Different actions of peroxisome proliferator-activated receptors: Molecular mechanisms and clinical importance

Current Opinion in Endocrinology and Diabetes

Volumn 13, Issue 2, 2006, Pages 162-170

  Simonson, Gregg D ^a,b   Kendall, David M ^a,c  

^a UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^b INTERNATIONAL DIABETES CENTER   (United States)

^c AMYLIN PHARMACEUTICALS INC   (United States)

Author keywords

Insulin resistance; Lipid metabolism; Peroxisome proliferator activated receptor; Type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; BEZAFIBRATE; CYTOKINE; EZETIMIBE; FENOFIBRATE; FIBRIC ACID DERIVATIVE; GEMFIBROZIL; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; METALLOPROTEINASE; METFORMIN; MURGLITAZAR; ORAL ANTIDIABETIC AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; POLYUNSATURATED FATTY ACID; RECEPTOR SUBTYPE; ROSIGLITAZONE; STATINE DERIVATIVE; TRIACYLGLYCEROL; TROGLITAZONE; UNCLASSIFIED DRUG;

ADIPOSE TISSUE; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; DISEASE MARKER; FATTY ACID OXIDATION; GLUCOSE METABOLISM; HUMAN; INFLAMMATION; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID METABOLISM; LIVER TOXICITY; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION; TISSUE DIFFERENTIATION;

EID: 33646053531     PISSN: 10683097     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.med.0000216965.36504.be     Document Type: Review

References (76)

1. Schoonjans K, Martin G, Staels B, Auwerx J. Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 1997; 8:159-166.
2. Chawala A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the x-files. Science 2001; 294:1866-1870.
3. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106:171-176.
4. Alberti KGMM, Zimmet PZ, for the WHO Consultation. Definition, diagnosis, and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation. Diab Med 1998; 15:539-553.
5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-2497.
6. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome [article online]. www.idf.org/webdata/docs/Metac_syndrome_def.pdf. [Accessed 2005]
7. ACE Position Statement on the Insulin Resistance Syndrome. Endocr Pract 2003; 9:240-252.
8. Simonson GS, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005; 16:465-472.
9. Reaven GM. Banting lecture 1988: Role of insulin resistance in human disease. Diabetes 1998; 37:1595-1606.
10. Kendall DM, Peters Harmel AL. Type 2 diabetes and the metabolic syndrome: understanding the role of insulin resistance. Am J Manag Care 2002; 8:S635-S653.
11. Hanley AJG, Williams K, Gonzalez C, et al. Prediction of type 2 diabetes using simple measures of insulin resistance. Diabetes 2003; 52:463-469.
12. Riesset J, Auwerx J, Vidal H. Regulation of gene expression by activation of the peroxisome proliferator-activated receptor gamma with rosiglitazone (BRL 49653) in human adipocytes. Biochem Biophys Res Commun 1999; 265:265-271.
13. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351:1106-1118. Outstanding comprehensive review of the TDZ class of PPARγ agonists. Excellent artwork shows the numerous effects of the TDZs on liver, adipose tissue and vasculature.
14. Chinetti-Gbaguidi G, Fruchart J-C, Staels B. Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. Curr Opin Pharmacol 2005; 5:177-183. This review highlights the role of all PPARs and describes the concept of selective PPAR modulators (SPPARMs) being responsible for the selective activation of specific genes.
15. Marx N, Sukhova G, Collins T, et al. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule 1 expression in human endothelial cells. Circulation 1999; 99:3125-3131.
16. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 1998; 393:790-793.
17. Gervois P, Torra IP, Fruchart JC, Staels B. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med 2000; 38:3-11.
18. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol; Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410-418.
19. Goldberg AC, Schonfeld G, Feldman EB, et al. Fenofibrate for the treatment of type IV and V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study. Clin Ther 1989; 11:69-83.
20. Boyle PJ, King AB, Olansky L, et al. Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002; 24:378-396.
21. Peters Harmel AL, Kendall DM, Buse JB, et al. Impact of adjunctive thiazolidinedione therapy on blood lipid levels and glycemic control in patients with type 2 diabetes. Curr Med Res Opin 2004; 20:215-223. This study describes the effect of adding either pioglitazone or rosiglitazone to metformin or sulfonylurea on lipid and glycemic measures.
22. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005; 28:1547-1554. This study presents data from a 'head-to-head' randomized study comparing the effects of pioglitazone and rosiglitazone on lipid metabolism, and demonstrates that members of the TZD class modify lipid panels quite differently.
23. Kendall DM. The dyslipidemia of diabetes mellitus: giving triglycerides and high-density lipoprotein cholesterol a higher priority? Endocrinol Metab Clin N Am 2005; 34:27-48. This review provides clinical evidence supporting the benefits of treating-to-target on triglycerides and HDL-C, and contains a practical treatment algorithm for treating this common dyslipidemia.
24. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Benzafibrate Infarction Prevention (BIP) study. Circulation 2000; 102:21-27.
25. Frick MH, Elo O, Haapa K, et al. 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 1987; 317:1237-1245.
26. Quinones MJ, Nicholas SB, Lyon CJ. Insulin resistance and the endothelium. Curr Diab Rep 2005; 5:246-253. This review explains the potential impact of insulin resistance on the endothelium and vascular wall.
27. Marx N, Sukhova G, Collins T, et al. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule 1 expression in human endothelial cells. Circulation 1999; 99:3125-3131.
28. Goya K, Sumitani S, Xu X, et al. Peroxisome proliferator activated receptor α agonists increase nitric oxide synthase expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2004; 24:658-663.
29. Delerive P, Fruchart C, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 2001; 169:453-459.
30. Tsuchida A, Yamauchi T, Takekawa S, et al. Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue. Diabetes 2005; 54:3358-3370. This study describes the impact of activation of PPARα, PPARγ, and both cell signaling pathways in combination on white adipose tissue, and presents an elegant model to explain their insulin sensitizing capability though enhancement of adiponectin action.
31. Okamoto H, Iwamoto T, Kotake S, et al. Inhibition of NF-kappaB signaling by fenofibrate, a peroxisome-activator receptor-alpha ligand, present a therapeutic strategy for rheumatoid arthritis. Clin Exp Rheumatol 2005; 23:323-330.
32. Koh KK, Ahn JY, Han SH, et al. Effects of fenofibrate on lipoproteins, vasomotor function and serological markers of inflammation, plaque stabilization, and hemostasis. Atherosclerosis 2004; 174:379-383.
33. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110:227-239. This update to the NCEP ATP III guidelines provides an excellent review of current clinical trials with cardiovascular endpoints and the most recent lipid targets based on cardiovascular risk.
34. Keech A, Simes RG, Barter P, et al. The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366:1960-1963. This large multinational randomized controlled trial showed that PPARα activation with fenofibrate did not significantly reduce primary outcome of reducing coronary events, but did reduce non-fatal myocardial infarctions and need for revascularization. The study results may have been partially masked by the large number of participants starting statin therapy.
35. Miyazaki Y, Mahankali A, Matsuda M, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002; 87:2784-2791.
36. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C and IκB-α. Diabetes 2002; 51:2005-2011.
37. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004; 39:188-196.
38. Strowig SM, Raskin P. Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes Obes Metab 2005; 7:633-641. This review article compares and contrasts the metabolic and clinical benefits of PPARγ activation with TZDs compared with metformin when combined with insulin therapy.
39. Nakamura T, Funahashi T, Yamashita S, et al. Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation: double-blind placebo-controlled trial. Diabetes Res Clin Pract 2001; 54:181-190.
40. Smith U, Gogg S, Johansson A, et al. Thiazolidinediones (PPARgamma agonists) but not PPARalpha agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes. FASEB J 2001; 15:215-220.
41. Shintani M, Nishimura H, Yonemitsu S, et al. Troglitazone not only increases GLUT4 but also induces its translocation in rat adipocytes. Diabetes 2001; 50:2296-2300.
42. Hammarstedt A, Sopasakis VR, Gogg S, et al. Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects. Diabetologia 2005; 48:96-104. This study demonstrates that PPARγ activation with piogltiazone increases insulin sensitivity before any significant changes in plasma lipid (free fatty acid) levels could be detected.
43. Vidal-Puig AJ, Considine RV, Jimenez-Linan M, et al. Peroxisome proliferator-activated receptor gene expression in human tissues: effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest 1997; 99:2416-2422.
44. Karlsson HKR, Hallsten K, Bjornholm M, et al. Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Diabetes 2005; 54:1459-1467. This study shows that PPARγ activation with rosiglitazone, but not metformin or placebo, results in insulin-mediated whole-body and leg muscle glucose disposal.
45. Miyazaki Y, He H, Manarino U, DeFronzo RA. Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. Diabetes 2003; 52:1943-1950.
46. Dhindsa S, Tripathy D, Sanalkumar N, et al. Free fatty acid-induced insulin resistance in the obese is not prevented by rosiglitazone treatment. J Clin Endocrinol Metab 2005; 90:5058-5063. This study shows that PPARγ activation with rosiglitazone decreases free fatty acid and triglyceride levels in an experimental model of acute hypertriglyceridemia, but is unable to prevent free fatty acid-induced insulin resistance.
47. Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis. Circ Res 2004; 94:1168-1178.
48. Gegick CG, Altheimer MD. Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors. Curr Med Res Opin 2004; 20:919-930.
49. Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 2005; 288:H1037-H1043. This review explores the ability of activation of PPARα and PPARγ to modify the cardiovascular system.
50. Hsueh WA, Jackson S, Law RE. Control of vascular cell proliferation and migration by PPARγ: a new approach to the macrovascular complications of diabetes. Diabetes Care 2001; 24:392-397.
51. Nishio K, Sakurai M, Kusuyama T, et al. A randomized comparison of pioglitazone to inhibit restenosis after coronary stenting in patients with type 2 diabetes. Diabetes Care 2006; 29:101-106. This study provides evidence supporting the mechanism of action of how pioglitazone prevents in-stent restenosis.
52. de-Dios ST, Bruemmer D, Dilley RJ, et al. Inhibitory activity of clinical thiazolidinedione peroxisome proliferator activating receptor-γ ligands toward internal mammary artery, radial artery and saphenous vein smooth muscle cell proliferation. Circulation 2003; 107:2548-2550.
53. Jiang C, Ting AT, Seed B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391:82-86.
54. Calnek DS, Mazzella L, Roser S, et al. Peroxisome proliferator-activated receptor-γ ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003; 23:52-57.
55. Campbell IW. The clinical significance of PPAR gamma agonism. Curr Mol Med 2005; 5:349-363. This practical review describes the potential metabolic and clinical impact of PPARγ activation using TZDs and places special emphasis on movement from visceral fat to subcutaneous fat stores.
56. Khan MA, St. Peter JV, Xue JL. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002; 25:708-711.
57. van Wijk JPH, de Koning EJP, Martens EP, Rabelink TJ. Thiazolidinediones and blood lipids in type 2 diabetes. Arterioscler Thromb Vasc Biol 2003; 23:1744-1749.
58. Buse JB, Tan MH, Prince MJ, Erickson PP. The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes. Diabetes Obes Metab 2004; 6:133-156.
59. Sakamoto J, Kimura H, Moriyama S, et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 2000; 278:704-711.
60. Nagashima K, Lopez C, Donovan D, et al. Effects of the PPARγ agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest 2005; 115:1323-1332. This study demonstrates the ability of the TZD pioglitazone to increase the clearance of very low-density lipoprotein particles through increased lipolysis.
61. Khan M, Berhanu B, Perez A, et al. Effects of pioglitazone in combination with stable statin therapy on lipid levels in subjects with type 2 diabetes and dyslipidemia after conversion from rosiglitazone: results from an open-label study. Diabetes 2005; 54 (Suppl 1):poster 553.
62. Lewin AJ, Kipnes MS, Meneghini LF, et al. Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to a thiazolidinedione therapy in patients with type 2 diabetes: a multicenter, randomized double blind placebo controlled trial. Clin Ther 2004; 36:379-389.
63. Gaudiani LM, Lewin A, Meneghini L, et al. Efficacy and safety of ezetimibe coadministered with simvastatin in thiazolidinedione treated type 2 diabetic patients. Diabetes Obes Metab 2005; 7:88-97.
64. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet 2005; 366:1279-1289. This important study was the first prospective randomized controlled clinical trial to be published showing that PPARγ activation with pioglitazone reduced all-cause mortality, non-fatal myocardial infarction and stroke in patients with type 2 diabetes. It also showed that this potential benefit must be weighed against the increased risk of congestive heart failure found in the pioglitazone-treated study participants.
65. Nesto RW, Bell D, Bonow R, et al. Thiazolidindione use, fluid retention, and congestive heart failure. A Consensus Statement from the American Heart Association and American Diabetes Association. Circulation 2003; 108:2941-2948.
66. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005; 111:583-590.
67. Brand CL, Sturis J, Gotfredsen, et al. Dual PPARα/γ activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284:E841-E854.
68. Buse JB, Rubin CJ, Frederich R, et al. Muraglitazar, a dual PPARα/γ activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes. Clin Ther 2005; 27:1181-1195. This study describes improvement in glucose and lipid parameters using a novel compound in the 'glitizar' class of dual PPARα/γ agonists.
69. Fagerberg B, Edwards S, Halmos T, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005; 48:1716-1725. This study showed that tesaglitazar - a dual PPAR activator - improved lipid parameters and significantly reduced fasting glucose and insulin levels.
70. Luquet S, Gaudel C, Holst D, et al. Roles of PPAR delta in lipid absorption and metabolism: a new target of the treatment of type 2 diabetes. Biochim Biophys Acta 2005; 1740:313-317. This excellent comprehensive review describes the role of PPARδ in lipid metabolism and provides evidence to support the role of this cell-signaling pathway as a critical lipid sensor in muscle and adipose tissue. It describes the potential of PPARδ agonists to treat metabolic syndrome.
71. Gilde AJ, van der Lee KAJM, Willemsen PHM, et al. Peroxisome proliferator-activated receptor (PPAR) α and PPARβ/δ, but not PPARγ, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 2003; 92:518-524.
72. Tanaka T, Yammamoto J, Iwasaki S, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A 2003; 100:15924-15929.
73. Muscat GEO, Dressel U. Cardiovascular disease and PPARδ: targeting the risk factors. Curr Opin Investig Drugs 2005; 6:887-894. This review details the current PPARδ undergoing clinical studies and provides a detailed description of how activation of this cell-signaling pathway may reduce traditional and non-traditional cardiovascular risk factors.
74. Kitz Kramer D, Al-Khalili L, Perrini S, et al. Direct activation of glucose transport in primary human myotubes after activation of peroxisom proliferator-activated receptor δ. Diabetes 2005; 54:1157-1163. This study clearly demonstrates the glucose-lowering effect of PPARγ in primary cultures of skeletal muscle and in adipocyte cell lines, and establishes activation of this cell signaling pathway as a potential therapy to treat type 2 diabetes.
75. Terada S, Wicke S, Holloszy JO, Han DH. The PPARδ activator GW505516 has no acute effect on glucose transport in skeletal muscle. Am J Physiol Endocrinol Metab 2005; Nov 8. [Epub ahead of print]
76. Lee CH, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science 2003; 302:453-457.