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Cited by 139Peroxisome Proliferator-Activated ReceptorsParaoxonase enzyme and polymorphismsAdipose Tissue and Metabolism

The opportunities and challenges of peroxisome proliferator-activated receptors ligands in clinical drug discovery and development

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Hong, Fan, Xu, Pengfei, Zhai, Yonggong·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19082189PMC PMC6121873
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Abstract

Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.

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  1. [1]Derosa G. Sahebkar A. Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice J. Cell. Physiol. 2018 233 153 161 10.1002/jcp.25804 28098353 · DOI
  2. [2]Grygiel-Gorniak B. Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications—A review Nutr. J. 2014 13 17 10.1186/1475-2891-13-17 24524207 PMC3943808 · DOI
  3. [3]Lagana A.S. Vitale S.G. Nigro A. Sofo V. Salmeri F.M. Rossetti P. Rapisarda A.M. La Vignera S. Condorelli R.A. Rizzo G. Pleiotropic actions of peroxisome proliferator-activated receptors (PPARs) in dysregulated metabolic homeostasis, inflammation and cancer: Current evidence and future perspectives Int. J. Mol. Sci. 2016 17 999 10.3390/ijms17070999 27347932 PMC4964375 · DOI
  4. [4]Xu P. Zhai Y. Wang J. The role of PPAR and its cross-talk with car and lxr in obesity and atherosclerosis Int. J. Mol. Sci. 2018 19 1260 10.3390/ijms19041260 29690611 PMC5979375 · DOI
  5. [5]Amber-Vitos O. Chaturvedi N. Nachliel E. Gutman M. Tsfadia Y. The effect of regulating molecules on the structure of the PPAR-RXR complex Biochim. Biophys. Acta 2016 1861 1852 1863 10.1016/j.bbalip.2016.09.003 27616290 · DOI
  6. [6]Echeverria F. Ortiz M. Valenzuela R. Videla L.A. Long-chain polyunsaturated fatty acids regulation of PPARs, signaling: Relationship to tissue development and aging Prostaglandins Leukotrienes Essent. Fatty Acids 2016 114 28 34 10.1016/j.plefa.2016.10.001 27926461 · DOI
  7. [7]Glatz J.F. Luiken J.J. From fat to fat (cd36/sr-b2): Understanding the regulation of cellular fatty acid uptake Biochimie 2017 136 21 26 10.1016/j.biochi.2016.12.007 28013071 · DOI
  8. [8]Nakamura M.T. Yudell B.E. Loor J.J. Regulation of energy metabolism by long-chain fatty acids Prog. Lipid Res. 2014 53 124 144 10.1016/j.plipres.2013.12.001 24362249 · DOI
  9. [9]Marcus S.L. Miyata K.S. Zhang B. Subramani S. Rachubinski R.A. Capone J.P. Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-coa oxidase genes but differentially induce expression Proc. Natl. Acad. Sci. USA 1993 90 5723 5727 10.1073/pnas.90.12.5723 8390676 PMC46794 · DOI
  10. [10]Zhang B. Marcus S.L. Miyata K.S. Subramani S. Capone J.P. Rachubinski R.A. Characterization of protein-DNA interactions within the peroxisome proliferator-responsive element of the rat hydratase-dehydrogenase gene J. Biol. Chem. 1993 268 12939 12945 8389766
  11. [11]Tontonoz P. Hu E. Graves R.A. Budavari A.I. Spiegelman B.M. MPPAR gamma 2: Tissue-specific regulator of an adipocyte enhancer Genes Dev. 1994 8 1224 1234 10.1101/gad.8.10.1224 7926726 · DOI
  12. [12]Tontonoz P. Hu E. Devine J. Beale E.G. Spiegelman B.M. PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene Mol. Cell. Biol. 1995 15 351 357 10.1128/MCB.15.1.351 7799943 PMC231968 · DOI
  13. [13]Yan S. Yang X.F. Liu H.L. Fu N. Ouyang Y. Qing K. Long-chain acyl-coa synthetase in fatty acid metabolism involved in liver and other diseases: An update World J. Gastroenterol. 2015 21 3492 3498 10.3748/wjg.v21.i12.3492 25834313 PMC4375570 · DOI
  14. [14]Dubois V. Eeckhoute J. Lefebvre P. Staels B. Distinct but complementary contributions of PPAR isotypes to energy homeostasis J. Clin. Investig. 2017 127 1202 1214 10.1172/JCI88894 28368286 PMC5373878 · DOI
  15. [15]Neels J.G. Grimaldi P.A. Physiological functions of peroxisome proliferator-activated receptor beta Physiol. Rev. 2014 94 795 858 10.1152/physrev.00027.2013 24987006 · DOI · Paper page
  16. [16]Cronet P. Petersen J.F. Folmer R. Blomberg N. Sjoblom K. Karlsson U. Lindstedt E.L. Bamberg K. Structure of the PPARalpha and -gamma ligand binding domain in complex with az 242; ligand selectivity and agonist activation in the PPAR family Structure 2001 9 699 706 10.1016/S0969-2126(01)00634-7 11587644 · DOI
  17. [18]Gampe R.T. Jr. Montana V.G. Lambert M.H. Miller A.B. Bledsoe R.K. Milburn M.V. Kliewer S.A. Willson T.M. Xu H.E. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors Mol. Cell 2000 5 545 555 10.1016/S1097-2765(00)80448-7 10882139 · DOI
  18. [19]Tan C.K. Zhuang Y. Wahli W. Synthetic and natural peroxisome proliferator-activated receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome Expert Opin. Ther. Targets 2017 21 333 348 10.1080/14728222.2017.1280467 28092722 · DOI
  19. [20]Gross B. Pawlak M. Lefebvre P. Staels B. PPARs in obesity-induced t2dm, dyslipidaemia and nafld Nat. Rev. Endocrinol. 2017 13 36 49 10.1038/nrendo.2016.135 27636730 · DOI · Paper page
  20. [21]Botta M. Audano M. Sahebkar A. Sirtori C.R. Mitro N. Ruscica M. PPAR agonists and metabolic syndrome: An established role? Int. J. Mol. Sci. 2018 19 1197 10.3390/ijms19041197 29662003 PMC5979533 · DOI
  21. [22]DePaoli A.M. Higgins L.S. Henry R.R. Mantzoros C. Dunn F.L. Group I.N.T.S. Can a selective PPARgamma modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care 2014 37 1918 1923 10.2337/dc13-2480 24722496 · DOI
  22. [23]Janani C. Ranjitha Kumari B.D. PPAR gamma gene—A review Diabetes Metab. Syndr. 2015 9 46 50 10.1016/j.dsx.2014.09.015 25450819 · DOI · Paper page
  23. [24]Koster I. Huppertz E. Hauner H. Schubert I. Costs of diabetes mellitus (codim) in germany, direct per-capita costs of managing hyperglycaemia and diabetes complications in 2010 compared to 2001 Exp. Clin. Endocrinol. Diabetes 2014 122 510 516 10.1055/s-0034-1375675 24918530 · DOI
  24. [25]Shah A.D. Langenberg C. Rapsomaniki E. Denaxas S. Pujades-Rodriguez M. Gale C.P. Deanfield J. Smeeth L. Timmis A. Hemingway H. Type 2 diabetes and incidence of cardiovascular diseases: A cohort study in 1.9 million people Lancet Diabetes Endocrinol. 2015 3 105 113 10.1016/S2213-8587(14)70219-0 25466521 PMC4303913 · DOI · Paper page
  25. [26]Chung J.W. Hartzler M.L. Smith A. Hatton J. Kelley K. Pharmacological agents utilized in patients with type-2 diabetes: Beyond lowering a1c P & T 2018 43 214 227 29622942 PMC5871242
  26. [27]Yasmin S. Jayaprakash V. Thiazolidinediones and PPAR orchestra as antidiabetic agents: From past to present Eur. J. Med. Chem. 2017 126 879 893 10.1016/j.ejmech.2016.12.020 27988463 · DOI
  27. [28]Investigators D.T. Gerstein H.C. Yusuf S. Bosch J. Pogue J. Sheridan P. Dinccag N. Hanefeld M. Hoogwerf B. Laakso M. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomised controlled trial Lancet 2006 368 1096 1105 16997664
  28. [29]Li Y. Zhang Y. Li X. Shi L. Tao W. Shi L. Yang M. Wang X. Yang Y. Yao Y. Association study of polymorphisms in mirnas with t2dm in chinese population Int. J. Med. Sci. 2015 12 875 880 10.7150/ijms.12954 26640407 PMC4643078 · DOI
  29. [30]Shaikh S. Muneera M.S. Thusleem O.A. Tahir M. Kondaguli A.V. Ruckmani K. Development and validation of a selective online dissolution method for rosiglitazone maleate J. Chromatogr. Sci. 2007 45 311 314 10.1093/chromsci/45.6.311 17626717 · DOI
  30. [31]Kahn B.B. McGraw T.E. Rosiglitazone, PPARgamma, and type 2 diabetes N. Engl. J. Med. 2010 363 2667 2669 10.1056/NEJMcibr1012075 21190462 PMC3733169 · DOI
  31. [32]Mitka M. Panel recommends easing restrictions on rosiglitazone despite concerns about cardiovascular safety JAMA 2013 310 246 247 10.1001/jama.2013.8141 23860970 · DOI
  32. [33]Tzanavaras P.D. Verdoukas A. Themelis D.G. Development and validation of a flow-injection assay for dissolution studies of the anti-depressant drug venlafaxine Anal. Sci. 2005 21 1515 1518 10.2116/analsci.21.1515 16379397 · DOI
  33. [34]Aronoff S. Rosenblatt S. Braithwaite S. Egan J.W. Mathisen A.L. Schneider R.L. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: A 6-month randomized placebo-controlled dose-response study. The pioglitazone 001 study group Diabetes Care 2000 23 1605 1611 10.2337/diacare.23.11.1605 11092281 · DOI
  34. [35]Levin D. Bell S. Sund R. Hartikainen S.A. Tuomilehto J. Pukkala E. Keskimaki I. Badrick E. Renehan A.G. Buchan I.E. Pioglitazone and bladder cancer risk: A multipopulation pooled, cumulative exposure analysis Diabetologia 2015 58 493 504 10.1007/s00125-014-3456-9 25481707 · DOI · Paper page
  35. [36]Lewis J.D. Habel L.A. Quesenberry C.P. Strom B.L. Peng T. Hedderson M.M. Ehrlich S.F. Mamtani R. Bilker W. Vaughn D.J. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes JAMA 2015 314 265 277 10.1001/jama.2015.7996 26197187 · DOI · Paper page
  36. [37]Derosa G. Maffioli P. Dipeptidyl peptidase-4 inhibitors: 3 years of experience Diabetes Technol. Ther. 2012 14 350 364 10.1089/dia.2011.0204 22324384 · DOI
  37. [38]Andukuri R. Drincic A. Rendell M. Alogliptin: A new addition to the class of dpp-4 inhibitors Diabetes Metab. Syndr. Obes. 2009 2 117 126 21437125 PMC3048010
  38. [39]Kaku K. Katou M. Igeta M. Ohira T. Sano H. Efficacy and safety of pioglitazone added to alogliptin in japanese patients with type 2 diabetes mellitus: A multicentre, randomized, double-blind, parallel-group, comparative study Diabetes Obes. Metab. 2015 17 1198 1201 10.1111/dom.12555 26277887 · DOI
  39. [40]Kim S.G. Kim D.M. Woo J.T. Jang H.C. Chung C.H. Ko K.S. Park J.H. Park Y.S. Kim S.J. Choi D.S. Efficacy and safety of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 24-weeks: A multicenter, randomized, double-blind, parallel-group, placebo controlled trial PLoS ONE 2014 9 e92843 10.1371/journal.pone.0092843 24736628 PMC3988010 · DOI
  40. [41]Jang J.Y. Bae H. Lee Y.J. Choi Y.I. Kim H.J. Park S.B. Suh S.W. Kim S.W. Han B.W. Structural basis for the enhanced anti-diabetic efficacy of lobeglitazone on PPARgamma Sci. Rep. 2018 8 31 10.1038/s41598-017-18274-1 29311579 PMC5758645 · DOI
  41. [42]Mittermayer F. Caveney E. De Oliveira C. Gourgiotis L. Puri M. Tai L.J. Turner J.R. Addressing unmet medical needs in type 2 diabetes: A narrative review of drugs under development Curr. Diabetes Rev. 2015 11 17 31 10.2174/1573399810666141224121927 25537454 PMC4428473 · DOI
  42. [43]Lee H.W. Kim B.Y. Ahn J.B. Kang S.K. Lee J.H. Shin J.S. Ahn S.K. Lee S.J. Yoon S.S. Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione Eur. J. Med. Chem. 2005 40 862 874 10.1016/j.ejmech.2005.03.019 15908051 · DOI
  43. [44]Moon K.S. Lee J.E. Lee H.S. Hwang I.C. Kim D.H. Park H.K. Choi H.J. Jo W. Son W.C. Yun H.I. Ckd-501, a novel selective PPARgamma agonist, shows no carcinogenic potential in icr mice following oral administration for 104 weeks J. Appl. Toxicol. 2014 34 1271 1284 10.1002/jat.2918 24026970 · DOI
  44. [45]Lee H.S. Chang M. Lee J.E. Kim W. Hwang I.C. Kim D.H. Park H.K. Choi H.J. Jo W. Cha S.W. Carcinogenicity study of ckd-501, a novel dual peroxisome proliferator-activated receptors alpha and gamma agonist, following oral administration to sprague dawley rats for 94-101 weeks Regul. Toxicol. Pharmacol. 2014 69 207 216 10.1016/j.yrtph.2014.04.003 24747398 · DOI
  45. [46]Kim S.H. Kim S.G. Kim D.M. Woo J.T. Jang H.C. Chung C.H. Ko K.S. Park J.H. Park Y.S. Kim S.J. Safety and efficacy of lobeglitazone monotherapy in patients with type 2 diabetes mellitus over 52 weeks: An open-label extension study Diabetes Res. Clin. Pract. 2015 110 e27 e30 10.1016/j.diabres.2015.09.009 26458774 · DOI
  46. [47]Shin D. Kim T.E. Yoon S.H. Cho J.Y. Shin S.G. Jang I.J. Yu K.S. Assessment of the pharmacokinetics of co-administered metformin and lobeglitazone, a thiazolidinedione antihyperglycemic agent, in healthy subjects Curr. Med. Res. Opin. 2012 28 1213 1220 10.1185/03007995.2012.703131 22697273 · DOI
  47. [48]Choi J.H. Banks A.S. Estall J.L. Kajimura S. Bostrom P. Laznik D. Ruas J.L. Chalmers M.J. Kamenecka T.M. Bluher M. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by cdk5 Nature 2010 466 451 456 10.1038/nature09291 20651683 PMC2987584 · DOI
  48. [49]He B.K. Ning Z.Q. Li Z.B. Shan S. Pan D.S. Ko B.C. Li P.P. Shen Z.F. Dou G.F. Zhang B.L. In vitro and in vivo characterizations of chiglitazar, a newly identified PPAR pan-agonist PPAR Res. 2012 2012 546548 10.1155/2012/546548 23150725 PMC3486420 · DOI
  49. [50]Konda V.R. Desai A. Darland G. Grayson N. Bland J.S. Kdt501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes PLoS ONE 2014 9 e87848 10.1371/journal.pone.0087848 24498211 PMC3907559 · DOI
  50. [51]Finlin B.S. Zhu B. Kok B.P. Godio C. Westgate P.M. Grayson N. Sims R. Bland J.S. Saez E. Kern P.A. The influence of a kdt501, a novel isohumulone, on adipocyte function in humans Front. Endocrinol. 2017 8 255 10.3389/fendo.2017.00255 29033896 PMC5626816 · DOI
  51. [52]Kern P.A. Finlin B.S. Ross D. Boyechko T. Zhu B. Grayson N. Sims R. Bland J.S. Effects of kdt501 on metabolic parameters in insulin-resistant prediabetic humans J. Endocr. Soc. 2017 1 650 659 10.1210/js.2017-00202 29264518 PMC5686568 · DOI
  52. [53]Raval P. Jain M. Goswami A. Basu S. Gite A. Godha A. Pingali H. Raval S. Giri S. Suthar D. Revisiting glitazars: Thiophene substituted oxazole containing alpha-ethoxy phenylpropanoic acid derivatives as highly potent PPARalpha/gamma dual agonists devoid of adverse effects in rodents Bioorganic Med. Chem. Lett. 2011 21 3103 3109 10.1016/j.bmcl.2011.03.020 21450468 · DOI
  53. [54]Dietz M. Mohr P. Kuhn B. Maerki H.P. Hartman P. Ruf A. Benz J. Grether U. Wright M.B. Comparative molecular profiling of the PPARalpha/gamma activator aleglitazar: PPAR selectivity, activity and interaction with cofactors ChemMedChem 2012 7 1101 1111 10.1002/cmdc.201100598 22489042 PMC3504387 · DOI
  54. [55]Henry R.R. Lincoff A.M. Mudaliar S. Rabbia M. Chognot C. Herz M. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (synchrony): A phase ii, randomised, dose-ranging study Lancet 2009 374 126 135 10.1016/S0140-6736(09)60870-9 19515415 · DOI
  55. [56]Lincoff A.M. Tardif J.C. Schwartz G.G. Nicholls S.J. Ryden L. Neal B. Malmberg K. Wedel H. Buse J.B. Henry R.R. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: The alecardio randomized clinical trial JAMA 2014 311 1515 1525 10.1001/jama.2014.3321 24682069 · DOI
  56. [57]Oleksiewicz M.B. Southgate J. Iversen L. Egerod F.L. Rat urinary bladder carcinogenesis by dual-acting PPARalpha + gamma agonists PPAR Res. 2008 2008 103167 10.1155/2008/103167 19197366 PMC2632771 · DOI
  57. [58]Sasarman A. Letowski J. Czaika G. Ramirez V. Nead M.A. Jacobs J.M. Morais R. Nucleotide sequence of the hemg gene involved in the protoporphyrinogen oxidase activity of escherichia coli k12 Can. J. Microbiol. 1993 39 1155 1161 10.1139/m93-174 7916647 · DOI
  58. [59]Stringer F. Scott G. Valbuena M. Kinley J. Nishihara M. Urquhart R. The effect of genetic polymorphisms in ugt2b15 on the pharmacokinetic profile of sipoglitazar, a novel anti-diabetic agent Eur. J. Clin. Pharmacol. 2013 69 423 430 10.1007/s00228-012-1382-7 22960998 · DOI
  59. [60]Guo L. Zhang L. Sun Y. Muskhelishvili L. Blann E. Dial S. Shi L. Schroth G. Dragan Y.P. Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPAR gamma agonists on rat primary hepatocytes and human hepg2 cells Mol. Divers. 2006 10 349 360 10.1007/s11030-006-9038-0 17031537 PMC12403194 · DOI
  60. [61]Henriksen K. Byrjalsen I. Qvist P. Beck-Nielsen H. Hansen G. Riis B.J. Perrild H. Svendsen O.L. Gram J. Karsdal M.A. Efficacy and safety of the PPARgamma partial agonist balaglitazone compared with pioglitazone and placebo: A phase iii, randomized, parallel-group study in patients with type 2 diabetes on stable insulin therapy Diabetes Metab. Res. Rev. 2011 27 392 401 10.1002/dmrr.1187 21328517 · DOI
  61. [62]Minoura H. Takeshita S. Kimura C. Hirosumi J. Takakura S. Kawamura I. Seki J. Manda T. Mutoh S. Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, fk614, ameliorates insulin resistance in zucker fatty rats Diabetes Obes. Metab. 2007 9 369 378 10.1111/j.1463-1326.2006.00619.x 17391165 · DOI
  62. [63]Minoura H. Takeshita S. Yamamoto T. Mabuchi M. Hirosumi J. Takakura S. Kawamura I. Seki J. Manda T. Ita M. Ameliorating effect of fk614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in zucker fatty rat Eur. J. Pharmacol. 2005 519 182 190 10.1016/j.ejphar.2005.05.042 16039648 · DOI
  63. [64]Minoura H. Takeshita S. Ita M. Hirosumi J. Mabuchi M. Kawamura I. Nakajima S. Nakayama O. Kayakiri H. Oku T. Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, fk614 Eur. J. Pharmacol. 2004 494 273 281 10.1016/j.ejphar.2004.04.038 15212984 · DOI
  64. [65]Colca J.R. Discontinued drugs in 2005: Endocrine and metabolic Expert Opin. Investig. Drugs 2007 16 129 136 10.1517/13543784.16.2.129 17243934 · DOI
  65. [66]Colca J.R. Tanis S.P. McDonald W.G. Kletzien R.F. Insulin sensitizers in 2013: New insights for the development of novel therapeutic agents to treat metabolic diseases Expert Opin. Investig. Drugs 2014 23 1 7 10.1517/13543784.2013.839659 24073940 · DOI
  66. [67]Diani A.R. Peterson T. Sawada G. Jodelis K. Wyse B.M. Gilchrist B.J. Hearron A.E. Chang A.Y. Ciglitazone, a new hypoglycemic agent. 5. Effect on renal lesions in c57bl/ksj-db/db mice Nephron 1986 42 72 77 10.1159/000183637 3941752 · DOI
  67. [68]Bortolini M. Wright M.B. Bopst M. Balas B. Examining the safety of PPAR agonists—current trends and future prospects Expert Opin. Drug Saf. 2013 12 65 79 10.1517/14740338.2013.741585 23134541 · DOI
  68. [69]Ansari A.S. de Lusignan S. Hinton W. Munro N. Taylor S. McGovern A. Glycemic control is an important modifiable risk factor for uveitis in patients with diabetes: A retrospective cohort study establishing clinical risk and ophthalmic disease burden J. Diabetes Its Complicat. 2018 32 602 608 10.1016/j.jdiacomp.2018.03.008 29656910 · DOI
  69. [70]Wanner C. Inzucchi S.E. Lachin J.M. Fitchett D. von Eynatten M. Mattheus M. Johansen O.E. Woerle H.J. Broedl U.C. Zinman B. Empagliflozin and progression of kidney disease in type 2 diabetes N. Engl. J. Med. 2016 375 323 334 10.1056/NEJMoa1515920 27299675 · DOI · Paper page
  70. [72]Leiter L.A. Lundman P. da Silva P.M. Drexel H. Junger C. Gitt A.K. DYSIS investigators Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in europe and canada: Results of the dyslipidaemia international study Diabet. Med. 2011 28 1343 1351 10.1111/j.1464-5491.2011.03360.x 21679231 · DOI
  71. [73]Feher M. Greener M. Munro N. Persistent hypertriglyceridemia in statin-treated patients with type 2 diabetes mellitus Diabetes Metab. Syndr. Obes. 2013 6 11 15 23341741 PMC3546754
  72. [74]Joshi S.R. Saroglitazar for the treatment of dyslipidemia in diabetic patients Expert Opin. Pharmacother. 2015 16 597 606 10.1517/14656566.2015.1009894 25674933 · DOI
  73. [75]Bodkin N.L. Pill J. Meyer K. Hansen B.C. The effects of k-111, a new insulin-sensitizer, on metabolic syndrome in obese prediabetic rhesus monkeys Horm. Metab. Res. 2003 35 617 624 10.1055/s-2003-43510 14605998 · DOI
  74. [76]Ortmeyer H.K. Bodkin N.L. Haney J. Yoshioka S. Horikoshi H. Hansen B.C. A thiazolidinedione improves in vivo insulin action on skeletal muscle glycogen synthase in insulin-resistant monkeys Int. J. Exp. Diabetes Res. 2000 1 195 202 10.1155/EDR.2000.195 11467410 PMC2477731 · DOI
  75. [77]Hannah J.S. Bodkin N.L. Paidi M.S. Anh-Le N. Howard B.V. Hansen B.C. Effects of acipimox on the metabolism of free fatty acids and very low lipoprotein triglyceride Acta Diabetol. 1995 32 279 283 10.1007/BF00576264 8750769 · DOI
  76. [78]Bodkin N.L. Hansen B.C. Antihypertensive effects of captopril without adverse effects on glucose tolerance in hyperinsulinemic rhesus monkeys J. Med. Primatol. 1995 24 1 6 10.1111/j.1600-0684.1995.tb00137.x 7563005 · DOI
  77. [79]Dey D. Medicherla S. Neogi P. Gowri M. Cheng J. Gross C. Sharma S.D. Reaven G.M. Nag B. A novel peroxisome proliferator-activated gamma (PPAR gamma) agonist, clx-0921, has potent antihyperglycemic activity with low adipogenic potential Metabolism 2003 52 1012 1018 10.1016/S0026-0495(03)00152-5 12898466 · DOI
  78. [81]Soleymanian T. Hamid G. Arefi M. Najafi I. Ganji M.R. Amini M. Hakemi M. Tehrani M.R. Larijani B. Non-diabetic renal disease with or without diabetic nephropathy in type 2 diabetes: Clinical predictors and outcome Ren. Fail. 2015 37 572 575 10.3109/0886022X.2015.1007804 25682971 · DOI
  79. [82]Centers for Disease Control and Prevention Incidence of end-stage renal disease attributed to diabetes among persons with diagnosed diabetes—united states and puerto rico, 1996–2007 MMWR 2010 59 1361 1366 21030940
  80. [83]Weil E.J. Lemley K.V. Mason C.C. Yee B. Jones L.I. Blouch K. Lovato T. Richardson M. Myers B.D. Nelson R.G. Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy Kidney Int. 2012 82 1010 1017 10.1038/ki.2012.234 22718189 PMC3472108 · DOI
  81. [84]Henique C. Bollee G. Lenoir O. Dhaun N. Camus M. Chipont A. Flosseau K. Mandet C. Yamamoto M. Karras A. Nuclear factor erythroid 2-related factor 2 drives podocyte-specific expression of peroxisome proliferator-activated receptor gamma essential for resistance to crescentic gn JASN 2016 27 172 188 10.1681/ASN.2014111080 25999406 PMC4696572 · DOI
  82. [86]Cole M.P. Rudolph T.K. Khoo N.K. Motanya U.N. Golin-Bisello F. Wertz J.W. Schopfer F.J. Rudolph V. Woodcock S.R. Bolisetty S. Nitro-fatty acid inhibition of neointima formation after endoluminal vessel injury Circ. Res. 2009 105 965 972 10.1161/CIRCRESAHA.109.199075 19797175 PMC2784279 · DOI · Paper page
  83. [87]Wang H. Liu H. Jia Z. Guan G. Yang T. Effects of endogenous PPAR agonist nitro-oleic acid on metabolic syndrome in obese zucker rats PPAR Res. 2010 2010 601562 10.1155/2010/601562 20671947 PMC2910468 · DOI
  84. [89]Nie H. Xue X. Li J. Liu X. Lv S. Guan G. Liu H. Liu G. Liu S. Chen Z. Nitro-oleic acid attenuates ogd/r-triggered apoptosis in renal tubular cells via inhibition of bax mitochondrial translocation in a PPAR-gamma-dependent manner Cell. Physiol. Biochem. 2015 35 1201 1218 10.1159/000373944 25766531 · DOI
  85. [90]Taygerly J.P. McGee L.R. Rubenstein S.M. Houze J.B. Cushing T.D. Li Y. Motani A. Chen J.L. Frankmoelle W. Ye G. Discovery of int131: A selective PPARgamma modulator that enhances insulin sensitivity Bioorganic Med. Chem. 2013 21 979 992 10.1016/j.bmc.2012.11.058 23294830 · DOI
  86. [91]Kintscher U. Goebel M. Int-131, a PPARgamma agonist for the treatment of type 2 diabetes Curr. Opin. Investig. Drugs 2009 10 381 387 19337960
  87. [92]Berge R.K. Tronstad K.J. Berge K. Rost T.H. Wergedahl H. Gudbrandsen O.A. Skorve J. The metabolic syndrome and the hepatic fatty acid drainage hypothesis Biochimie 2005 87 15 20 10.1016/j.biochi.2004.11.011 15733731 · DOI
  88. [93]Berge R.K. Hvattum E. Impact of cytochrome p450 system on lipoprotein metabolism. Effect of abnormal fatty acids (3-thia fatty acids) Pharmacol. Ther. 1994 61 345 383 10.1016/0163-7258(94)90016-7 7938178 · DOI
  89. [94]Vaagenes H. Madsen L. Asiedu D.K. Lillehaug J.R. Berge R.K. Early modulation of genes encoding peroxisomal and mitochondrial beta-oxidation enzymes by 3-thia fatty acids Biochem. Pharmacol. 1998 56 1571 1582 10.1016/S0006-2952(98)00193-2 9973177 · DOI
  90. [96]Hafstad A.D. Khalid A.M. Hagve M. Lund T. Larsen T.S. Severson D.L. Clarke K. Berge R.K. Aasum E. Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss Cardiovasc. Res. 2009 83 519 526 10.1093/cvr/cvp132 19398469 · DOI
  91. [97]Laurent D. Gounarides J.S. Gao J. Boettcher B.R. Effects of cevoglitazar, a dual PPARalpha/gamma agonist, on ectopic fat deposition in fatty zucker rats Diabetes Obes. Metabol. 2009 11 632 636 19175377
  92. [98]Chen H. Dardik B. Qiu L. Ren X. Caplan S.L. Burkey B. Boettcher B.R. Gromada J. Cevoglitazar, a novel peroxisome proliferator-activated receptor-alpha/gamma dual agonist, potently reduces food intake and body weight in obese mice and cynomolgus monkeys Endocrinology 2010 151 3115 3124 10.1210/en.2009-1366 20484464 · DOI
  93. [99]Colca J.R. Discontinued drugs in 2008: Endocrine and metabolic Expert Opin. Investig. Drugs 2009 18 1243 1255 10.1517/13543780903132673 19678796 · DOI
  94. [100]Murakami K. Tobe K. Ide T. Mochizuki T. Ohashi M. Akanuma Y. Yazaki Y. Kadowaki T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: Effect of ppar-alpha activation on abnormal lipid metabolism in liver of zucker fatty rats Diabetes 1998 47 1841 1847 10.2337/diabetes.47.12.1841 9836514 · DOI
  95. [101]Nomura M. Kinoshita S. Satoh H. Maeda T. Murakami K. Tsunoda M. Miyachi H. Awano K. (3-substituted benzyl)thiazolidine-2,4-diones as structurally new antihyperglycemic agents Bioorganic Med. Chem. Lett. 1999 9 533 538 10.1016/S0960-894X(99)00039-6 10098657 · DOI
  96. [102]Doebber T.W. Kelly L.J. Zhou G. Meurer R. Biswas C. Li Y. Wu M.S. Ippolito M.C. Chao Y.S. Wang P.R. Mk-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities Biochem. Biophys. Res. Commun. 2004 318 323 328 10.1016/j.bbrc.2004.04.032 15120604 · DOI
  97. [103]Oleksiewicz M.B. Thorup I. Nielsen H.S. Andersen H.V. Hegelund A.C. Iversen L. Guldberg T.S. Brinck P.R. Sjogren I. Thinggaard U.K. Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo Toxicol. Pathol. 2005 33 552 560 10.1080/01926230500214657 16076770 · DOI
  98. [104]Evans J.L. Lin J.J. Goldfine I.D. Novel approach to treat insulin resistance, type 2 diabetes, and the metabolic syndrome: Simultaneous activation of PPARalpha, PPARgamma, and PPARdelta Curr. Diabetes Rev. 2005 1 299 307 10.2174/157339905774574365 18220606 · DOI
  99. [105]Cheang W.S. Tian X.Y. Wong W.T. Huang Y. The peroxisome proliferator-activated receptors in cardiovascular diseases: Experimental benefits and clinical challenges Br. J. Pharmacol. 2015 172 5512 5522 10.1111/bph.13029 25438608 PMC4667853 · DOI
  100. [106]Goto T. Nakayama R. Yamanaka M. Takata M. Takazawa T. Watanabe K. Maruta K. Nagata R. Nagamine J. Tsuchida A. Effects of dsp-8658, a novel selective peroxisome proliferator-activated receptors a/gamma modulator, on adipogenesis and glucose metabolism in diabetic obese mice Exp. Clin. Endocrinol. Diabetes 2015 123 492 499 26011171
  101. [107]Bray G.A. Fruhbeck G. Ryan D.H. Wilding J.P. Management of obesity Lancet 2016 387 1947 1956 10.1016/S0140-6736(16)00271-3 26868660 · DOI · Paper page
  102. [108]Xu P. Dai S. Wang J. Zhang J. Liu J. Wang F. Zhai Y. Preventive obesity agent montmorillonite adsorbs dietary lipids and enhances lipid excretion from the digestive tract Sci. Rep. 2016 6 19659 10.1038/srep19659 26891902 PMC4759552 · DOI
  103. [110]Vazquez-Carrera M. Unraveling the effects of PPARbeta/delta on insulin resistance and cardiovascular disease Trends Endocrinol. Metab. 2016 27 319 334 10.1016/j.tem.2016.02.008 27005447 · DOI
  104. [111]Vassilatou E. Nonalcoholic fatty liver disease and polycystic ovary syndrome World J. Gastroenterol. 2014 20 8351 8363 10.3748/wjg.v20.i26.8351 25024594 PMC4093689 · DOI
  105. [112]Xu P. Hong F. Wang J. Cong Y. Dai S. Wang S. Wang J. Jin X. Wang F. Liu J. Microbiome remodeling via the montmorillonite adsorption-excretion axis prevents obesity-related metabolic disorders EBioMedicine 2017 16 251 261 10.1016/j.ebiom.2017.01.019 28126594 PMC5474441 · DOI
  106. [113]Lovren F. Teoh H. Verma S. Obesity and atherosclerosis: Mechanistic insights Can. J. Cardiol. 2015 31 177 183 10.1016/j.cjca.2014.11.031 25661552 · DOI
  107. [114]Oda N. Imamura S. Fujita T. Uchida Y. Inagaki K. Kakizawa H. Hayakawa N. Suzuki A. Takeda J. Horikawa Y. The ratio of leptin to adiponectin can be used as an index of insulin resistance Metabolism 2008 57 268 273 10.1016/j.metabol.2007.09.011 18191059 · DOI
  108. [115]Lalloyer F. Staels B. Fibrates, glitazones, and peroxisome proliferator-activated receptors Arterioscler. Thromb. Vasc. Biol. 2010 30 894 899 10.1161/ATVBAHA.108.179689 20393155 PMC2997800 · DOI
  109. [116]Robins S.J. Collins D. Wittes J.T. Papademetriou V. Deedwania P.C. Schaefer E.J. McNamara J.R. Kashyap M.L. Hershman J.M. Wexler L.F. Relation of gemfibrozil treatment and lipid levels with major coronary events: Va-hit: A randomized controlled trial JAMA 2001 285 1585 1591 10.1001/jama.285.12.1585 11268266 · DOI
  110. [117]Rodriguez-Cuenca S. Carobbio S. Barcelo-Coblijn G. Prieur X. Relat J. Amat R. Campbell M. Dias A.R. Bahri M. Gray S.L. P465l PPARgamma mutation confers partial resistance to the hypolipidemic action of fibrates Diabetes Obes. Metab. 2018 10.1111/dom.13370 29790245 PMC6589924 · DOI
  111. [118]Seiler C. Suter T.M. Hess O.M. Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with bezafibrate J. Am. Coll. Cardiol. 1995 26 1615 1622 10.1016/0735-1097(95)00379-7 7594094 · DOI
  112. [119]Khera A.V. Qamar A. Reilly M.P. Dunbar R.L. Rader D.J. Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 levels in patients with dyslipidemia Am. J. Cardiol. 2015 115 178 182 10.1016/j.amjcard.2014.10.018 25432415 · DOI
  113. [120]Evans M. Anderson R.A. Graham J. Ellis G.R. Morris K. Davies S. Jackson S.K. Lewis M.J. Frenneaux M.P. Rees A. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus Circulation 2000 101 1773 1779 10.1161/01.CIR.101.15.1773 10769276 · DOI
  114. [121]Song D. Chu Z. Min L. Zhen T. Li P. Han L. Bu S. Yang J. Gonzale F.J. Liu A. Gemfibrozil not fenofibrate decreases systemic glucose level via PPARalpha Die Pharm. 2016 71 205 212 27209701
  115. [122]Parhofer K.G. The treatment of disorders of lipid metabolism Deutsch. Arzteblatt Int. 2016 113 261 268 10.3238/arztebl.2016.0261 27151464 PMC4860871 · DOI
  116. [123]Committee of Principal Investigators WHO Cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: Mortality follow-up. Report of the committee of principal investigators Lancet 1980 2 379 385 6105515
  117. [124]Fazio S. Linton M.F. The role of fibrates in managing hyperlipidemia: Mechanisms of action and clinical efficacy Curr. Atheroscler. Rep. 2004 6 148 157 10.1007/s11883-004-0104-8 15023300 · DOI · Paper page
  118. [126]Moutzouri E. Kei A. Elisaf M.S. Milionis H.J. Management of dyslipidemias with fibrates, alone and in combination with statins: Role of delayed-release fenofibric acid Vasc. Health Risk Manag. 2010 6 525 539 20730069 PMC2922314
  119. [127]Chachad S.S. Gole M. Malhotra G. Naidu R. Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects Clin. Ther. 2014 36 967 973 10.1016/j.clinthera.2014.04.017 24844853 · DOI
  120. [128]Zhang X. Chen G. Zhang T. Ma Z. Wu B. Effects of pegylated lipid nanoparticles on the oral absorption of one bcs ii drug: A mechanistic investigation Int. J. Nanomed. 2014 9 5503 5514 PMC4251747 25473287
  121. [129]Brown W.V. Treatment of hypercholesterolaemia with fenofibrate: A review Curr. Med. Res. Opin. 1989 11 321 330 10.1185/03007998909115214 2649318 · DOI
  122. [130]Pellegrini M. Pallottini V. Marin R. Marino M. Role of the sex hormone estrogen in the prevention of lipid disorder Curr. Med. Chem. 2014 21 2734 2742 10.2174/0929867321666140303123602 24606523 · DOI
  123. [132]Ericsson C.G. Hamsten A. Nilsson J. Grip L. Svane B. de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients Lancet 1996 347 849 853 10.1016/S0140-6736(96)91343-4 8622389 · DOI
  124. [133]Staels B. Dallongeville J. Auwerx J. Schoonjans K. Leitersdorf E. Fruchart J.C. Mechanism of action of fibrates on lipid and lipoprotein metabolism Circulation 1998 98 2088 2093 10.1161/01.CIR.98.19.2088 9808609 · DOI · Paper page
  125. [134]Saku K. Gartside P.S. Hynd B.A. Kashyap M.L. Mechanism of action of gemfibrozil on lipoprotein metabolism J. Clin. Investig. 1985 75 1702 1712 10.1172/JCI111879 3923042 PMC425514 · DOI
  126. [135]Mikhailidis D.P. Jagroon I.A. Ciprofibrate versus gemfibrozil in the treatment of mixed hyperlipidemias: An open-label, multicenter study Metabolism 2001 50 1385 1386 10.1053/S0026-0495(01)90010-1 11715936 · DOI
  127. [136]Rizos E. Bairaktari E. Ganotakis E. Tsimihodimos V. Mikhailidis D.P. Elisaf M. Effect of ciprofibrate on lipoproteins, fibrinogen, renal function, and hepatic enzymes J. Cardiovasc. Pharmacol. Ther. 2002 7 219 226 10.1177/107424840200700404 12490967 · DOI
  128. [137]Fruchart J.C. Selective peroxisome proliferator-activated receptor alpha modulators (sPPARmalpha): The next generation of peroxisome proliferator-activated receptor alpha-agonists Cardiovasc. Diabetol. 2013 12 82 10.1186/1475-2840-12-82 23721199 PMC3682868 · DOI · Paper page
  129. [140]Schima S.M. Maciejewski S.R. Hilleman D.E. Williams M.A. Mohiuddin S.M. Fibrate therapy in the management of dyslipidemias, alone and in combination with statins: Role of delayed-release fenofibric acid Expert Opin. Pharmacother. 2010 11 731 738 10.1517/14656560903575639 20210682 · DOI
  130. [141]Athyros V.G. Mikhailidis D.P. Papageorgiou A.A. Didangelos T.P. Peletidou A. Kleta D. Karagiannis A. Kakafika A.I. Tziomalos K. Elisaf M. Targeting vascular risk in patients with metabolic syndrome but without diabetes Metabolism 2005 54 1065 1074 10.1016/j.metabol.2005.03.010 16092057 · DOI
  131. [142]Mohiuddin S.M. Pepine C.J. Kelly M.T. Buttler S.M. Setze C.M. Sleep D.J. Stolzenbach J.C. Efficacy and safety of abt-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: A phase 3, randomized, controlled study Am. Heart J. 2009 157 195 203 10.1016/j.ahj.2008.08.027 19081418 · DOI
  132. [143]Shek A. Ferrill M.J. Statin-fibrate combination therapy Ann. Pharmacother. 2001 35 908 917 10.1345/aph.10315 11485144 · DOI · Paper page
  133. [144]Backes J.M. Gibson C.A. Ruisinger J.F. Moriarty P.M. Fibrates: What have we learned in the past 40 years? Pharmacotherapy 2007 27 412 424 10.1592/phco.27.3.412 17316152 · DOI
  134. [145]Chalasani N. Younossi Z. Lavine J.E. Diehl A.M. Brunt E.M. Cusi K. Charlton M. Sanyal A.J. 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 2012 55 2005 2023 10.1002/hep.25762 22488764 · DOI
  135. [146]Ratziu V. Bellentani S. Cortez-Pinto H. Day C. Marchesini G. A position statement on nafld/nash based on the easl 2009 special conference J. Hepatol. 2010 53 372 384 10.1016/j.jhep.2010.04.008 20494470 · DOI
  136. [148]Cariou B. Hanf R. Lambert-Porcheron S. Zair Y. Sauvinet V. Noel B. Flet L. Vidal H. Staels B. Laville M. Dual peroxisome proliferator-activated receptor alpha/delta agonist gft505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects Diabetes Care 2013 36 2923 2930 10.2337/dc12-2012 23715754 PMC3781493 · DOI
  137. [149]Cariou B. Zair Y. Staels B. Bruckert E. Effects of the new dual PPAR alpha/delta agonist gft505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism Diabetes Care 2011 34 2008 2014 10.2337/dc11-0093 21816979 PMC3161281 · DOI
  138. [150]Bays H.E. Hallen J. Vige R. Fraser D. Zhou R. Hustvedt S.O. Orloff D.G. Kastelein J.J. Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week clinical trial J. Clin. Lipidol. 2016 10 181 191 10.1016/j.jacl.2015.10.012 26892135 · DOI
  139. [152]Billin A.N. PPAR-beta/delta agonists for type 2 diabetes and dyslipidemia: An adopted orphan still looking for a home Expert Opin. Investig. Drugs 2008 17 1465 1471 10.1517/13543784.17.10.1465 18808307 · DOI
  140. [153]Strain J.D. Farver D.K. Clem J.R. A review on the rationale and clinical use of concomitant rosuvastatin and fenofibrate/fenofibric acid therapy Clin. Pharmacol. 2010 2 95 104 10.2147/CPAA.S7375 22291492 PMC3262365 · DOI
  141. [154]Harchaoui K.E. Visser M.E. Kastelein J.J. Stroes E.S. Dallinga-Thie G.M. Triglycerides and cardiovascular risk Curr. Cardiol. Rev. 2009 5 216 222 10.2174/157340309788970315 20676280 PMC2822144 · DOI
  142. [155]Stone N.J. Robinson J.G. Lichtenstein A.H. Bairey Merz C.N. Blum C.B. Eckel R.H. Goldberg A.C. Gordon D. Levy D. Lloyd-Jones D.M. 2013 acc/aha guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the american college of cardiology/american heart association task force on practice guidelines J. Am. Coll. Cardiol. 2014 63 2889 2934 10.1016/j.jacc.2013.11.002 24239923 · DOI · Paper page
  143. [156]Baigent C. Keech A. Kearney P.M. Blackwell L. Buck G. Pollicino C. Kirby A. Sourjina T. Peto R. Collins R. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins Lancet 2005 366 1267 1278 16214597
  144. [158]Shitara Y. Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme a (hmg-coa) reductase inhibitors: Drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions Pharmacol. Ther. 2006 112 71 105 10.1016/j.pharmthera.2006.03.003 16714062 · DOI
  145. [159]Aoki T. Nishimura H. Nakagawa S. Kojima J. Suzuki H. Tamaki T. Wada Y. Yokoo N. Sato F. Kimata H. Pharmacological profile of a novel synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase Arzneimittel-Forschung 1997 47 904 909 9296275
  146. [160]Wakida Y. Suzuki S. Nomura H. Isomura T. Additional treatment with fenofibrate for patients treated with pitavastatin under ordinary medical practice for hypertriglyceridemia in japan (approach-j study) Jpn. Clin. Med. 2011 2 57 66 10.4137/JCM.S7863 23885192 PMC3699489 · DOI
  147. [162]Bisgaier C.L. Oniciu D.C. Srivastava R.A.K. Comparative evaluation of gemcabene and PPAR ligands in transcriptional assays of peroxisome proliferator-activated receptors: Implication for the treatment of hyperlipidemia and cardiovascular disease J. Cardiovasc. Pharmacol. 2018 72 3 10 10.1097/FJC.0000000000000580 29621036 PMC6039382 · DOI
  148. [163]Ridker P.M. MacFadyen J.G. Thuren T. Everett B.M. Libby P. Glynn R.J. Group C.T. Effect of interleukin-1beta inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: Exploratory results from a randomised, double-blind, placebo-controlled trial Lancet 2017 390 1833 1842 10.1016/S0140-6736(17)32247-X 28855077 · DOI · Paper page
  149. [164]Srivastava R.A.K. Cornicelli J.A. Markham B. Bisgaier C.L. Gemcabene, a first-in-class lipid-lowering agent in late-stage development, down-regulates acute-phase c-reactive protein via c/ebp-delta-mediated transcriptional mechanism Mol. Cell. Biochem. 2018 10.1007/s11010-018-3353-5 29644527 PMC6223808 · DOI
  150. [165]Zhao H.P. Zhang X.S. Xiang B.R. Discontinued drugs in 2010: Cardiovascular drugs Expert Opin. Investig. Drugs 2011 20 1311 1325 10.1517/13543784.2011.611500 21870899 · DOI
  151. [166]Sprecher D.L. Lipids, lipoproteins, and peroxisome proliferator activated receptor-delta Am. J. Cardiol. 2007 100 S20 S24 10.1016/j.amjcard.2007.08.009 18047848 · DOI
  152. [167]Sprecher D.L. Massien C. Pearce G. Billin A.N. Perlstein I. Willson T.M. Hassall D.G. Ancellin N. Patterson S.D. Lobe D.C. Triglyceride:High-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist Arterioscler. Thromb. Vasc. Biol. 2007 27 359 365 10.1161/01.ATV.0000252790.70572.0c 17110604 · DOI
  153. [168]Reilly S.M. Lee C.H. PPAR delta as a therapeutic target in metabolic disease FEBS Lett. 2008 582 26 31 10.1016/j.febslet.2007.11.040 18036566 PMC2275052 · DOI · Paper page
  154. [169]Madrazo J.A. Kelly D.P. The PPAR trio: Regulators of myocardial energy metabolism in health and disease J. Mol. Cell. Cardiol. 2008 44 968 975 10.1016/j.yjmcc.2008.03.021 18462747 · DOI
  155. [170]Schmuth M. Jiang Y.J. Dubrac S. Elias P.M. Feingold K.R. Thematic review series: Skin lipids. Peroxisome proliferator-activated receptors and liver x receptors in epidermal biology J. Lipid Res. 2008 49 499 509 10.1194/jlr.R800001-JLR200 18182682 · DOI
  156. [171]Iwashita A. Muramatsu Y. Yamazaki T. Muramoto M. Kita Y. Yamazaki S. Mihara K. Moriguchi A. Matsuoka N. Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo J. Pharmacol. Exp. Ther. 2007 320 1087 1096 10.1124/jpet.106.115758 17167170 · DOI
  157. [172]Peters J.M. Hollingshead H.E. Gonzalez F.J. Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease Clin. Sci. 2008 115 107 127 10.1042/CS20080022 18616431 PMC2705117 · DOI
  158. [173]Hirschfield G.M. Gershwin M.E. The immunobiology and pathophysiology of primary biliary cirrhosis Ann. Rev. Pathol. 2013 8 303 330 10.1146/annurev-pathol-020712-164014 23347352 · DOI · Paper page
  159. [176]Bays H.E. Schwartz S. Littlejohn T. 3rd Kerzner B. Krauss R.M. Karpf D.B. Choi Y.J. Wang X. Naim S. Roberts B.K. 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. 2011 96 2889 2897 10.1210/jc.2011-1061 21752880 · DOI
  160. [177]Haczeyni F. Wang H. Barn V. Mridha A.R. Yeh M.M. Haigh W.G. Ioannou G.N. Choi Y.J. McWherter C.A. Teoh N.C. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice Hepatol. Commun. 2017 1 663 674 10.1002/hep4.1072 29404484 PMC5721439 · DOI
  161. [178]Jones D. Boudes P.F. Swain M.G. Bowlus C.L. Galambos M.R. Bacon B.R. Doerffel Y. Gitlin N. Gordon S.C. Odin J.A. Seladelpar (mbx-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: A double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study Lancet. Gastroenterol. Hepatol. 2017 2 716 726 10.1016/S2468-1253(17)30246-7 28818518 · DOI · Paper page
  162. [179]Wertheimer A. Morlock R. Becker M.A. A revised estimate of the burden of illness of gout Curr. Ther. Res. Clin. Exp. 2013 75 1 4 10.1016/j.curtheres.2013.04.003 24465034 PMC3898191 · DOI
  163. [180]Edwards N.L. Sundy J.S. Forsythe A. Blume S. Pan F. Becker M.A. Work productivity loss due to flares in patients with chronic gout refractory to conventional therapy J. Med. Econ. 2011 14 10 15 10.3111/13696998.2010.540874 21138339 · DOI
  164. [181]Brook R.A. Forsythe A. Smeeding J.E. Lawrence Edwards N. Chronic gout: Epidemiology, disease progression, treatment and disease burden Curr. Med. Res. Opin. 2010 26 2813 2821 10.1185/03007995.2010.533647 21050059 · DOI
  165. [182]Aronow W.S. Harding P.R. Khursheed M. Vangrow J.S. Papageorge’s N.P. Effect of halofenate on serum uric acid Clin. Pharmacol. Ther. 1973 14 371 373 10.1002/cpt1973143371 4572799 · DOI
  166. [183]Aronow W.S. Harding P.R. Khursheed M. Vangrow J.S. Papageorge’s N.P. Mays J. Effect of halofenate on serum lipids Clin. Pharmacol. Ther. 1973 14 358 365 10.1002/cpt1973143358 4572798 · DOI
  167. [184]Poiley J. Steinberg A.S. Choi Y.J. Davis C.S. Martin R.L. McWherter C.A. Boudes P.F. Arhalofenate Flare Study I. A randomized, double-blind, active- and placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout Arthritis Rheumatol. 2016 68 2027 2034 10.1002/art.39684 26989892 PMC5129473 · DOI
  168. [185]Tong M. Deochand C. Didsbury J. de la Monte S.M. T3d-959: A multi-faceted disease remedial drug candidate for the treatment of alzheimer’s disease J. Alzheimer’s Dis. 2016 51 123 138 10.3233/JAD-151013 26836193 PMC5577391 · DOI
  169. [186]Tong M. Dominguez C. Didsbury J. de la Monte S.M. Targeting alzheimer’s disease neuro-metabolic dysfunction with a small molecule nuclear receptor agonist (t3d-959) reverses disease pathologies J. Alzheimer’s Dis. Parkinsonism 2016 6 pii:238 10.4172/2161-0460.1000238 27525190 PMC4979550 · DOI
  170. [187]Jemal A. Bray F. Center M.M. Ferlay J. Ward E. Forman D. Global cancer statistics CA Cancer J. Clin. 2011 61 69 90 10.3322/caac.20107 21296855 · DOI
  171. [188]Koyi H. Hillerdal G. Branden E. A prospective study of a total material of lung cancer from a county in sweden 1997–1999: Gender, symptoms, type, stage, and smoking habits Lung Cancer 2002 36 9 14 10.1016/S0169-5002(01)00451-2 11891027 · DOI
  172. [189]Schiller J.H. Harrington D. Belani C.P. Langer C. Sandler A. Krook J. Zhu J. Johnson D.H. Eastern Cooperative Oncology G. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer N. Engl. J. Med. 2002 346 92 98 10.1056/NEJMoa011954 11784875 · DOI · Paper page
  173. [190]Blanquicett C. Roman J. Hart C.M. Thiazolidinediones as anti-cancer agents Cancer Ther. 2008 6 25 34 19079765 PMC2600565
  174. [191]Nemenoff R.A. Weiser-Evans M. Winn R.A. Activation and molecular targets of peroxisome proliferator-activated receptor-gamma ligands in lung cancer PPAR Res. 2008 2008 156875 10.1155/2008/156875 18509496 PMC2396386 · DOI
  175. [192]Pishvaian M.J. Marshall J.L. Wagner A.J. Hwang J.J. Malik S. Cotarla I. Deeken J.F. He A.R. Daniel H. Halim A.B. A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies Cancer 2012 118 5403 5413 10.1002/cncr.27526 22570147 PMC3726261 · DOI
  176. [193]Copland J.A. Marlow L.A. Kurakata S. Fujiwara K. Wong A.K. Kreinest P.A. Williams S.F. Haugen B.R. Klopper J.P. Smallridge R.C. Novel high-affinity PPARgamma agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21waf1/cip1 Oncogene 2006 25 2304 2317 10.1038/sj.onc.1209267 16331265 · DOI
  177. [194]Shimazaki N. Togashi N. Hanai M. Isoyama T. Wada K. Fujita T. Fujiwara K. Kurakata S. Anti-tumour activity of cs-7017, a selective peroxisome proliferator-activated receptor gamma agonist of thiazolidinedione class, in human tumour xenografts and a syngeneic tumour implant model Eur. J. Cancer 2008 44 1734 1743 10.1016/j.ejca.2008.04.016 18511262 · DOI
  178. [195]Budman D.R. Calabro A. Studies of synergistic and antagonistic combinations of conventional cytotoxic agents with the multiple eicosanoid pathway modulator ly 293111 Anti-Cancer Drugs 2004 15 877 881 10.1097/00001813-200410000-00008 15457128 · DOI
  179. [196]Schwartz G.K. Weitzman A. O’Reilly E. Brail L. de Alwis D.P. Cleverly A. Barile-Thiem B. Vinciguerra V. Budman D.R. Phase i and pharmacokinetic study of ly293111, an orally bioavailable ltb4 receptor antagonist, in patients with advanced solid tumors J. Clin. Oncol. 2005 23 5365 5373 10.1200/JCO.2005.02.766 15939925 · DOI
  180. [197]Tong W.G. Ding X.Z. Talamonti M.S. Bell R.H. Adrian T.E. Leukotriene b4 receptor antagonist ly293111 induces s-phase cell cycle arrest and apoptosis in human pancreatic cancer cells Anti-Cancer Drugs 2007 18 535 541 10.1097/01.cad.0000231477.22901.8a 17414622 · DOI
  181. [198]Cleynen I. Boucher G. Jostins L. Schumm L.P. Zeissig S. Ahmad T. Andersen V. Andrews J.M. Annese V. Brand S. Inherited determinants of crohn’s disease and ulcerative colitis phenotypes: A genetic association study Lancet 2016 387 156 167 10.1016/S0140-6736(15)00465-1 26490195 PMC4714968 · DOI
  182. [199]Ricote M. Huang J. Fajas L. Li A. Welch J. Najib J. Witztum J.L. Auwerx J. Palinski W. Glass C.K. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein Proc. Natl. Acad. Sci. USA 1998 95 7614 7619 10.1073/pnas.95.13.7614 9636198 PMC22700 · DOI
  183. [200]Gosset P. Charbonnier A.S. Delerive P. Fontaine J. Staels B. Pestel J. Tonnel A.B. Trottein F. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells Eur. J. Immunol. 2001 31 2857 2865 10.1002/1521-4141(2001010)31:10<2857::AID-IMMU2857>3.0.CO;2-X 11592060 · DOI
  184. [201]Lewis J.D. Lichtenstein G.R. Deren J.J. Sands B.E. Hanauer S.B. Katz J.A. Lashner B. Present D.H. Chuai S. Ellenberg J.H. Rosiglitazone for active ulcerative colitis: A randomized placebo-controlled trial Gastroenterology 2008 134 688 695 10.1053/j.gastro.2007.12.012 18325386 PMC2276587 · DOI
  185. [202]Bertin B. Dubuquoy L. Colombel J.F. Desreumaux P. PPAR-gamma in ulcerative colitis: A novel target for intervention Cur. Drug Targets 2013 14 1501 1507 10.2174/13894501113149990162 23651165 · DOI
  186. [204]Avouac J. Konstantinova I. Guignabert C. Pezet S. Sadoine J. Guilbert T. Cauvet A. Tu L. Luccarini J.M. Junien J.L. Pan-PPAR agonist iva337 is effective in experimental lung fibrosis and pulmonary hypertension Ann. Rheum. Dis. 2017 76 1931 1940 10.1136/annrheumdis-2016-210821 28801346 · DOI
  187. [205]Xu P. Hong F. Wang J. Wang J. Zhao X. Wang S. Xue T. Xu J. Zheng X. Zhai Y. DBZ is a putative PPARgamma agonist that prevents high fat diet-induced obesity, insulin resistance and gut dysbiosis Biochim. Biophys. Acta 2017 1861 2690 2701 10.1016/j.bbagen.2017.07.013 28736228 · DOI
  188. [206]Wang J. Xu P. Xie X. Li J. Zhang J. Wang J. Hong F. Li J. Zhang Y. Song Y. DBZ (danshensu bingpian zhi), a novel natural compound derivative, attenuates atherosclerosis in apolipoprotein e-deficient mice J. Am. Heart Assoc. 2017 6 pii:e006297 10.1161/JAHA.117.006297 28971954 PMC5721843 · DOI
  189. [207]Taniguchi A. Fukushima M. Sakai M. Tokuyama K. Nagata I. Fukunaga A. Kishimoto H. Doi K. Yamashita Y. Matsuura T. Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese japanese type 2 diabetic patients Metabolism 2001 50 477 480 10.1053/meta.2001.21028 11288046 · DOI
  190. [208]Balakumar P. Rose M. Ganti S.S. Krishan P. Singh M. PPAR dual agonists: Are they opening pandora’s box? Pharmacol. Res. 2007 56 91 98 10.1016/j.phrs.2007.03.002 17428674 · DOI
  191. [209]Pollock C.B. Rodriguez O. Martin P.L. Albanese C. Li X. Kopelovich L. Glazer R.I. Induction of metastatic gastric cancer by peroxisome proliferator-activated receptordelta activation PPAR Res. 2010 2010 571783 10.1155/2010/571783 21318167 PMC3026990 · DOI
  192. [210]Fievet C. Fruchart J.C. Staels B. PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome Curr. Opin. Pharmacol. 2006 6 606 614 10.1016/j.coph.2006.06.009 16973418 · DOI

Cited by

Sorted by citations

Authors
Hong, F., Xu, P., & Zhai, Y.
Affiliations
Beijing Normal University (CN)
Corresponding author
  • Xu, Pengfei
  • Zhai, Yonggong
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-07-27
Volume
19
Issue
8
Pages
2189
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms19082189
PMC
PMC6121873
OpenAlex
W2883888207
Cited by
139
References
16
Citations by year
2026: 7 · 2025: 16 · 2024: 7 · 2023: 18 · 2022: 15 · 2021: 27 · 2020: 28 · 2019: 19 · 2018: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (31571164, 31271207)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
peroxisome proliferator-activated receptors, PPAR ligands, PPARα, PPARδ, PPARγ, fibrates, thiazolidinediones, type 2 diabetes, dyslipidemia, drug discovery, drug development, metabolic disorders, glycolipid metabolism
MeSH terms
Animals, Anti-Inflammatory Agents, Hypolipidemic Agents, Disease Models, Animal, Humans, Ligands, Metabolic Diseases, Molecular Conformation, Protein Isoforms, Peroxisome Proliferator-Activated Receptors, Mice, Rats, Drug Discovery, Molecular Targeted Therapy

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