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Role of peroxisome proliferator-activated receptors in non-alcoholic fatty liver disease inflammation

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Abstract

Overweight and obesity have been identified as the most important risk factors for many diseases, including cardiovascular disease, type 2 diabetes and lipid disorders, such as non-alcoholic fatty liver disease (NAFLD). The metabolic changes associated with obesity are grouped to define metabolic syndrome, which is one of the main causes of morbidity and mortality in industrialized countries. NAFLD is considered to be the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver diseases worldwide. Inflammation plays an important role in the development of numerous liver diseases, contributing to the progression to more severe stages, such as non-alcoholic steatohepatitis and hepatocellular carcinoma. Peroxisome proliferator-activated receptors (PPARs) are binder-activated nuclear receptors that are involved in the transcriptional regulation of lipid metabolism, energy balance, inflammation and atherosclerosis. Three isotypes are known: PPAR-α, PPARδ/β and PPAR-γ. These isotypes play different roles in diverse tissues and cells, including the inflammatory process. In this review, we discuss current knowledge on the role PPARs in the hepatic inflammatory process involved in NAFLD as well as new pharmacological strategies that target PPARs.

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References

  1. Sonsuz A, Basaranoglu M, Ozbay G (2000) Relationship between aminotransferase levels and histopathological findings in patients with nonalcoholic steatohepatitis inducible nitric oxide synthase activity is expressed not only in inflamed but also in normal colonic mucosa in patients with ulcerat. Am J Gastroenterol 95:1370–1371

    Article  PubMed  CAS  Google Scholar 

  2. Stephen S, Baranova A, Younossi ZM (2012) Nonalcoholic fatty liver disease and bariatric surgery. Expert Rev Gastroenterol Hepatol 6:163–171. https://doi.org/10.1586/egh.11.97

    Article  PubMed  Google Scholar 

  3. Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62:S47–S64. https://doi.org/10.1016/j.jhep.2014.12.012

    Article  PubMed  Google Scholar 

  4. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231. https://doi.org/10.1056/NEJMra011775

    Article  PubMed  CAS  Google Scholar 

  5. Musso G, Gambino R, Cassader M, Pagano G (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 43:617–649. https://doi.org/10.3109/07853890.2010.518623

    Article  PubMed  Google Scholar 

  6. Charlton MR, Kondo M, Roberts SK et al (1997) Liver transplantation for cryptogenic cirrhosis. Liver Transpl Surg 3:359–364. https://doi.org/10.1002/lt.500030402

    Article  PubMed  CAS  Google Scholar 

  7. Mccullough AJ (2002) Update on nonalcoholic fatty liver disease. J Clin Gastroenterol 34:255–262

    Article  PubMed  Google Scholar 

  8. Sass DA, Chang P, Chopra KB (2005) Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci 50:171–180. https://doi.org/10.1007/s10620-005-1267-z

    Article  PubMed  Google Scholar 

  9. Edens MA, Kuipers F, Stolk RP (2009) Non-alcoholic fatty liver disease is associated with cardiovascular disease risk markers. Obes Rev 10:412–419. https://doi.org/10.1111/j.1467-789X.2009.00594.x

    Article  PubMed  CAS  Google Scholar 

  10. Dowman JK, Tomlinson JW, Newsome PN (2010) Pathogenesis of non-alcoholic fatty liver disease. QJM 103:71–83. https://doi.org/10.1093/qjmed/hcp158

    Article  PubMed  CAS  Google Scholar 

  11. Targher G, Day CP, Bonora E (2010) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363:1341–1350. https://doi.org/10.1056/NEJMra0912063

    Article  PubMed  CAS  Google Scholar 

  12. Gaggini M, Morelli M, Buzzigoli E et al (2013) Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5:1544–1560. https://doi.org/10.3390/nu5051544

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Szabo G, Mandrekar P, Golganiuc A (2007) Innate immune response and hepatic inflammation. Semin Liver Dis 27:339–350. https://doi.org/10.1055/s-2007-991511

    Article  PubMed  CAS  Google Scholar 

  14. Weiß J, Rau M, Geier A (2014) Non-alcoholic fatty liver disease: epidemiology, clinical course, investigation, and treatment. Dtsch Arztebl Int 111:447–452. https://doi.org/10.3238/arztebl.2014.0447

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bogdanos DP, Gao B, Gershwin ME (2013) Liver Immunology. In: Comprehensive physiology. Wiley, Hoboken

  16. Serino M, Menghini R, Fiorentino L et al (2007) Mice heterozygous for tumor necrosis factor-a converting enzyme are protected from obesity-induced insulin resistance and diabetes. Diabetes 56:2541–2546. https://doi.org/10.2337/db07-0360

    Article  PubMed  CAS  Google Scholar 

  17. Wunderlich FT, Ströhle P, Könner AC et al (2010) Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab 12:237–249. https://doi.org/10.1016/j.cmet.2010.06.011

    Article  PubMed  CAS  Google Scholar 

  18. Ahmed W, Ziouzenkova O, Brown J et al (2007) PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J Intern Med 262:184–198. https://doi.org/10.1111/j.1365-2796.2007.01825.x

    Article  PubMed  CAS  Google Scholar 

  19. Poulsen LLC, Siersbæk M, Mandrup S (2012) PPARs: fatty acid sensors controlling metabolism. Semin Cell Dev Biol 23:631–639. https://doi.org/10.1016/j.semcdb.2012.01.003

    Article  PubMed  CAS  Google Scholar 

  20. Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPARα in energy metabolism and vascular homeostasis. J Clin Invest 116:571–580. https://doi.org/10.1172/JCI27989

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94:4312–4317. https://doi.org/10.1073/pnas.94.9.4312

    Article  PubMed  CAS  Google Scholar 

  22. Giordano Mp G, Attianese Desvergne B (2015) Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function. Nucl Recept Signal 13:1–32. https://doi.org/10.1621/nrs.13001

    Article  CAS  Google Scholar 

  23. Neels JG, Grimaldi PA (2014) Physiological functions of peroxisome proliferator-activated receptor. Physiol Rev 94:795–858. https://doi.org/10.1152/physrev.00027.2013

    Article  PubMed  CAS  Google Scholar 

  24. Heikkinen S, Auwerx J, Argmann CA (2007) PPARgamma in human and mouse physiology. Biochim Biophys Acta Lipids Lipid Metab 1771:999–1013. https://doi.org/10.1016/j.bbalip.2007.03.006

    Article  CAS  Google Scholar 

  25. Day C (1999) Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med 16:179–192. https://doi.org/10.1046/j.1464-5491.1999.00023.x

    Article  PubMed  CAS  Google Scholar 

  26. Crisafulli C, Cuzzocrea S (2008) The role endogenous and exogenous ligands for the peroxisome proliferator-activated receptor alpha (PPAR-alpha) in the regulation of inflammation in macrophAGES. Shock 32:62–73. https://doi.org/10.1097/SHK.0b013e31818bbad6

    Article  CAS  Google Scholar 

  27. Rigamonti E, Chinetti-Gbaguidi G, Staels B (2008) Regulation of macrophage functions by PPAR-α, PPAR-γ, and LXRs in mice and men. Arterioscler Thromb Vasc Biol 28:1050–1059. https://doi.org/10.1161/ATVBAHA.107.158998

    Article  PubMed  CAS  Google Scholar 

  28. Escher P, Michalik L, Wahli W (2001) Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142:4195–4202

    Article  PubMed  CAS  Google Scholar 

  29. Hashimoto T, Cook WS, Qi C et al (2000) Defect in peroxisome proliferator-activated receptor ??-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 275:28918–28928. https://doi.org/10.1074/jbc.M910350199

    Article  PubMed  CAS  Google Scholar 

  30. Delerive P, Gervois P, Fruchart JC, Staels B (2000) Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators. J Biol Chem 275:36703–36707. https://doi.org/10.1074/jbc.M004045200

    Article  PubMed  CAS  Google Scholar 

  31. Ricote M, Glass C (2007) PPARs and molecular mechanisms of transrepression. Biochim Biophys Acta Mol Cell Biol Lipids 1771:926–935. https://doi.org/10.1016/j.bbalip.2007.02.013

    Article  CAS  Google Scholar 

  32. Glass CK, Saijo K (2010) Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10:365–376. https://doi.org/10.1038/nri2748

    Article  PubMed  CAS  Google Scholar 

  33. Mogilenko DA, Kudriavtsev IV, Shavva VS et al (2013) Peroxisome proliferator-activated receptor α positively regulates complement C3 expression but inhibits tumor necrosis factor-mediated activation of C3 gene in mammalian hepatic-derived cells. J Biol Chem 288:1726–1738. https://doi.org/10.1074/jbc.M112.437525

    Article  PubMed  CAS  Google Scholar 

  34. Ramanan S, Zhao W, Riddle DR, Robbins ME (2010) Review article: role of PPARs in radiation-induced brain injury. PPAR Res. https://doi.org/10.1155/2010/234975

    Article  PubMed  Google Scholar 

  35. Liu Q, Pan R, Ding L et al (2017) Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries. Int Immunopharmacol 49:132–141. https://doi.org/10.1016/j.intimp.2017.05.026

    Article  PubMed  CAS  Google Scholar 

  36. Heritage ML, Jaskowski LA, Bridle KR et al (2017) Combination curcumin and vitamin E treatment attenuates diet-induced steatosis in Hfe−/− mice. World J Gastrointest Pathophysiol 8:67. https://doi.org/10.4291/wjgp.v8.i2.67

    Article  PubMed  PubMed Central  Google Scholar 

  37. Adi N, Adi J, Lassance-Soares RM, Kurlansky P, Yu H, Webster KA (2016) High protein/fish oil diet prevents hepatic steatosis in NONcNZO10 mice; association with diet/genetics-regulated micro-RNAs. J Diabetes Metab. https://doi.org/10.4172/2155-6156.1000676

    Article  PubMed  PubMed Central  Google Scholar 

  38. Valenzuela R, Echeverria F, Ortiz M et al (2017) Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice. Lipids Health Dis 16:1–16. https://doi.org/10.1186/s12944-017-0450-5

    Article  Google Scholar 

  39. Hussein G, Goto H, Oda S et al (2006) Antihypertensive potential and mechanism of action of astaxanthin: III. Antioxidant and histopathological effects in spontaneously hypertensive rats. Biol Pharm Bull 29:684–688. https://doi.org/10.1248/bpb.29.684

    Article  PubMed  CAS  Google Scholar 

  40. Jia Y, Kim JY, Jun HJ et al (2012) The natural carotenoid astaxanthin, a PPAR-?? agonist and PPAR-?? antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes. Mol Nutr Food Res 56:878–888. https://doi.org/10.1002/mnfr.201100798

    Article  PubMed  CAS  Google Scholar 

  41. Jia Y, Wu C, Kim J et al (2016) Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferator-activated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt. J Nutr Biochem 28:9–18. https://doi.org/10.1016/j.jnutbio.2015.09.015

    Article  PubMed  CAS  Google Scholar 

  42. Liss KHH, Finck BN (2017) PPARs and nonalcoholic fatty liver disease. Biochimie 136:65–74. https://doi.org/10.1016/j.biochi.2016.11.009

    Article  PubMed  CAS  Google Scholar 

  43. Shiri-Sverdlov R, Wouters K, Gorp PJV et al (2006) Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J Hepatol 44:732–741. https://doi.org/10.1016/j.jhep.2005.10.033

    Article  PubMed  CAS  Google Scholar 

  44. Zhang N, Lu Y, Shen X et al (2015) Fenofibrate treatment attenuated chronic endoplasmic reticulum stress in the liver of nonalcoholic fatty liver disease mice. Pharmacology 95:173–180. https://doi.org/10.1159/000380952

    Article  PubMed  CAS  Google Scholar 

  45. Abd El-Haleim EA, Bahgat AK, Saleh S (2016) Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression. World J Gastroenterol 22:2931–2948. https://doi.org/10.3748/wjg.v22.i10.2931

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Laurin J, Lindor KD, Crippin JS et al (1996) Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis : a pilot study. Hepatology 23:1464–1467

    Article  PubMed  CAS  Google Scholar 

  47. Fernández-Miranda C, Pérez-Carreras M, Colina F et al (2008) A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 40:200–205. https://doi.org/10.1016/j.dld.2007.10.002

    Article  PubMed  CAS  Google Scholar 

  48. El-Haggar SM, Mostafa TM (2015) Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease. Hepatol Int 9:471–479. https://doi.org/10.1007/s12072-015-9633-1

    Article  PubMed  Google Scholar 

  49. Ishibashi S, Yamashita S, Arai H et al (2016) Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: a randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 249:36–43. https://doi.org/10.1016/j.atherosclerosis.2016.02.029

    Article  PubMed  CAS  Google Scholar 

  50. Honda Y, Kessoku T, Ogawa Y et al (2017) Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep 7:1–11. https://doi.org/10.1038/srep42477

    Article  CAS  Google Scholar 

  51. Takei K, Han SI, Murayama Y et al (2017) Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice. J Diabetes Investig 8:446–452. https://doi.org/10.1111/jdi.12621

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. da Costa Leite LFC, Veras Mourão RH, de Lima Mdo CA et al (2007) Synthesis, biological evaluation and molecular modeling studies of arylidene-thiazolidinediones with potential hypoglycemic and hypolipidemic activities. Eur J Med Chem 42:1263–1271. https://doi.org/10.1016/j.ejmech.2007.02.015

    Article  PubMed  CAS  Google Scholar 

  53. Araújo S, Soares e Silva A, Gomes F, et al (2016) Effects of the new thiazolidine derivative LPSF/GQ-02 on hepatic lipid metabolism pathways in non-alcoholic fatty liver disease (NAFLD). Eur J Pharmacol 788:306–314. https://doi.org/10.1016/j.ejphar.2016.06.043

  54. Soares e Silva AK, de Oliveira Cipriano Torres D, dos Santos Gomes FO et al (2015) LPSF/GQ-02 Inhibits the development of hepatic steatosis and inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD). PLoS One 10:e0123787. https://doi.org/10.1371/journal.pone.0123787

  55. Gross B, Staels B (2007) PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. Best Pract Res Clin Endocrinol Metab 21:687–710. https://doi.org/10.1016/j.beem.2007.09.004

    Article  PubMed  CAS  Google Scholar 

  56. Nadra K, Anghel SI, Joye E et al (2006) Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor. Mol Cell Biol 26:3266–3281. https://doi.org/10.1128/MCB.26.8.3266-3281.2006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Grimaldi PA (2007) Regulatory functions of PPARβ in metabolism: implications for the treatment of metabolic syndrome. Biochim Biophys Acta Mol Cell Biol Lipids 1771:983–990. https://doi.org/10.1016/j.bbalip.2007.02.006

    Article  CAS  Google Scholar 

  58. Leibowitz MD, Fiévet C, Hennuyer N et al (2000) Activation of PPARdelta alters lipid metabolism in db/db mice. FEBS Lett 473:333–336. https://doi.org/10.1016/S0014-5793(00)01554-4

    Article  PubMed  CAS  Google Scholar 

  59. Oliver WR, Shenk JL, Snaith MR et al (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98:5306–5311. https://doi.org/10.1073/pnas.091021198

    Article  PubMed  CAS  Google Scholar 

  60. Graham TL, Mookherjee C, Suckling KE et al (2005) The PPARδ agonist GW0742X reduces atherosclerosis in LDLR−/− mice. Atherosclerosis 181:29–37. https://doi.org/10.1016/j.atherosclerosis.2004.12.028

    Article  PubMed  CAS  Google Scholar 

  61. Stienstra R, Duval C, Müller M, Kersten S (2007) PPARs, obesity, and inflammation. PPAR Res. https://doi.org/10.1155/2007/95974

    Article  PubMed Central  PubMed  Google Scholar 

  62. Shearer BG, Billin AN (2007) The next generation of PPAR drugs: do we have the tools to find them? Biochim Biophys Acta Mol Cell Biol Lipids 1771:1082–1093. https://doi.org/10.1016/j.bbalip.2007.05.005

    Article  CAS  Google Scholar 

  63. Michalik L, Auwerx J, Berger JP et al (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58:726–741. https://doi.org/10.1124/pr.58.4.5.(NR1C1)

    Article  PubMed  CAS  Google Scholar 

  64. Odegaard J, Ricardo-Gonzalez R, Goforth MH et al (2007) Macrophage-specific PPAR&ggr; controls alternative activation and improves insulin resistance. Nature 447:1116–1120. https://doi.org/10.1038/nature05894.Macrophage-specific

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Serrano-Marco L, Barroso E, El Kochairi I et al (2012) The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia 55:743–751. https://doi.org/10.1007/s00125-011-2401-4

    Article  PubMed  CAS  Google Scholar 

  66. Sznaidman ML, Haffner CD, Maloney PR et al (2003) Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity. Bioorganic Med Chem Lett 13:1517–1521. https://doi.org/10.1016/S0960-894X(03)00207-5

    Article  CAS  Google Scholar 

  67. Kostadinova R, Montagner A, Gouranton E et al (2012) GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation. Cell Biosci 2:1–16. https://doi.org/10.1186/2045-3701-2-34

    Article  CAS  Google Scholar 

  68. Lee HJ, Yeon JE, Ko EJ et al (2015) Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease. World J Gastroenterol 21:12787–12799. https://doi.org/10.3748/wjg.v21.i45.12787

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Barroso E, Rodríguez-Calvo R, Serrano-Marco L et al (2011) The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-lipin 1-PPARα pathway leading to increased fatty acid oxidation. Endocrinology 152:1848–1859. https://doi.org/10.1210/en.2010-1468

    Article  PubMed  CAS  Google Scholar 

  70. Lee MY, Chung CH, Lee MY et al (2012) Peroxisome proliferator-activated receptor δ agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp Mol Med 44:578–585. https://doi.org/10.3858/emm.2012.44.10.066

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Shan W, Palkar PS, Murray IA et al (2008) Ligand activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol Sci 105:418–428. https://doi.org/10.1093/toxsci/kfn142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Sanderson LM, Boekschoten MV, Desvergne B et al (2010) Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver. Physiol Genomics 41:42–52. https://doi.org/10.1152/physiolgenomics.00127.2009

    Article  PubMed  CAS  Google Scholar 

  73. Tontonoz P, Hu E, Graves RA et al (1994) mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 8:1224–1234

    Article  PubMed  CAS  Google Scholar 

  74. Tontonoz P, Hu E, Devine J et al (1995) PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol 15:351–357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM et al (1996) PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 15:5336–5348

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Sfeir Z, Ibrahimi A, Amri E et al (1997) Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. Prostaglandins Leukot Essent Fat Acids 57:17–21. https://doi.org/10.1016/S0952-3278(97)90487-7

    Article  CAS  Google Scholar 

  77. Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79:1147–1156. https://doi.org/10.1016/0092-8674(94)90006-X

    Article  PubMed  CAS  Google Scholar 

  78. Yu S, Matsusue K, Kashireddy P et al (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression. J Biol Chem 278:498–505. https://doi.org/10.1074/jbc.M210062200

    Article  PubMed  CAS  Google Scholar 

  79. Gavrilova O, Haluzik M, Matsusue K et al (2003) Liver peroxisome proliferator-activated receptor γ contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278:34268–34276. https://doi.org/10.1074/jbc.M300043200

    Article  PubMed  CAS  Google Scholar 

  80. Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V et al (2011) Role for PPAR in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J 25:2538–2550. https://doi.org/10.1096/fj.10-173716

    Article  PubMed  CAS  Google Scholar 

  81. Yu S, Matsusue K, Kashireddy P et al (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression. J Biol Chem 278:498–505. https://doi.org/10.1074/jbc.M210062200

    Article  PubMed  CAS  Google Scholar 

  82. Pettinelli P, Videla LA (2011) Up-regulation of PPAR-γ mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 96:1424–1430. https://doi.org/10.1210/jc.2010-2129

    Article  PubMed  CAS  Google Scholar 

  83. Nakamuta M, Kohjima M, Morizono S et al (2005) Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med 16:631–635

    PubMed  CAS  Google Scholar 

  84. Chinetti G, Fruchart JC, Staels B (2003) Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function. Curr Opin Lipidol 14:459–468. https://doi.org/10.1097/01.mol.0000092630.86399.00

    Article  PubMed  CAS  Google Scholar 

  85. Pascual G, Fong AL, Ogawa S et al (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ. Nature 437:759–763. https://doi.org/10.1038/nature03988

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Konstantinopoulos PA, Vandoros GP, Sotiropoulou-Bonikou G et al (2007) NF-κB/PPARγ and/or AP-1/PPARγ “on/off” switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression. Int J Colorectal Dis 22:57–68. https://doi.org/10.1007/s00384-006-0112-y

    Article  PubMed  Google Scholar 

  87. Villanueva CJ, Tontonoz P (2010) Licensing PPARγ to work in macrophages. Immunity 33:647–649. https://doi.org/10.1016/j.immuni.2010.11.017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Wynn TA, Chawla A, Pollard JW (2013) Origins and hallmarks of macrophages: development, homeostasis, and disease. Nature 496:445–455. https://doi.org/10.1038/nature12034.origins

  89. Ginhoux F, Schultze JL, Murray PJ et al (2016) New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 17:34–40. https://doi.org/10.1038/ni.3324

    Article  PubMed  CAS  Google Scholar 

  90. Baffy G (2009) Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 51:212–223. https://doi.org/10.1016/j.jhep.2009.03.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Dixon LJ, Barnes M, Tang H et al (2013) Kupffer cells in the liver. In: Comprehensive Physiology. Wiley, Hoboken

  92. Luo W, Xu Q, Wang Q et al (2017) Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci Rep 7:1–13. https://doi.org/10.1038/srep44612

    Article  Google Scholar 

  93. Zhong X, Liu H (2017) Honokiol attenuates diet-induced nonalcoholic steatohepatitis by regulating macrophage polarization through activating PPARgamma. J Gastroenterol Hepatol 33:524–532. https://doi.org/10.1111/jgh.13853

    Article  CAS  Google Scholar 

  94. Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470–477. https://doi.org/10.1038/nature07202

    Article  PubMed  CAS  Google Scholar 

  95. Isley WL (2003) Hepatotoxicity of thiazolidinediones. Expert Opinion Drug Saf 2:581–586

    Article  CAS  Google Scholar 

  96. Yki-Järvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118. https://doi.org/10.1056/NEJMra041001

    Article  PubMed  Google Scholar 

  97. Nan YM, Han F, Kong LB et al (2011) Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice. Scand J Gastroenterol 46:358–369. https://doi.org/10.3109/00365521.2010.525717

    Article  PubMed  CAS  Google Scholar 

  98. Nan YM, Fu N, Wu WJ et al (2009) Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice. Scand J Gastroenterol 44:358–365. https://doi.org/10.1080/00365520802530861

    Article  PubMed  CAS  Google Scholar 

  99. Deng W, Meng Z, Sun A, Yang Z (2017) Pioglitazone suppresses inflammation and fibrosis in nonalcoholic fatty liver disease by down-regulating PDGF and TIMP-2: evidence from in vitro study. Cancer Biomarkers 20:411–415. https://doi.org/10.3233/CBM-170157

    Article  PubMed  CAS  Google Scholar 

  100. van der Veen JN, Lingrell S, Gao X, et al (2016) Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine N-methyltransferase-(PEMT) deficient mice. Am J Physiol Gastrointest Liver Physiol 4:ajpgi.00243.2015. https://doi.org/10.1152/ajpgi.00243.2015

  101. Chen W, Lin Y, Zhou X et al (2016) Rosiglitazone protects rat liver against acute liver injury by the NF-kB pathway. Can J Physiol Pharmacol. https://doi.org/10.1139/cjpp-2015-0230

    Article  PubMed  Google Scholar 

  102. Boettcher E, Csako G, Pucino F et al (2012) Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 35:66–75. https://doi.org/10.1111/j.1365-2036.2011.04912.x

    Article  PubMed  CAS  Google Scholar 

  103. Sanyal AJ, Chalasani N, Kowdley KV et al (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685. https://doi.org/10.1056/NEJMoa0907929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Lago RM, Singh PP, Nesto RW (2007) Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370:1129–1136. https://doi.org/10.1016/S0140-6736(07)61514-1

    Article  PubMed  CAS  Google Scholar 

  105. Tuccori M, Filion KB, Yin H et al (2016) Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. https://doi.org/10.1136/bmj.i1541

    Article  PubMed  PubMed Central  Google Scholar 

  106. Lecka-Czernik B (2010) Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep 8:178–184. https://doi.org/10.1007/s11914-010-0027-y

    Article  PubMed  PubMed Central  Google Scholar 

  107. Marchesini G, Day CP, Dufour JF et al (2016) EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64:1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004

    Article  Google Scholar 

  108. Chalasani N, Younossi Z, Lavine JE 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 55:2005–2023. https://doi.org/10.1002/hep.25762

    Article  PubMed  Google Scholar 

  109. García-Ruiz I, Rodríguez-Juan C, Díaz-Sanjuán T et al (2007) Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice. Hepatology 46:414–423. https://doi.org/10.1002/hep.21687

    Article  PubMed  CAS  Google Scholar 

  110. Brand CL, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF, Andersen B, Ye JM, Sauerberg P, Wassermann KSJ (2002) Dual PPARalpha/gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 284:E841–E854. https://doi.org/10.1152/ajpendo.00348.2002

    Article  PubMed  Google Scholar 

  111. Harrity T, Farrelly D, Tieman A et al (2006) Preserves-cell function in db/db mice. Diabetes 55:240–248

    Article  PubMed  CAS  Google Scholar 

  112. Ye J-M, Iglesias MA, Watson DG et al (2003) PPARalpha/gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly. Am J Physiol Endocrinol Metab 284:531–540. https://doi.org/10.1152/ajpendo.00299.2002

    Article  Google Scholar 

  113. Henry RR, Lincoff AM, Mudaliar S et al (2009) Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 374:126–135. https://doi.org/10.1016/S0140-6736(09)60870-9

    Article  PubMed  CAS  Google Scholar 

  114. Hamrén B, Öhman KP, Svensson MK, Karlsson MO (2012) Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J Clin Pharmacol 52:1317–1327. https://doi.org/10.1177/0091270011416937

    Article  PubMed  CAS  Google Scholar 

  115. Jain MR, Giri SR, Bhoi B et al (2017) Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. https://doi.org/10.1111/liv.13634

    Article  PubMed Central  PubMed  Google Scholar 

  116. Cariou B, Hanf R, Lambert-Porcheron S et al (2013) Dual peroxisome proliferator- activated receptor α/δ agonist gft505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36:2923–2930. https://doi.org/10.2337/dc12-2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Cariou B, Zaïr Y, Staels B, Bruckert E (2011) Effects of the new dual PPARα/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34:2008–2014. https://doi.org/10.2337/dc11-0093

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Staels B, Rubenstrunk A, Noel B et al (2013) 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. https://doi.org/10.1002/hep.26461

    Article  PubMed  CAS  Google Scholar 

  119. Ratziu V, Harrison SA, Francque S et al (2016) Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:1147–1159e5. https://doi.org/10.1053/j.gastro.2016.01.038

  120. Wettstein G, Luccarini J-M, Poekes L et al (2017) The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol Commun 1:524–537. https://doi.org/10.1002/hep4.1057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank the following Brazilian foundations for financial support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (the Brazilian National Council for Scientific and Technological Development) (CNPq; #301777/2012-8) and CAPES/PNPD Program for Silva AKS post-Doc scholarship.

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  1. Laboratory of Ultrastructure, Aggeu Magalhães Institute (IAM), Avenida Professor Moraes Rego, s/n, Cidade Universitária, Recife, PE, 50670-420, Brazil

    Amanda Karolina Soares Silva & Christina Alves Peixoto

  2. Biological Sciences of the Federal University of Pernambuco, Recife, PE, Brazil

    Amanda Karolina Soares Silva

  3. Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil

    Christina Alves Peixoto

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  1. Amanda Karolina Soares Silva
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The two authors contributed equally in the elaboration of the manuscript.

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Correspondence to Christina Alves Peixoto.

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Silva, A.K.S., Peixoto, C.A. Role of peroxisome proliferator-activated receptors in non-alcoholic fatty liver disease inflammation. Cell. Mol. Life Sci. 75, 2951–2961 (2018). https://doi.org/10.1007/s00018-018-2838-4

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