Thiazolidinediones and the preservation of β-cell function, cellular proliferation and apoptosis

Diabetes, Obesity and Metabolism

Volumn 10, Issue 8, 2008, Pages 617-625

  Decker, Michael ^a   Hofflich, Heather ^a   Elias, Alan N ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anti inflammatory; Apoptosis; Beta cell; Diabetes; Thiazolidinedione

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; AMILORIDE; ANTIDIABETIC AGENT; FIBRIC ACID DERIVATIVE; GLIBENCLAMIDE; ISOXAZOLIDINEDIONE; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; PLACEBO; RAMIPRIL; ROSIGLITAZONE; SULFONYLUREA DERIVATIVE; TROGLITAZONE;

ADIPOGENESIS; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ATHEROSCLEROSIS; BINDING AFFINITY; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; COLITIS; DIABETES MELLITUS; DRUG EFFICACY; DRUG POTENCY; DRUG RECEPTOR BINDING; ENERGY EXPENDITURE; FLUID RETENTION; GLUCONEOGENESIS; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIVER INJURY; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREAS ISLET BETA CELL; PREGNANCY DIABETES MELLITUS; REVIEW; SIDE EFFECT; WEIGHT GAIN;

EID: 47949090686     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/j.1463-1326.2007.00745.x     Document Type: Review

References (100)

1. Pimenta W, Korytkowski M, Mitrakou A et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 1995; 273: 1855-1861.
2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865.
3. Cnop M, Grupping A, Hoorens A, Bouwens L, Pipeleers-Marichal M, Pipeleers D. Endocytosis of low-density lipoprotein by human pancreatic beta cells and uptake in lipid-storing vesicles, which increase with age. Am J Pathol 2000; 156: 237-244.
4. Einhorn D, Reaven GM, Cobin RH et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003; 9: 237-252.
5. Smith SA, Porter LE, Biswas N, Freed, MI. Rosiglitazone, but not glyburide, reduces circulating proinsulin and the proinsulin: Insulin ratio in type 2 diabetes. J Clin Endocrinol Metab 2004; 89: 6048-6053.
6. Grundy SM, Brewer HB Jr., Cleeman JI, Smith SC Jr., Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433-438.
7. Virkamaki A, Korsheninnikova E, Seppala-Lindroos A. Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 2001; 50: 2337-2343.
8. Lin X, Denmeade SR, Isaacs JT. The genetics of programmed (apoptotic) cell death. Cancer Surv 1995; 25: 173-194.
9. Shimabukuro M, Koyama K, Lee Y, Unger RH. Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 1997; 100: 290-295.
10. Francis GA, Annicotte JS, Auwerx J. PPAR-alpha effects on the heart and other vascular tissues. Am J Physiol Heart Circ Physiol 2003; 285: H1-H9.
11. Smith SA, Lister CA, Toseland CD, Buckingham RE. Rosiglitazone prevents the onset of hyperglycaemia and proteinuria in the Zucker diabetic fatty rat. Diabetes Obes Metab 2000; 2: 363-372.
12. Baggio LL, and Drucker DJ. Therapeutic approaches to preserve islet mass in type 2 diabetes. Annu Rev Med 2006; 57: 265-281.
13. Bell DS. Beta-cell rejuvenation with thiazolidinediones. Am J Med 2003; 115 (Suppl. 8A): 20S-23S.
14. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102-110.
15. Ovalle F, Bell DS. Clinical evidence of thiazolidinedione-induced improvement of pancreatic beta-cell function in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2002; 4: 56-59.
16. Prigeon RL, Kahn SE, Porte D Jr. Effect of troglitazone on B cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 1998; 83: 819-823.
17. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J et al. 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.
18. Patel DD, Knight BL, Wiggins D, Humphreys SM, Gibbons GF. Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice. J Lipid Res 2001; 42: 328-337.
19. Weng JR, Chen CY, Pinzone JJ, Ringel MD, Chen CS. Beyond peroxisome proliferator-activated receptor gamma signaling: The multi-facets of the antitumor effect of thiazolidinediones. Endocr Relat Cancer 2006; 13: 401-413.
20. Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell 1995; 83: 841-850.
21. Mangelsdorf DJ, Thummel C, Beato M et al. The nuclear receptor superfamily: The second decade. Cell 1995; 83: 835-839.
22. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM et al. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 1996; 15: 5336-5348.
23. Zhu Y, Alvares K, Huang Q, Rao MS, Reddy JK. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem 1993; 268: 26817-26820.
24. Zhu Y, Qi C, Korenberg JR et al. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A 1995; 92: 7921-7925.
25. Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev 1994; 8: 1224-1234.
26. Fajas L, Egler V, Reiter R, Miard S, Lefebvre AM, Auwerx J. PPARgamma controls cell proliferation and apoptosis in an RB-dependent manner. Oncogene 2003; 22: 4186-4193.
27. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996; 137: 354-366.
28. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: From orphan receptors to drug discovery. J Med Chem 2000; 43: 527-550.
29. Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S. Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators. J Biol Chem 2000; 275: 33201-33204.
30. Lee JW, Lee YC, Na SY, Jung DJ, Lee SK. Transcriptional coregulators of the nuclear receptor superfamily: Coactivators and corepressors. Cell Mol Life Sci 2001; 58: 289-297.
31. Tontonoz P, Graves RA, Budavari AI et al. Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res 1994; 22: 5628-5634.
32. Berger A, Monnard I, Baur M, Charbonnet C, Safonova I, Jomard A. Epidermal anti-inflammatory properties of 5,11,14 20:3: effects on mouse ear edema, PGE2 levels in cultured keratinocytes, and PPAR activation. Lipids Health Dis 2002; 1: 5.
33. Picard F, Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 2002; 22: 167-197.
34. Xu HE, Lambert MH, Montana VG et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999; 3: 397-403.
35. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995; 83: 813-819.
36. Nolte RT, Wisely GB, Westin S et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 1998; 395: 137-143.
37. Suh N, Wang Y, Honda T et al. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 1999; 59: 336-341.
38. Cobb JE, Blanchard SG, Boswell E et al. N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J Med Chem 1998; 41: 5055-5069.
39. Li AC, Brown KK, Silvestre MJ et al. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000; 106: 523-531.
40. Henke BR, Adkison KK, Blanchard SG et al. Synthesis and biological activity of a novel series of indole-derived PPARgamma agonists. Bioorg Med Chem Lett 1999; 9: 3329-3334.
41. Grindflek E, Sundvold H, Klungland H, Lien S. Characterisation of porcine peroxisome proliferator-activated receptors gamma 1 and gamma 2: detection of breed and age differences in gene expression. Biochem Biophys Res Commun 1998; 249: 713-718.
42. Houseknecht KL, Bidwell CA, Portocarrero CP, Spurlock ME. Expression and cDNA cloning of porcine peroxisome proliferator-activated receptor gamma (PPARgamma). Gene 1998; 225: 89-96.
43. Sundvold H, Brzozowska A, Lien S. Characterisation of bovine peroxisome proliferator-activated receptors gamma 1 and gamma 2: Genetic mapping and differential expression of the two isoforms. Biochem Biophys Res Commun 1997; 239: 857-861.
44. McNeel RL, Mersmann HJ. Nutritional deprivation reduces the transcripts for transcription factors and adipocyte-characteristic proteins in porcine adipocytes. J Nutr Biochem 2000; 11: 139-146.
45. Vidal-Puig A, Jimenez-Linan M, Lowell BB et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. J Clin Invest 1996; 97: 2553-2561.
46. Kahn BB. Dietary regulation of glucose transporter gene expression: tissue specific effects in adipose cells and muscle. J Nutr 1994; 124 (Suppl. 8): 1289S-1295S.
47. Raclot T, Groscolas R, Langin D, Ferre P. Site-specific regulation of gene expression by n-3 polyunsaturated fatty acids in rat white adipose tissues. J Lipid Res 1997; 38: 1963-1972.
48. Hertzel AV, Bernlohr DA. Regulation of adipocyte gene expression by polyunsaturated fatty acids. Mol Cell Biochem 1998; 188: 33-39.
49. Barak Y, Nelson MC, Ong ES et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999; 4: 585-595.
50. Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 2000; 16: 145-171.
51. Shao D, Lazar MA. Peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein alpha, and cell cycle status regulate the commitment to adipocyte differentiation. J Biol Chem 1997; 272: 21473-21478.
52. Rattarasarn C. Physiological and pathophysiological regulation of regional adipose tissue in the development of insulin resistance and type 2 diabetes. Acta Physiol (Oxf) 2006; 186: 87-101.
53. Smith SR, De Jonge L, Volaufova J, Li Y, Xie H, Bray G.A. Effect of pioglitazone on body composition and energy expenditure: A randomized controlled trial. Metabolism 2005; 54: 24-32.
54. Sotiropoulos KB, Clermont A, Yasuda Y et al. Adipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPAR{gamma} agonist's effects on edema and weight gain. FASEB J 2006; 20: 1203-1205.
55. DeFronzo RA. Lilly lecture 1987. The triumvirate: Beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667-687.
56. Semple RK, Chatterjee VK, O'Rahilly S. PPAR gamma and human metabolic disease. J Clin Invest 2006; 116: 581-589.
57. Debril MB, Renaud JP, Fajas L, Auwerx J. The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med 2001; 79: 30-47.
58. Samaha FF, Szapary PO, Iqbal N et al. Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 624-630.
59. Steppan CM, Brown EJ, Wright CM et al. A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A 2001; 98: 502-506.
60. Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 2002; 13: 18-23.
61. Stumvoll M, Wahl HG, Loblein K et al. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity. Diabetes 2001; 50: 876-881.
62. Altshuler D, Hirschhorn JN, Klannemark M et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76-80.
63. Finegood DT, McArthur MD, Kojwang D et al. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death. Diabetes 2001; 50: 1021-1029.
64. Higa M, Zhou YT, Ravazzola M, Baetens D, Orci L, Unger RH. Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats. Proc Natl Acad Sci U S A 1999; 96: 11513-11518.
65. Shimabukuro M, Zhou YT, Lee Y, Unger RH. Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats. J Biol Chem 1998; 273: 3547-3550.
66. Sreenan S, Sturis J, Pugh W, Burant CF, Polonsky KS. Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol 1996; 271: E742-E747.
67. Buchanan TA, Xiang AH, Peters RK et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51: 2796-2803.
68. Moore GB, Chapman H, Holder JC et al. Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice. Biochem Biophys Res Commun 2001; 286: 735-741.
69. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 1992; 41: 1422-1428.
70. Jia DM, Otsuki M. Troglitazone stimulates pancreatic growth in normal rats. Pancreas 2002; 24: 303-312.
71. Jia DM, Tabaru A, Nakamura H, Fukumitsu KI, Akiyama T, Otsuki M. Troglitazone prevents and reverses dyslipidemia, insulin secretory defects, and histologic abnormalities in a rat model of naturally occurring obese diabetes. Metabolism 2000; 49: 1167-1175.
72. Zeender E, Maedler K, Bosco D, Berney T, Donath MY, Halban PA. Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab 2004; 89: 5059-5066.
73. Maedler K, Fontana A, Ris F et al. FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication. Proc Natl Acad Sci U S A 2002; 99: 8236-8241.
74. Maedler K, Sergeev P, Ris F et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002; 110: 851-860.
75. Maedler K, Spinas GA, Lehmann R et al. Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 2001; 50: 1683-1690.
76. Giannoukakis N, Rudert WA, Trucco M, Robbins PD. Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. J Biol Chem 2000; 275: 36509-36513.
77. Grey ST, Arvelo MB, Hasenkamp W, Bach FH, Ferran C. A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. J Exp Med 1999; 190: 1135-1146.
78. Dupraz P, Cottet S, Hamburger F, Dolci W, Felley-Bosco E, Thorens B. Dominant negative MyD88 proteins inhibit interleukin-1beta/ interferon-gamma-mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells. J Biol Chem 2000; 275: 37672-37678.
79. Baker MS, Chen X, Cao XC, Kaufman DB. Expression of a dominant negative inhibitor of NF-kappaB protects MIN6 beta-cells from cytokine-induced apoptosis. J Surg Res 2001; 97: 117-122.
80. Heimberg H, Heremans Y, Jobin C et al. Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 2001; 50: 2219-2224.
81. Riachy R, Vandewalle B, Kerr Conte J et al. 1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: Implication of the antiapoptotic protein A20. Endocrinology 2002; 143: 4809-4819.
82. Rehman KK, Bertera S, Bottino R et al. Protection of islets by in situ peptide-mediated transduction of the Ikappa B kinase inhibitor Nemo-binding domain peptide. J Biol Chem 2003; 278: 9862-9868.
83. Walter H, Lubben G. Potential role of oral thiazolidinedione therapy in preserving beta-cell function in type 2 diabetes mellitus. Drugs 2005; 65: 1-13.
84. Pihlajamaki J, Karjalainen L, Karhapaa P et al. G-250A substitution in promoter of hepatic lipase gene is associated with dyslipidemia and insulin resistance in healthy control subjects and in members of families with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol 2000; 20: 1789-1795.
85. Yue TL, Bao W, Gu JL et al. Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with myocardial injury. Diabetes 2005; 54: 554-562.
86. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI. "Rosiglitazone monotherapy is effective in patients with type 2 diabetes." J Clin Endocrinol Metab 2001; 86: 280-288.
87. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. "Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study. The Pioglitazone 027 Study Group." Clin Ther 2000; 22: 1395-1409.
88. Rosenblatt S, Miskin B, Glazer NB, Prince MJ, Robertson KE. "The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus." Coron Artery Dis 2001; 12: 413-423.
89. Juhl B, Hollingdal M, Porksen N, Prange A, Lonnqvist F, Schmitz O. "Influence of rosiglitazone treatment on beta-cell function in type 2 diabetes: Evidence of an increased ability of glucose to entrain high-frequency insulin pulsatility." J Clin Endocrinol Metab 2003; 88: 3794-3800.
90. Campbell JW. Long-term glycemic controls with pioglitazone in patients with type 2 diabetes mellitus. Program of the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA. 2003; 272.
91. Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA. TRIPOD (Troglitazone in the Prevention of Diabetes): A randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials 1998; 19: 217-231.
92. The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 54: 1150-1156.
93. Gerstein HC, Yusuf S, Bosch J, et al., on behalf of the DREAM trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: A randomized controlled trial. Lancet 2006: 368: 1096-1105.
94. Greene ME, Blumberg B, McBride OW et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: Expression in hematopoietic cells and chromosomal mapping. Gene Expr 1995; 4: 281-299.
95. Leininger MT, Portocarrero CP, Houseknecht KL. Peroxisome proliferator-activated receptor gamma1 expression in porcine white blood cells: Dynamic regulation with acute endotoxemia. Biochem Biophys Res Commun 1999; 263: 749-753.
96. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998; 391: 79-82.
97. Consoli A, Devangelio E. Thiazolidinediones and inflammation. Lupus 2005; 14: 794-797.
98. Wang N, Verna L, Chen NG et al. Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem 2002; 277: 34176-34181.
99. Redondo S, Ruiz E, Santos-Gallego CG, Padilla E, Tejerina T. Pioglitazone induces vascular smooth muscle cell apoptosis through a peroxisome proliferator-activated receptor-gamma, transforming growth factor-beta1, and a Smad2-dependent mechanism. Diabetes 2005; 54: 811-817.
100. Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000; 49: 497-505.