke and myocardial infarction in patients with T2DM.

    CAS  PubMed  Google Scholar 

  197. 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. JAMA 298, 1180–1188 (2007).

    CAS  PubMed  Google Scholar 

  198. Kernan, W. N. et al. Pioglitazone after ischemic stroke or transient ischemic attack. N. Engl. J. Med. 374, 1321–1331 (2016). Landmark study on the ability of pioglitazone to reduce risk of stroke or myocardial infarction compared with placebo in patients with insulin resistance but without diabetes with a recent history of ischaemic stroke or transient ischaemic attack.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Spence, J. D. et al. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 76, 526–535 (2019).

    PubMed  PubMed Central  Google Scholar 

  200. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).

    CAS  PubMed  Google Scholar 

  201. Hoogwerf, B. J. et al. Perspectives on some controversies in cardiovascular disease risk assessment in the pharmaceutical development of glucose-lowering medications. Diabetes Care 39, S219–S227 (2016).

    CAS  PubMed  Google Scholar 

  202. Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373, 2125–2135 (2009). This study, which enrolled more than 4,000 patients, found that rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with other glucose-lowering drugs.

    CAS  PubMed  Google Scholar 

  203. US Food and Drug Administration. FDA Drug Safety Communication: FDA eliminates the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing diabetes medicines (FDA, 2015).

  204. Choi, Y. J. et al. Effects of the PPAR-delta agonist MBX-8025 on atherogenic dyslipidemia. Atherosclerosis 220, 470–476 (2012).

    CAS  PubMed  Google Scholar 

  205. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005). This large study found that fenofibrate statistically significantly reduces total cardiovascular events and primarily non-fatal myocardial infarctions.

    CAS  PubMed  Google Scholar 

  206. Ginsberg, H. N. et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

    PubMed  Google Scholar 

  207. Jani, R. H. et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol. Ther. 16, 63–71 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Wettstein, G. et al. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol. Commun. 1, 524–537 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Boubia, B. et al. Design, synthesis, and evaluation of a novel series of indole sulfonamide peroxisome proliferator activated receptor (PPAR) alpha/gamma/delta triple activators: discovery of lanifibranor, a new antifibrotic clinical candidate. J. Med. Chem. 61, 2246–2265 (2018).

    CAS  PubMed  Google Scholar 

  210. Ruzehaji, N. et al. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann. Rheum. Dis. 75, 2175–2183 (2016).

    CAS  PubMed  Google Scholar 

  211. Avouac, J. et al. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann. Rheum. Dis. 76, 1931–1940 (2017).

    CAS  PubMed  Google Scholar 

  212. Stumvoll, M. & Haring, H. U. Glitazones: clinical effects and molecular mechanisms. Ann. Med. 34, 217–224 (2002).

    CAS  PubMed  Google Scholar 

  213. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03008070 (2020).

  214. Inventiva. Inventiva’s lanifibranor meets the primary and key secondary endpoints in the Phase IIb NATIVE clinical trial in non-alcoholic steatohepatitis (NASH). Inventiva https://inventivapharma.com/inventivas-lanifibranor-meets-the-primary-and-key-secondary-endpoints-in-the-phase-iib-native-clinical-trial-in-non-alcoholic-steatohepatitis-nash/ (2020).

  215. Bonds, D. E. et al. Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience. Diabetologia 55, 1641–1650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Davis, T. M. et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54, 280–290 (2011).

    CAS  PubMed  Google Scholar 

  217. Lee, M., Saver, J. L., Liao, H. W., Lin, C. H. & Ovbiagele, B. Pioglitazone for secondary stroke prevention: a systematic review and meta-analysis. Stroke 48, 388–393 (2017).

    CAS  PubMed  Google Scholar 

  218. DeFronzo, R. A., Inzucchi, S., Abdul-Ghani, M. & Nissen, S. E. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab. Vasc. Dis. Res. 16, 133–143 (2019).

    CAS  PubMed  Google Scholar 

  219. Portillo-Sanchez, P. et al. Effect of pioglitazone on bone mineral density in patients with nonalcoholic steatohepatitis: a 36-month clinical trial. J. Diab. 11, 223–231 (2019).

    CAS  Google Scholar 

  220. Filipova, E., Uzunova, K., Kalinov, K. & Vekov, T. Pioglitazone and the risk of bladder cancer: a meta-analysis. Diabetes Ther. 8, 705–726 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Balas, B. et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J. Hepatol. 47, 565–570 (2007).

    CAS  PubMed  Google Scholar 

  222. Young, L. H. et al. Heart failure after ischemic stroke or transient ischemic attack in insulin-resistant patients without diabetes mellitus treated with pioglitazone. Circulation 138, 1210–1220 (2018). This secondary analysis of the IRIS trial found that pioglitazone did not increase the risk of heart failure.

    PubMed  PubMed Central  Google Scholar 

  223. van der Meer, R. W. et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation 119, 2069–2077 (2009).

    PubMed  Google Scholar 

  224. Clarke, G. D. et al. Pioglitazone improves left ventricular diastolic function in subjects with diabetes. Diabetes Care 40, 1530–1536 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Lehrke, M. & Marx, N. Diabetes mellitus and heart failure. Am. J. Cardiol. 120, S37–S47 (2017).

    CAS  PubMed  Google Scholar 

  226. DeFronzo, R. A. et al. Revitalization of pioglitazone: the optimum agent to be combined with a sodium-glucose co-transporter-2 inhibitor. Diabetes Obes. Metab. 18, 454–462 (2016).

    CAS  PubMed  Google Scholar 

  227. Munigoti, S. P. & Harinarayan, C. V. Role of glitazars in atherogenic dyslipidemia and diabetes: two birds with one stone? Indian J. Endocrinol. Metab. 18, 283–287 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Hirschfield, G. et al. LBP-002 — Treatment efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis patients: 12- and 26-week analysis from an ongoing international, randomized, dose raging phase 2 study. J. Hepatol. 68, S105–S106 (2018).

    Google Scholar 

  229. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus (WHO, 1999).

  230. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 285, 2486–2497 (2001).

    Google Scholar 

  231. Alberti, K. G., Zimmet, P., Shaw, J. & IDF Epidemiology Task Force Consensus Group. The metabolic syndrome — a new worldwide definition. Lancet 366, 1059–1062 (2005).

    PubMed  Google Scholar 

  232. Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and international association for the Study of Obesity. Circulation 120, 1640–1645 (2009).

    CAS  PubMed  Google Scholar 

  233. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03350165 (2019).

  234. Bril, F. et al. Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 42, 1481–1488 (2019).

    CAS  PubMed  Google Scholar 

  235. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT03459079 (2020).

  236. Sumida, Y. & Yoneda, M. Current and future pharmacological therapies for NAFLD/NASH. J. Gastroenterol. 53, 362–376 (2018).

    CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Sven Francque, Gyongyi Szabo.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium

    Sven Francque

  2. Translational Research in Inflammation and Immunology (TWI2N), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Sven Francque

  3. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Gyongyi Szabo

  4. Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Health System, Durham, NC, USA

    Manal F. Abdelmalek

  5. Nutrition & Metabolism, Human Development & Health, Faculty of Medicine, University Hospital Southampton, Southampton, UK

    Christopher D. Byrne

  6. Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA

    Kenneth Cusi

  7. Hepatology, Department of Clinical Research, University Hospital of Bern, Bern, Switzerland

    Jean-François Dufour

  8. University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland

    Jean-François Dufour

  9. Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, University Clinics Düsseldorf, Düsseldorf, Germany

    Michael Roden

  10. Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Michael Roden

  11. German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany

    Michael Roden

  12. Departments of Nutrition and Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Frank Sacks

  13. Channing Division, Department of Medicine Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA

    Frank Sacks

  14. Department of Hepatology & Gastroenterology, Charité University Medical Center, Berlin, Germany

    Frank Tacke

Authors
  1. Sven Francque
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gyongyi Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manal F. Abdelmalek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher D. Byrne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth Cusi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-François Dufour
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Roden
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Frank Sacks
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank Tacke
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.S. and S.F. researched data for the article, made a substantial contribution to discussion of content, wrote the article, and reviewed/edited the manuscript before submission. M.F.A., C.D.B., K.C., J.-F.D., M.R., F.S. and F.T. made a substantial contribution to the discussion of content and reviewed/edited the manuscript before submission.

Corresponding authors

Correspondence to Sven Francque or Gyongyi Szabo.

Ethics declarations

Competing interests

S.F. has a senior clinical research mandate from the Fund for Scientific Research (FWO) Flanders (1802154N) and has acted as advisor and/or lecturer for Roche, Gilead, Abbvie, Bayer, BMS, MSD, Janssen, Actelion, Astellas, Genfit, Inventiva, Intercept, Genentech and Galmed. G.S. has received research support from NIAAA (NIH), Gilead, Intercept, Allergan, Genfit, Novartis, SignaBlock, Shire, the University of Florida, BMS, Genentech, Takeda, and Vertex. She is a consultant/advisory board member for Allergan, Arrow Diagnostics, Pandion Therapeutics, Glympse Bio, Quest Diagnostic, Surrozen, Innovate Biopharmaceuticals, Alnylam, Zomagen, Novartis, Durect, Generon and Terrafirma. She is an author for UptoDate, editor for the American Association for the Study of Liver Diseases and Editor-in-Chief of Hepatology Communications. M.F.A. is supported by the National Institute of Health (NIH)/NIDDK Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN, U01DK061713, PI: A.M. Diehl) and is an advisor/consultant for Bristol Myers Squibb, NGM Pharma, Inventiva, Taiwan J, Immuron, Prometheus, and Novo-Nordisk. Her institution receives funding for research from NIH/NIDDK, Inventiva, Enyo, Enanta, Allergan, Novartis, Genfit, Intercept, BMS, NGM Parma, Gilead, Conatus, Durect, Poxel, Madrigal, Celgene, Galactin, Galmed, Novo-Nordisk, Taiwan J, Prometheus, TARGET NASH, and Progenity. She serves on speaker’s bureau for Simply Speaking NASH, iHEP NASH, PRIME NASH Programming, Clinical Care Options, and Alexion. C.D.B. is supported by the National Institute for Health Research (NIHR) through the NIHR Southampton Biomedical Research Centre. He is a consultant for Inventiva. K.C. has received research support for the University of Florida as principal investigator from the NIH, Cirius, Echosens, Inventiva, Novartis, Novo Nordisk, Poxel, TARGET NASH and Zydus. He is a consultant for Allergan, Astra-Zeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Genentech, Gilead, Janssen, Merck, Pfizer, Poxel, Prosciento, Novo Nordisk, Sanofi-Aventis, and TARGET NASH. J.-F.D. is a consultant/advisory board member for Abbvie, Allergan, Bayer, Bristol-Myers Squibb, Falk, Genfit, Genkyotex, Gilead Science, HepaRegenix, Intercept Pharma, Lilly, Merck, and Novartis. He serves as an investigator of studies supported by Abbvie, Bayer, BMS, Falk, Genfit, Gilead Science, Intercept, Inventiva, Lilly, Merck, and Novartis. M.R. has received research support from the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Federal Ministry of Health, grants from the European Fonds for Regional Development (EFRE-0400191), German Research Foundation (DFG, SFB 1116/2) and the Schmutzler Stiftung, serves as investigator of studies supported by Boehringer-Ingelheim Pharma, Nutricia/Danone, and Sanofi, and was advisor/consultant for Bristol-Myers Squibb, Eli Lilly, Gilead, Intercept Pharma, Novo Nordisk, Novartis, Poxel, Prosciento, Sanofi, Servier, and TARGET NASH. F.S. is a consultant to Pfizer, AstraZeneca, and Abbvie. F.T. has received research funding at Charité University Medicine Berlin from Allergan, Bristol-Myers Squibb, Galapagos, and Inventiva. He is a consultant for Allergan, Bayer, Boehringer Ingelheim, Galapagos, Galmed, Intercept, Inventiva, and Pfizer.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Francque, S., Szabo, G., Abdelmalek, M.F. et al. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol 18, 24–39 (2021). https://doi.org/10.1038/s41575-020-00366-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-020-00366-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing