Drug insight: Mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors

Nature Clinical Practice Endocrinology and Metabolism

Volumn 3, Issue 2, 2007, Pages 145-156

  Gervois, Philippe ^a,b,c   Fruchart, Jean Charles ^a,b   Staels, Bart ^a,b  

^a UNIV LILLE   (France)

^b INSERM   (France)

^c INSTITUT PASTEUR DE LILLE   (France)

Author keywords

Atherosclerosis; Clinical trial; Fibrates; Peroxisome proliferator activated receptors; Thiazolidinediones

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; BEZAFIBRATE; FATTY ACID; FATTY ACID DERIVATIVE; FENOFIBRATE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; LG 100641; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PIOGLITAZONE; PLACEBO; RAGAGLITAZAR; ROSIGLITAZONE; SIMVASTATIN; TESAGLITAZAR; TROGLITAZONE; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ATHEROSCLEROSIS; BLOOD VESSEL WALL; CARDIOVASCULAR DISEASE; CLINICAL PRACTICE; CLINICAL TRIAL; CORONARY ARTERY ATHEROSCLEROSIS; DEEP VEIN THROMBOSIS; DISEASE COURSE; DRUG DESIGN; DRUG EFFICACY; DRUG FATALITY; DRUG MECHANISM; DRUG SAFETY; DYSLIPIDEMIA; EDEMA; ENDOTHELIUM CELL; ENERGY METABOLISM; GENE CONTROL; GLUCOSE METABOLISM; HEART FAILURE; HUMAN; HYPERGLYCEMIA; HYPERINSULINEMIA; HYPOLIPEMIA; INSULIN RESISTANCE; INSULIN SENSITIVITY; LEUKOCYTE; LIPID METABOLISM; LUNG EMBOLISM; MACROPHAGE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREATITIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; THROMBOSIS; WEIGHT GAIN;

ANIMALS; ATHEROSCLEROSIS; DRUG DESIGN; ENERGY METABOLISM; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; MICE; MICE, MUTANT STRAINS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS;

EID: 33846429592     PISSN: 17458366     EISSN: 17458374     Source Type: Journal    
DOI: 10.1038/ncpendmet0397     Document Type: Review

References (78)

1. Feige JN et al. (2006) From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res 45: 120-159
2. Marx N et al. (2004) Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res 94: 1168-1178
3. Fu J et al. (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Nature 425: 90-93
4. Gervois P et al. (1999) Fibrates increase human REV-ERBα expression in liver via a novel peroxisome proliferator-activated receptor response element. Mol Endocrinol 13: 400-409
5. Delerive P et al. (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
6. Gervois P et al. (2004) Global suppression of IL-6-induced acute phase response gene expression after in vivo chronic treatment with the peroxisome proliferator-activated receptor α activator fenofibrate. J Biol Chem 279: 16154-16160
7. Gervois P et al. (2000) Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med 38: 3-11
8. Vu-Dac N et al. (2003) Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator activated receptor α. J Biol Chem 278: 17982-17985
9. Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340: 115-126
10. Marx N et al. (1999) PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99: 3125-3131
11. Shu H et al. (2000) Activation of PPARα or γ reduces secretion of matrix metalloproteinase 9 but not interleukin-8 from human monocytic THP-1 cells. Biochem Biophys Res Commun 267: 345-349
12. Ridker PM et al. (2000) C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342: 836-843
13. Danesh J et al. (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 294: 1799-1809
14. Gervois P et al. (2001) Negative regulation of human fibrinogen gene expression by peroxisome proliferator-activated receptor α agonists via inhibition of CCAAT box/enhancer-binding protein β. J Biol Chem 276: 33471-33477
15. Kleemann R et al. (2003) Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing p50-NF-κB-C/EBP-β complex formation. Blood 101: 545-551
16. Wu KK et al. (2005) Increased hypercholesterolemia and atherosclerosis in mice lacking both ApoE and leptin receptor. Atherosclerosis 181: 251-259
17. Tordjman K et al. (2001) PPARα deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J Clin Invest 107: 1025-1034
18. Staels B and Fruchart JC (2005) Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54: 2460-2470
19. Frick MH et al. (1987) Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317: 1237-1245
20. Elkeles RS et al. (1998) Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care 21: 641-648
21. FIELD-Investigators (2005) 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
22. ACCORD Trial Homepage [http://www.accordtrial.org/ public/index.cfm] (accessed 8 September 2006)
23. He W et al. (2003) Adipose-specific peroxisome proliferator-activated receptor γ knockout mice causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 100: 15712-15717
24. Barak Y et al. (1999) PPAR γ is required for placenta, cardiac, and adipose tissue development. Mol Cell 4: 585-595
25. Kubota N et al. (1999) PPAR γ mediates high fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 4: 597-609
26. Rosen ED et al. (1999) PPAR γ is required for the differentiation of adipose tissue in vitro and in vivo. Mol Cell 4: 611-617
27. Savage DB et al. (2003) Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-γ. Diabetes 52: 910-917
28. Chao L et al. (2000) Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest 106: 1221-1228
29. Walczak R and Tontonoz P (2002) PPARadigms and PPARadoxes: expanding roles for PPARγ in the control of lipid metabolism. J Lipid Res 43: 177-186
30. De Vos P et al. (1996) Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor γ. J Clin Invest 98: 1004-1009
31. Iwaki M et al. (2003) Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52: 1655-1663
32. Nawrocki AR et al. (2006) Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor γ agonists. J Biol Chem 281: 2654-2660
33. Weisberg SP et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796-1808
34. Xu H et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821-1830
35. Pasceri V et al. (2000) Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators. Circulation 101: 235-238
36. Li AC and Palinski W (2006) Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annu Rev Pharmacol Toxicol 46: 1-39
37. Pascual G et al. (2005) A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ. Nature 437: 759-763
38. Chen Z et al. (2001) Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 21: 372-377
39. Li AC et al. (2000) Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 106: 523-531
40. Chawla A et al. (2001) A PPAR γ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7: 161-171
41. Xiang AH et al. (2006) Effect of pioglitazone on pancreatic-β cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes 55: 517-522
42. Mayerson AB et al. (2002) The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51: 797-802
43. Bajaj M et al. (2003) Pioglitazone reduces hepatic fat content and augments splanchnic glucose uptake in patients with type 2 diabetes. Diabetes 52: 1364-1370
44. Turner RC et al. (1998) Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 316: 823-828
45. Malmberg K et al. (2000) Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 102: 1014-1019
46. Sunayama S et al. (1999) Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance. Atherosclerosis 146: 187-193
47. Goldberg RB et al. (2005) A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28: 1547-1554
48. Langenfeld MR et al. (2005) Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 111: 2525-2531
49. Sidhu JS et al. (2004) Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 24: 930-934
50. Choi D et al. (2004) Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care 27: 2654-2660
51. Marx N et al. (2005) Pioglitazone reduces neointima volume after coronary stent implantation: a randomized, placebo-controlled, double-blind trial in nondiabetic patients. Circulation 112: 2792-2798
52. Meisner F et al. (2006) Effect of rosiglitazone treatment on plaque inflammation and collagen content in nondiabetic patients. Data from a randomized placebo-controlled trial. Arterioscler Thromb Vasc Biol 26: 845-850
53. Dormandy JA et al. (2005) 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
54. PROactive (online 9 February 2006) The official PROactive results [http://www.proactive-results.com/ html/results.htm] (accessed 9 September 2006)
55. Home PD et al. (2005) Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia 48: 1726-1735
56. Xu HE et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397-403
57. Bastie C et al. (1999) Expression of peroxisome proliferator-activated receptor PPARδ promotes induction of PPARγ and adipocyte differentiation in 3T3C2 fibroblasts. J Biol Chem 274: 21920-21925
58. Barak Y et al. (2002) Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA 99: 303-308
59. Tanaka T et al. (2003) Activation of peroxisome proliferator-activated receptor δ induces fatty acids oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 100: 15924-15929
60. Wang YX et al. (2003) Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113: 159-170
61. Lee CH et al. (2003) Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science 302: 453-457
62. Van der Veen JN et al. (2005) Reduced cholesterol absorption upon PPARδ activation coincides with decreased intestinal expression of NPC1L1. J Lipid Res 46: 526-534
63. Leibowitz MD et al. (2000) Activation of PPARδ alters lipid metabolism in db/db mice. FEBS Lett 473: 333-336
64. Akiyama TE et al. (2004) Peroxisome proliferator-activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a Western diet. J Biol Chem 279: 20874-20881
65. Dressel U et al. (2003) The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol 17: 2477-2493
66. Rival Y et al. (2002) PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells. Eur J Pharmacol 435: 143-151
67. Li AC et al. (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Invest 114: 1538-1540
68. Graham TL et al. (2005) The PPARδ agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis 181: 29-37
69. Camp HS et al. (2000) Differential activation of peroxisome proliferator-activated receptor-γ by troglitazone and rosiglitazone. Diabetes 49: 539-547
70. Derosa G et al. (2004) Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with glimepiride: a twelve-month, multicenter, double-blind, randomized, controlled, parallel-group trial. Clin Ther 26: 744-754
71. Mukherjee R et al. (2000) A selective peroxisome proliferator-activated receptor-γ (PPARγ) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes. Mol Endocrinol 14: 1425-1433
72. Berger JP et al. (2003) Distinct properties and advantages of a novel peroxisome proliferator-activated protein-γ selective modulator. Mol Endocrinol 17: 662-676
73. Schiffrin EL et al. (2005) Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 288: 1037-1043
74. Finck BN et al. (2002) The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J Clin Invest 109: 121-130
75. Chakrabarti R et al. (2003) Ragaglitazar: a novel PPAR α PPAR γ agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models. Br J Pharmacol 140: 527-537
76. Hegarty BD et al. (2004) Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo-a study using the novel PPARα/γ agonist tesaglitazar. Endocrinology 145: 3158-3164
77. Skrumsager BK et al. (2003) Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR α and γ agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol 43: 1244-1256
78. Saad MF et al. (2004) Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 27: 1324-1329