The PPARs: From orphan receptors to drug discovery

Journal of Medicinal Chemistry

Volumn 43, Issue 4, 2000, Pages 527-550

  Willson, Timothy M ^a   Brown, Peter J ^a   Sternbach, Daniel D ^a   Henke, Brad R ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [1 CARBOXY 2 [4 [2 (5 METHYL 2 PHENYL 4 OXAZOLYL)ETHOXY]PHENYL]ETHYLAMINO]BENZOIC ACID METHYL ESTER; 4 [4 [3 (4 ACETYL 3 HYDROXY 2 PROPYLPHENOXY)PROPOXY]PHENOXY]ACETIC ACID; 5 (2,4 DIOXO 5 THIAZOLIDINYLMETHYL) 2 METHOXY N [4 (TRIFLUOROMETHYL)BENZYL]BENZAMIDE; 6 [1 (5,6,7,8 TETRAHYDRO 3,5,5,8,8 PENTAMETHYL 2 NAPHTHYL)CYCLOPROPYL]NICOTINIC ACID; ANTIDIABETIC AGENT; ANTILIPEMIC AGENT; BEXAROTENE; BEZAFIBRATE; CELL NUCLEUS RECEPTOR; CLOFIBRATE; FARGLITAZAR; FENOFIBRATE; FIBRIC ACID DERIVATIVE; GW 0207; GW 2433; ICOSANOID; L 796449; LIGAND; N (2 BENZOYLPHENYL) O [2 (METHYL 2 PYRIDINYLAMINO)ETHYL]TYROSINE; NONSTEROID ANTIINFLAMMATORY AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PIOGLITAZONE; PIRINIXIC ACID; RECEPTOR SUBTYPE; REGLITAZAR; ROSIGLITAZONE; SB 213068; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; UREIDO THIOISOBUTYRIC ACID;

ATHEROSCLEROSIS; COLORECTAL CANCER; DIABETES MELLITUS; DRUG STRUCTURE; DRUG TARGETING; DYSLIPIDEMIA; HORMONE RECEPTOR INTERACTION; HUMAN; HYPERTENSION; INFLAMMATION; LIGAND BINDING; NONHUMAN; OBESITY; PROTEIN STRUCTURE; REVIEW;

ANIMALS; DIABETES MELLITUS; DRUG DESIGN; HUMANS; HYPERLIPIDEMIAS; HYPERTENSION; INFLAMMATION; LIGANDS; MODELS, MOLECULAR; NEOPLASMS; NUCLEAR PROTEINS; OBESITY; RECEPTORS, CYTOPLASMIC AND NUCLEAR; TRANSCRIPTION FACTORS;

EID: 0033998334     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990554g     Document Type: Review

References (326)

1. Lichtenstein, A. H.; Kennedy, E.; Barrier, P.; Ernst, N. D.; Grundy, S. M.; Leveille, G. A.; Van Horne, L.; Williams, C. L.; Booth, S. L. Dietary fat consumption and health. Nutr. Rev. 1998, 56, S3-S28.
2. Harris, M. I.; Flegal, K. M.; Cowie, C. C.; Eberhardt, M. S.; Goldstein, D. E.; Little, R. R.; Weidmeyer, H. M.; Byrd-Holt, D. D. Prevelence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The third National Health and Nutrition Examination Survey, 1988-1994. Diabetes Care 1998, 21, 518-524.
3. Howard, B. V. Diet, insulin resistance, and atherosclerosis. Int. Congr. Ser. 1995, 1100, 446-450.
4. Barzilai, N.; Gupta, G. Revisiting the role of fat mass in the life extension induced by caloric restriction. J. Gerontol., Ser. A 1999, 54A, B89-B96.
5. Grundy, S. M. The optimal ratio of fat-to-carbohydrate in the diet. Annu. Rev. Nutr. 1999, 19, 325-341.
6. Simopoulos, A. P. Evolutionary aspects of omega-3 fatty acids in the food supply. Prostaglandins, Leukotrienes Essent. Fatty Acids 1999, 60, 421-429.
7. Lichtenstein, A. H. Dietary fat: a history. Nutr. Rev. 1999, 57, 11-14.
8. Jump, D. B.; Clarke, S. D. Regulation of gene expression by dietary fat. Annu. Rev. Nutr. 1999, 19, 63-90.
9. Issemann, I.; Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990, 347, 645-650.
10. Mangelsdorf, D. J.; Evans, R. M. The RXR heterodimers and orphan receptors. Cell 1995, 83, 841-850.
11. A unified nomenclature system for the nuclear receptor superfamily. Cell 1999, 97, 161-163.
12. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.; Glass, C. K.; Milburn, M. V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ. Nature 1998, 395, 137-143.
13. Uppenberg, J.; Svensson, C.; Jaki, M.; Bertilsson, G.; Jendeberg, L.; Berkenstam, A. Crystal structure of the ligand binding domain of the human nuclear receptor PPARy. J. Biol. Chem. 1998, 273, 31108-31112.
14. Xu, H. E.; Lambert, M. H.; Montana, V. G.; Parks, D. J.; Blanchard, S. G.; Brown, P. J.; Sternbach, D. D.; Lehmann, J. M.; Wisely, G. B.; Willson, T. M.; Kliewer, S. A.; Milburn, M. V. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell 1999, 3, 397-403.
15. Kliewer, S. A.; Forman, B. M.; Blumberg, B.; Ong, E. S.; Borgmeyer, U.; Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7355-7359.
16. Castillo, G.; Brun, R. P.; Rosenfield, J. K.; Hauser, S.; Park, C. W.; Troy, A. E.; Wright, M. E.; Spiegelman, B. M. An adipogenic cofactor bound by the differentiation domain of PPARγ. EMBO J. 1999, 18, 3676-3687.
17. Hu, E.; Kim, J. B.; Sarraf, P.; Spiegelman, B. M. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ. Science 1996, 274, 2100-2103.
18. Zhang, B.; Berger, J.; Zhou, G.; Elbrecht, A.; Biswas, S.; White-Carrington, S.; Szalkowski, D.; Moller, D. E. Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor γ. J. Biol. Chem. 1996, 277, 31771-31774.
19. Adams, M.; Reginato, M. J.; Shao, D.; Lazar, M. A.; Chatterjee, V. K. Transcriptional activation by peroxisome proliferator-activated receptor γ is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J. Biol. Chem. 1997, 272, 5128-5132.
20. Camp, H. S.; Tafuri, S. R.; Leff, T. c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-γ1 and negatively regulates its transcriptional activity. Endocrinology 1999, 140, 392-397.
21. Juge-Aubry, C. E.; Hammar, E.; Siegrist-Kaiser, C.; Pernin, A.; Takeshita, A.; Chin, W. W.; Burger, A. G.; Meier, C. A. Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor a by phosphorylation of a ligand-independent trans-activating domain. J. Biol. Chem. 1999, 274, 10505-10510.
22. Shao, D.; Rangwala, S. M.; Bailey, S. T.; Krakow, S. L.; Reginato, M. J.; Lazar, M. A. Interdomain communication regulating ligand binding by PPAR-γ. Nature 1998, 396, 377-380.
23. Kliewer, S. A.; Umesono, K.; Noonan, D. J.; Heyman, R. A.; Evans, R. M. Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors. Nature 1992, 358, 771-774.
24. Wahli, W.; Braissant, O.; Desvergne, B. Peroxisome proliferator activated receptors: Transcriptional regulators of adipogenesis, lipid metabolism and more. Chem. Biol. 1995, 2, 261-266.
25. McDonnell, D. P.; Vegeto, E.; Gleeson, M. A. G. Nuclear hormone receptors as targets for new drug discovery. Bio/Technology 1993, 11, 1256-1261.
26. Göttlicher, M.; Widmark, E.; Li, Q.; Gustafsson, J. A. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 4653-4657.
27. Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). J. Biol. Chem. 1995, 270, 12953-12956.
28. Freedman, L. P. Increasing the complexity of coactivation in nuclear receptor signaling. Cell 1999, 97, 5-8.
29. Xu, L.; Glass, C. K.; Rosenfeld, M. G. Coactivator and corepressor complexes in nuclear receptor function. Curr. Opin. Genet. Dev. 1999, 9, 140-147.
30. Zhu, Y.; Qi, C.; Calandra, C.; Rao, M. S.; Reddy, J. K. Cloning and identification of mouse steroid receptor coactivator-1 (mSRC-1), as a coactivator of peroxisome proliferator-activated receptor γ. Gene Expression 1996, 6, 185-195.
31. Direnzo, J.; Soderstrom, M.; Kurokawa, R.; Ogliastro, M.-H.; Ricote, M.; Ingrey, S.; Horlein, A.; Rosenfeld, M. G.; Glass, C. K. Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol. Cell. Biol. 1997, 17, 2166-2176.
32. Dowell, P.; Ishmael, J. E.; Avram, D.; Peterson, V. J.; Nevrivy, D. J.; Leid, M. p300 functions as a coactivator for the peroxisome proliferator-activated receptor α. J. Biol. Chem. 1997, 272, 33435-33443.
33. Zhu, Y.; Qi, C.; Jain, S.; Rao, M. S.; Reddy, J. K. Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor. J. Biol. Chem. 1997, 272, 25500-25506.
34. Yuan, C.-X.; Ito, M.; Fondell, J. D.; Fu, Z.-Y.; Roeder, R. G. The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 7939-7944.
35. Puigserver, P.; Wu, Z.; Park, C. W.; Graves, R.; Wright, M.; Spiegelman, B. M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92, 829-839.
36. Treuter, E.; Albrektsen, T.; Johansson, L.; Leers, J.; Gustafsson, J.-A. A regulatory role for RIP140 in nuclear receptor activation. Mol. Endocrinol. 1998, 12, 864-881.
37. Miyata, K. S.; McCaw, S. E.; Meertens, L. M.; Patel, H. V.; Rachubinski, R. A.; Capone, J. P. Receptor-interacting protein 140 interacts with and inhibits transactivation by peroxisome proliferator-activated receptor α and liver-X-receptor α. Mol. Cell. Endocrinol. 1998, 146, 69-76.
38. Heinlein, C. A.; Ting, H.-J.; Yeh, S.; Chang, C. Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor γ. J. Biol. Chem. 1999, 274, 16147-16152.
39. Krey, G.; Braissant, O.; L'Horset, F.; Kalkhoven, E.; Perroud, M.; Parker, M. G.; Wahli, W. Fatty acids eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol. 1997, 11, 779-791.
40. Zhou, G.; Cummings, R.; Li, Y.; Mitra, S.; Wilkinson, H. A.; Elbrecht, A.; Hermes, J. D.; Schaeffer, J. M.; Smith, R. G.; Moller, D. E. Nuclear receptors have distinct affinities for coactivators: characterization by fluorescence resonance energy transfer. Mol. Endocrinol. 1998, 12, 1594-1604.
41. Kliewer, S. A.; Sundseth, S. S.; Jones, S. A.; Brown, P. J.; Wisely, G. B.; Koble, C.; Devchand, P.; Wahli, W.; Willson, T. M.; Lenhard, J. M.; Lehmann, J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 4318-4323.
42. Berger, J.; Bailey, P.; Biswas, C.; Cullinan, C. A.; Doebber, T. W.; Hayes, N. S.; Saperstein, R.; Smith, R. G.; Leibowitz, M. D. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-γ: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 1996, 137, 4189-4195.
43. Young, P. W.; Buckle, D. R.; Cantello, B. C. C.; Chapman, H.; Clapham, J. C.; Coyle, P. J.; Haigh, D.; Hindley, R. M.; Holder, J. C.; Kallender, H.; Latter, A. J.; Lawrie, K. W. M.; Mossakowska, D.; Murphy, G. J.; Cox, L. R.; Smith, S. A. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor γ. J. Pharmacol. Exp. Ther. 1998, 284, 751-759.
44. Brown, P. J.; Smith-Oliver, T. A.; Charifson, P. S.; Tomkinson, N. C. O.; Fivush, A. M.; Sternbach, D. D.; Wade, L. E.; Orband-Miller, L.; Parks, D. J.; Blanchard, S. G.; Kliewer, S. A.; Lehmann, J. M.; Willson, T. M. Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chem. Biol. 1997, 4, 909-918.
45. Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Eibrecht, A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.; Tanen, M.; Ventre, J.; Wu, M. S.; Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; Moller, D. E. Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects. J. Biol. Chem. 1999, 274, 6718-6725.
46. Nichols, J. S.; Parks, D. J.; Consler, T. G.; Blanchard, S. G. Development of a scintillation proximity assay for peroxisome proliferator-activated receptor γ ligand binding domain. Anal. Biochem. 1998, 257, 112-119.
47. 313 in ligand binding. J. Biol. Chem. 1999, 274, 7913-7922.
48. Willson, T. M.; Wahli, W. Peroxisome proliferator-activated receptor agonists. Curr. Opin. Chem. Biol. 1997, 1, 235-241.
49. Kliewer, S. A.; Lehmann, J. M.; Willson, T. M. Orphan nuclear receptors: shifting endocrinology into reverse. Science 1999, 284, 757-760.
50. Dreyer, C.; Krey, G.; Keller, H.; Givel, F.; Helftenbein, G.; Wahli, W. Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992, 68, 879-887.
51. Bell, A. R.; Savory, R.; Horley, N. J.; Choudhury, A. I.; Dickins, M.; Gray, T. J. B.; Salter, A. M.; Bell, D. R. Molecular basis of nonresponsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidemia. Biochem. J. 1998, 332, 689-693.
52. Sher, T.; Yi, H. F.; McBride, O. W.; Gonzalez, F. J. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 1993, 32, 5598-5604.
53. Mukherjee, R.; Jow, L.; Noonan, D.; McDonnell, D. P. Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J. Steroid Biochem. Mol. Biol. 1994, 51, 157-166.
54. Braissant, O.; Foufelle, F.; Scotto, C.; Dauca, M.; Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat. Endocrinology 1996, 137, 354-366.
55. Auboeuf, D.; Rieusset, J.; Fajas, L.; Vallier, P.; Frering, V.; Riou, J. P.; Staels, B.; Auwerx, J.; Laville, M.; Vidal, H. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-α in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 1997, 46, 1319-1327.
56. Lemberger, T.; Staels, B.; Saladin, R.; Desvergne, B.; Auwerx, J.; Wahli, W. Regulation of the peroxisome proliferator-activated receptor α gene by glucocorticoids. J. Biol. Chem. 1994, 269, 24527-24530.
57. Lemberger, T.; Saladin, R.; Vazquez, M.; Assimacopoulos, F.; Staels, B.; Desvergne, B.; Wahli, W.; Auwerx, J. Expression of the peroxisome proliferator-activated receptor α gene is stimulated by stress and follows a diurnal rhythm. J. Biol. Chem. 1996, 271, 1764-1769.
58. Cattley, R. C.; Deluca, J.; Elcombe, C.; Fenner-Crisp, P.; Lake, B. G.; Marsman, D. S.; Pastoor, T. A.; Popp, J. A.; Robinson, D. E.; Schwetz, B.; Tugwood, J.; Wahli, W. Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul. Toxicol. Pharmacol. 1998, 27, 47-60.
59. Roberts, R. A.; James, N. H.; Woodyatt, N. J.; Macdonald, N.; Tugwood, J. D. Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor α (PPARα). Carcinogenesis 1998, 19, 43-48.
60. Blumcke, S.; Schwartzkopf, W.; Lobeck, H.; Edmondson, N. A.; Prentice, D. E.; Blane, G. F. Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. Atherosclerosis 1983, 46, 105-116.
61. Hanefeld, M.; Kemmer, C.; Leonhardt, W.; Kunze, K. D.; Jaross, W.; Haller, H. Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver. Atherosclerosis 1980, 36, 159-172.
62. Bentley, P.; Calder, I.; Elcombe, C.; Grasso, P.; Stringer, D.; Wiegand, H. J. Hepatic peroxisome proliferation in rodents and its significance for humans. Food Chem. Toxicol. 1993, 31, 857-907.
63. Ashby, J.; Brady, A.; Elcombe, C. R.; Elliott, B. M.; Ishmael, J.; Odum, J.; Tugwood, J. D.; Kettle, S.; Purchase, I. F. H. Mechanistically based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum. Exp. Toxicol. 1994, 13, S1-S117.
64. Heuvel, J. P. V. Peroxisome proliferator-activated receptors (PPARs) and carcinogenesis. Toxicol. Sci. 1999, 47, 1-8.
65. Palmer, C. N. A.; Hsu, M.-H.; Griffin, K. J.; Raucy, J. L.; Johnson, E. F. Peroxisome proliferator activated receptor-α expression in human liver. Mol. Pharmacol. 1998, 53, 14-22.
66. Gervois, P.; Torra, I. P.; Chinetti, G.; Grotzinger, T.; Dubois, G.; Fruchart, J.-C.; Fruchart-Najib, J.; Leitersdorf, E.; Staels, B. A truncated human peroxisome proliferator-activated receptor α splice variant with dominant negative activity. Mol. Endocrinol. 1999, 13, 1535-1549.
67. Lambe, K. G.; Woodyatt, N. J.; Macdonald, N.; Chevalier, S.; Roberts, R. A. Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter. Toxicol. Lett. 1999, 110, 119-127.
68. Gaw, A.; Packard, C. J.; Shepherd, J. Fibrates. Handb. Exp. Pharmacol. 1994, 109, 325-348.
69. Hawke, R. L.; Chapman, J. M.; Winegar, D. A.; Salisbury, J. A.; Welch, R. M.; Brown, A.; Franzmann, K. W.; Sigel, C. Potent hypocholesterolemic activity of novel ureido phenoxyisobutyrates correlates with their intrinsic fibrate potency and not with their ACAT inhibitory activity. J. Lipid Res. 1997, 38, 1189-1203.
70. Brown, P. J.; Hurley, K. P.; Stuart, L. W.; Willson, T. M. Generation of secondary alkylamines on solid support by borane reduction. Application to the parallel synthesis of PPAR ligands. Synthesis 1997, 778-782.
71. Brown, P. J.; Winegar, D. A.; Plunket, K. D.; Moore, L. B.; Lewis, M. C.; Wilson, J. G.; Sundseth, S. S.; Koble, C. S.; Wu, Z.; Chapman, J. M.; Lehmann, J. L.; Kliewer, S. A.; Willson, T. M. A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARα agonist with potent lipid-lowering activity. J. Med. Chem. 1999, 42, 3785-3788.
72. Banner, C. D.; Götllicher, M.; Widmark, E.; Sjövall, J.; Rafter, J. J.; Gustafsson, J. A. A systematic analytical chemistry/cell assay approach to isolate activators of orphan nuclear receptors from biological extracts: characterization of peroxisome proliferator-activated receptor activators in plasma. J. Lipid Res. 1993, 34, 1583-1591.
73. Forman, B. M.; Chen, J.; Evans, R. M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 4312-4317.
74. Jüngling, E. J.; Kammermeier, H. A one-vial method for routine extraction and quantification of free fatty acids in blood and tissue by HPLC. Anal. Biochem. 1988, 171, 150-157.
75. Yu, K.; Bayona, W.; Kallne, C. B.; Harding, H. P.; Ravera, C. P.; McMahon, G.; Brown, M.; Lazar, M. A. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 1995, 270, 23975-23983.
76. 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.
77. Shepherd, J. Lipoprotein metabolism: an overview. Drugs 1994, 47, 1-10.
78. Malmendier, C. L.; Lontie, J.-F.; Delcroix, C.; Dubois, D. Y.; Magot, T.; Der, L. Apolipoproteins C-II and C-III metabolism in hypertriglyceridemic patients. Effect of a drastic triglyceride reduction by combined diet restriction and fenofibrate administration. Atherosclerosis 1989, 77, 139-149.
79. Staels, B.; Ngoc, V.-D.; Kosykh, V. A.; Saladin, R.; Fruchart, J.-C.; Dallongeville, J.; Auwerx, J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase: a potential mechanism for the hypolipidemic action of fibrates. J. Clin. Invest. 1995, 95, 705-712.
80. Hertz, R.; Bishara-Shieban, J.; Bar-Tana, J. Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J. Biol. Chem. 1995, 270, 13470-13475.
81. Palmer, C. N. A.; Hsu, M. H.; Muerhoff, A. S.; Griffin, K. J.; Johnson, E. F. Interaction of the peroxisome proliferator-activated receptor α with the retinoid X receptor α unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter. J. Biol. Chem. 1994, 269, 18083-18089.
82. Issemann, I.; Prince, R.; Tugwood, J.; Green, S. A role for fatty acids and liver fatty acid binding protein in peroxisome proliferation? Biochem. Soc. Trans. 1992, 20, 824-827.
83. Schoonjans, K.; Peinado-Onsurbe, J.; Lefebvre, A.-M.; Heyman, R. A.; Briggs, M.; Deeb, S.; Staels, B.; Auwerx, J. PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996, 15, 5336-5348.
84. Berthou, L.; Duverger, N.; Emmanuel, F.; Langouet, S.; Auwerx, J.; Guillouzo, A.; Fruchart, J.-C.; Rubin, E.; Denefle, P.; Staels, B.; Branellec, D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J. Clin. Invest. 1996, 97, 2408-2416.
85. Staels, B.; Auwerx, J. Regulation of apo A-I gene expression by fibrates. Atherosclerosis 1998, 137, s19-s23.
86. Vu-Dac, N.; Chopin-Delannoy, S.; Gervois, P.; Bonnelye, E.; Martin, G.; Fruchart, J.-C.; Laudet, V.; Staels, B. The nuclear receptors peroxisome proliferator-activated receptor α and Rev-erbα mediate the species-specific regulation of apolipoprotein A-I expression by fibrates. J. Biol. Chem. 1998, 273, 25713-25720.
87. Lee, S. S.-T.; Pineau, T.; Drago, J.; Lee, E. J.; Owens, J. W.; Kroetz, D. L.; Fernandez-Salguero, P. M.; Westphal, H.; Gonzalez, F. J. Targeted disruption of the a isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol. 1995, 15, 3012-3022.
88. Peters, J. M.; Hennuyer, N.; Staels, B.; Fruchart, J.-C.; Fievet, C.; Gonzalez, F. J.; Auwerx, J. Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor α-deficient mice. J. Biol. Chem. 1997, 272, 27307-27312.
89. Gaw, A.; Shepherd, J. Fibric acid derivatives. Lipoproteins Health Dis. 1999, 1145-1160.
90. Ross, S. D.; Allen, I. E.; Connelly, J. E.; Korenblat, B. M.; Smith, M. E.; Bishop, D.; Luo, D. Clinical outcomes in statin treatment trials: a meta-analysis. Arch. Intern. Med. 1999, 159, 1793-1802.
91. Grundy, S. M. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am. J. Cardiol. 1998, 81, 18B-25B.
92. Oliver, M. F.; Heady, J. A.; Morris, J. N.; Cooper, J. WHO cooperative trial on the primary prevention of ischemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984, 2, 600-604.
93. Ericsson, C. G.; Nilsson, J.; Grip, L.; Svane, B.; Hamsten, A. Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (the bezafibrate coronary atherosclerosis intervention trial [BECAIT]). Am. J. Cardiol. 1997, 80, 1125-1129.
94. Rutolo, G.; Ericsson, C.-G.; Tettamanti, C.; Karpe, F.; Grip, L.; Svane, B.; Nilsson, J.; De Faire, U.; Hamsten, A. Treatment effects on serum lipoprotein lipids, apolipoproteins and low-density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention trial (BECAIT). J. Am. Coll. Cardiol. 1998, 32, 1648-1656.
95. Rubins, H. B.; Robins, S. J.; Collins, D.; Fye, C. L.; Anderson, J. W.; Elam, M. B.; Faas, F. H.; Linares, E.; Schaefer, E. J.; Schectman, G.; Wilt, T. J.; Wittes, J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N. Engl. J. Med. 1999, 341, 410-418.
96. Libby, P.; Hansson, G. K.; Pober, J. S. Atherogenesis and inflammation. Mol. Basis Cardiovasc. Dis. 1999, 349-366.
97. Marx, N.; Sukhova, G. K.; Collins, T.; Libby, P.; Plutzky, J. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 1999, 99, 3125-3131.
98. Thurberg, B. L.; Collins, T. The nuclear factor-κB/inhibitor of κB autoregulatory system and atherosclerosis. Curr. Opin. Lipidol. 1998, 9, 387-396.
99. Spencer, N. F. L.; Poynter, M. E.; Im, S.-Y.; Daynes, R. A. Constitutive activation of NF-κB in an animal model of aging. Int. Immunol. 1997, 9, 1581-1588.
100. Poynter, M. E.; Daynes, R. A. Peroxisome proliferator-activated receptor α activation modulates cellular redox status, represses nuclear factor-κB signaling, and reduces inflammatory cytokine production in aging. J. Biol. Chem. 1998, 273, 32833-32841.
101. Kinlay, S.; Selwyn, A. P.; Libby, P.; Ganz, P. Inflammation, the endothelium, and the acute coronary syndromes. J. Cardiovasc. Pharmacol. 1998, 32, S62-S66.
102. Staels, B.; Koenig, W.; Habib, A.; Merval, R.; Lebret, M.; Torra, I. P.; Delerive, P.; Fadel, A.; Chinetti, G.; Fruchart, J.-C.; Najib, J.; Maclouf, J.; Tedgui, A. Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature 1998, 393, 790-793.
103. Delerive, P.; Bosscher, K. D.; Besnard, S.; Berghe, W. V.; Peters, J. M.; Gonzalez, F. J.; Fruchart, J.-C.; Tedgui, A.; Haegemann, G.; Staels, B. Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J. Biol. Chem. 1999, 45, 32048-32054.
104. 4 pathway to inflammation control. Nature 1996, 384, 39-43.
105. Alegret, M.; Ferrando, R.; Vazquez, M.; Adzet, T.; Merlos, M. C.; Laguna, J. C. Relationship between plasma lipids and palmitoyl-CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates. Br. J. Pharmacol. 1994, 112, 551-556.
106. Alegret, M.; Cerqueda, E.; Ferrando, R.; Vazquez, M.; Sanchez, R. M.; Adzet, T.; Merlos, M.; Laguna, J. C. Selective modification of rat hepatic microsomal fatty acid chain elongation and desaturation by fibrates: relationship with peroxisome proliferation. Br. J. Pharmacol. 1995, 114, 1351-1358.
107. Vazquez, M.; Munoz, S.; Alegret, M.; Adzet, T.; Merlos, M.; Laguna, J. C. Differential effects of fibrates on the acyl composition of microsomal phospholipids in rats. Br. J. Pharmacol. 1995, 116, 2067-2075.
108. Vazquez, M.; Merlos, M.; Adzet, T.; Laguna Juan, C. Decreased susceptibility to copper-induced oxidation of rat-lipoproteins after fibrate treatment: influence of fatty acid composition. Br. J. Pharmacol. 1996, 117, 1155-1162.
109. Gonzalez, F. J. Recent update on the PPARα-null mouse. Biochimie 1997, 79, 139-144.
110. Costet, P.; Legendre, C.; More, J.; Edgar, A.; Galtier, P.; Pineau, T. Peroxisome proliferator-activated receptor α-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J. Biol. Chem. 1998, 273, 29577-29585.
111. Torra, I. P.; Gervois, P.; Staels, B. Peroxisome proliferator-activated receptor α in metabolic disease, inflammation, atherosclerosis and aging. Curr. Opin. Lipidol. 1999, 10, 151-159.
112. Jacobsson, A.; Stadler, U.; Glotzer, M. A.; Kozak, L. P. Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression. J. Biol. Chem. 1985, 260, 16250-16254.
113. Cabrero, A.; Llaverias, G.; Roglans, N.; Alegret, M.; Sanchez, R.; Adzet, T.; Laguna, J. C.; Vazquez, M. Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats. Biochem. Biophys. Res. Commun. 1999, 260, 547-556.
114. Brun, S.; Carmona, M. C.; Mampel, T.; Vinas, O.; Giralt, M.; Iglesias, R.; Villarroya, F. Activators of peroxisome proliferator-activated receptor-α induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth. Diabetes 1999, 48, 1217-1222.
115. Krook, A.; Digby, J.; O'Rahilly, S.; Zierath, J. R.; Wallberg-Henriksson, H. Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients. Diabetes 1998, 47, 1528-1531.
116. Acin, A.; Rodriguez, M.; Rique, H.; Canet, E.; Boutin, J. A.; Galizzi, J.-P. Cloning and characterization of the 5′ flanking region of the human uncoupling protein 3 (UCP3) gene. Biochem. Biophys. Res. Commun. 1999, 258, 278-283.
117. Teruel, T.; Clapham, J. C.; Smith, S. A. PPARα activation by Wy 14643 induces transactivation of the rat UCP-1 promoter without increasing UCP-1 mRNA levels and attenuates PPARγ-mediated increases in UCP-1 mRNA levels induced by rosiglitazone in fetal rat brown adipocytes. Biochem. Biophys. Res. Commun. 1999, 264, 311-315.
118. Kobayashi, M.; Shigeta, Y.; Hirata, Y.; Omori, Y.; Sakamoto, N.; Nambu, S.; Baba, S. Improvement of glucose tolerance in NIDDM by clofibrate. Randomized double-blind study. Diabetes Care 1988, 11, 495-499.
119. Jones, I. R.; Swai, A.; Taylor, R.; Miller, M.; Laker, M. F.; Alberti, K. G. Lowering of plasma glucose concentrations with bezafibrate in patients with moderately controlled NIDDM. Diabetes Care 1990, 13, 855-863.
120. Inoue, I.; Takahashi, K.; Katayama, S.; Akabane, S.; Negishi, K.; Suzuki, M.; Ishii, J.; Kawazu, S. Improvement of glucose tolerance by bezafibrate in nonobese patients with hyperlipidemia and impaired glucose tolerance. Diabetes Res. Clin. Pract. 1994, 25, 199-205.
121. Ruyter, B.; Andersen, O.; Dehli, A.; Ostlund Farrants, A.-K.; Gjoen, T.; Thomassen, M. S. Peroxisome proliferator activated receptors in Atlantic salmon (Salmo salar): effects on PPAR transcription and acyl-CoA oxidase activity in hepatocytes by peroxisome proliferators and fatty acids. Biochim. Biophys. Acta 1997, 1348, 331-338.
122. Zhu, Y.; Alvares, K.; Huang, Q.; Rao, M. S.; Reddy, J. K. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J. Biol. Chem. 1993, 268, 26817-26820.
123. Aperlo, C.; Pognonec, P.; Saladin, R.; Auwerx, J.; Boulukos, K. E. cDNA cloning and characterization of the transcriptional activities of the hamster peroxisome proliferator-activated receptor haPPARγ. Gene 1995, 162, 297-302.
124. Houseknecht, K. L.; Bidwell, C. A.; Portocarrero, C. P.; Spurlock, M. E. Expression and cDNA cloning of porcine peroxisome proliferator-activated receptor γ (PPARγ). Gene 1998, 225, 89-96.
125. Hotta, K.; Gustafson, T. A.; Yoshioka, S.; Ortmeyer, H. K.; Bodkin, N. L.; Hansen, B. C. Relationships of PPARγ and PPARγ2 mRNA levels to obesity, diabetes and hyperinsulinemia in rhesus monkeys. Int. J. Obes. 1998, 22, 1000-1010.
126. Greene, M. E.; Blumberg, B.; McBride, O. W.; Yi, H. F.; Kronquist, K.; Kwan, K.; Hsieh, L.; Greene, G.; Nimer, S. D. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expression 1995, 4, 281-299.
127. Eibrecht, A.; Chen, Y.; Cullinan, C. A.; Hayes, N.; Leibowitz, M. D.; Moller, D. E.; Berger, J. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors γ1 and γ2. Biochem. Biophys. Res. Commun. 1996, 224, 431-437.
128. Lambe, K. G.; Tugwood, J. D. A human peroxisome-proliferator-activated receptor-γ is activated by inducers of adipogenesis, including thiazolidinedione drugs. Eur. J. Biochem. 1996, 239, 1-7.
129. Beamer, B. A.; Negri, C.; Yen, C.-J.; Gavrilova, O.; Rumberger, J. M.; Durcan, M. J.; Yarnall, D. P.; Hawkins, A. L.; Griffin, C. A.; Burns, D. K.; Roth, J.; Reitman, M.; Shuldiner, A. R. Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-γ (hPPARγ) gene. Biochem. Biophys. Res. Commun. 1997, 233, 756-759.
130. Fajas, L.; Auboeuf, D.; Raspe, E.; Schoonjans, K.; Lefebvre, A.-M.; Saladin, R.; Najib, J.; Laville, M.; Fruchart, J.-C.; Deeb, S.; Vidal-Puig, A.; Flier, J.; Briggs, M. R.; Staels, B.; Vidal, H.; Auwerx, J. The organization, promoter analysis, and expression of the human PPARγ gene. J. Bioi. Chem. 1997, 272, 18779-18789.
131. Mukherjee, R.; Jow, L.; Croston, G. E.; Paterniti, J. R., Jr. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists. J. Biol. Chem. 1997, 272, 8071-8076.
132. Fajas, L.; Fruchart, J.-C.; Auwerx, J. PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter. FEBS Lett. 1998, 438, 55-60.
133. 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 γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 7614-7619.
134. Chawla, A.; Schwarz, E. J.; Dimaculangan, D. D.; Lazar, M. A. Peroxisome proliferator-activated receptor (PPAR) γ: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 1994, 135, 798-800.
135. Tontonoz, P.; Hu, E.; Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 1994, 79, 1147-1156.
136. Tontonoz, P.; Hu, E.; Graves, R. A.; Budavari, A. I.; Spiegelman, B. M. mPPARγ2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994, 8, 1224-1234.
137. Saladin, R.; Fajas, L.; Dana, S.; Halvorsen, Y.-D.; Auwerx, J.; Briggs, M. Differential regulation of peroxisome proliferator activated receptor γ1 (PPARγ1) and PPARγ2 messenger RNA expression in the early stages of adipogenesis. Cell Growth Differ. 1999, 10, 43-48.
138. Werman, A.; Hollenberg, A.; Solanes, G.; Bjorbaek, C.; Vidal-Puig, A. J.; Flier, J. S. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor γ (PPARγ) Differential activity of PPARγ1 and - 2 isoforms and influence of insulin. J. Biol. Chem. 1997, 272, 20230-20235.
139. Fajas, L.; Fruchart, J.-C.; Auwerx, J. Transcriptional control of adipogenesis. Curr. Opin. Cell Biol. 1998, 10, 165-173.
140. Spiegelman, B. M.; Flier, J. S. Adipogenesis and obesity: rounding out the big picture. Cell 1996, 87, 377-389.
141. Tontonoz, P.; Hu, E.; Devine, J.; Beale, E. G.; Spiegelman, B. M. PPAR-γ2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol. Cell. Biol. 1995, 15, 351-357.
142. Schoonjans, K.; Watanabe, M.; Suzuki, H.; Mahfoudi, A.; Krey, G.; Wahli, W.; Grimaldi, P.; Staels, B.; Yamamoto, T.; Auwerx, J. Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J. Biol. Chem. 1995, 270, 19269-19276.
143. Martin, G.; Schoonjans, K.; Lefebvre, A.-M.; Staels, B.; Auwerx, J. Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARα and PPARγ activators. J. Biol. Chem. 1997, 272, 28210-28217.
144. Sfeir, Z.; Ibrahimi, A.; Amri, E.; Grimaldi, P.; Abumrad, N. Regulation of FAT/CD36 gene expression: further evidence in support of a role of the protein in fatty acid binding/transport. Prostaglandins Leukotrienes Essent. Fatty Acids 1997, 57, 17-21.
145. Kallen, C. B.; Lazar, M. A. Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 5793-5796.
146. De Vos, P.; Lefebvre, A.-M.; Miller, S. G.; Guerre-Millo, M.; Wong, K.; Saladin, R.; Hamann, L. G.; Staels, B.; Briggs, M. R.; Auwerx, J. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor γ. J. Clin. Invest. 1996, 98, 1004-1009.
147. Hofmann, C.; Lorenz, K.; Braithwaite, S. S.; Colca, J. R.; Palazuk, B. J.; Hotamisligil, G. S.; Spiegelman, B. M. Altered gene expression for tumor necrosis factor-α and its receptors during drug and dietary modulation of insulin resistance. Endocrinology 1994, 134, 264-270.
148. Aubert, J.; Champigny, O.; Saint-Marc, P.; Negrel, R.; Collins, S.; Ricquier, D.; Ailhaud, G. Up-regulation of UCP-2 gene expression by PPAR agonists in preadipose and adipose cells. Biochem. Biophys. Res. Commun. 1997, 238, 606-611.
149. Cambon, B.; Reyne, Y.; Nougues, J. In vitro induction of UCP1 mRNA in preadipocytes from rabbit considered as a model of large mammals brown adipose tissue development: importance of PPARγ agonists for cells isolated in the postnatal period. Mol. Cell. Endocrinol. 1998, 146, 49-58.
150. Camirand, A.; Marie, V.; Rabelo, R.; Silva, J. E. Thiazolidinediones stimulate uncoupling protein-2 expression in cell lines representing white and brown adipose tissues and skeletal muscle. Endocrinology 1998, 139, 428-431.
151. Sears, I. B.; MacGinnitie, M. A.; Kovacs, L. G.; Graves, R. A. Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor γ. Mol. Cell. Biol. 1996, 16, 3410-3419.
152. Tai, T.-A. C.; Jennermann, C.; Brown, K. K.; Oliver, B. B.; MacGinnitie, M. A.; Wilkison, W. O.; Brown, H. R.; Lehmann, J. M.; Kliewer, S. A.; Morris, D. C.; Graves, R. A. Activation of the nuclear receptor peroxisome proliferator-activated receptor γ promotes brown adipocyte differentiation. J. Biol. Chem. 1996, 277, 29909-29914.
153. Kelly, L. J.; Vicario, P. P.; Thompson, G. M.; Candelore, M. R.; Doebber, T. W.; Ventre, J.; Wu, M. S.; Meurer, R.; Forrest, M. J.; Conner, M. W.; Cascieri, M. A.; Moller, D. E. Peroxisome proliferator-activated receptors γ and α mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology 1998, 139, 4920-4927.
154. Ribon, V.; Johnson, J. H.; Camp, H. S.; Saltiel, A. R. Thiazolidinediones and insulin resistance: peroxisome proliferator-activated receptor γ activation stimulates expression of the CAP gene. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14751-14756.
155. Hulin, B.; McCarthy, P. A.; Gibbs, E. M. The glitazone family of antidiabetic agents. Curr. Pharm. Des. 1996, 2, 85-102.
156. Kletzien, R. F.; Clarke, S. D.; Ulrich, R. G. Enhancement of adipocyte differentiation by an insulin-sensitizing agent. Mol. Pharmacol. 1992, 41, 393-398.
157. Ibrahimi, A.; Teboul, L.; Gaillard, D.; Amri, E. Z.; Ailhaud, G.; Young, P.; Cawthorne, M. A.; Grimaldi, P. A. Evidence for a common mechanism of action for fatty acids and thiazolidinedione antidiabetic agents on gene expression in preadipose cells. Mol. Pharmacol. 1994, 46, 1070-1076.
158. Harris, P. K. W.; Kletzien, R. F. Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene. Mol. Pharmacol. 1994, 45, 439-445.
159. 2 is a ligand for the adipocyte determination factor PPARγ. Cell 1995, 83, 803-812.
160. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the anti-hyperglycemic activity of thiazolidinediones. J. Med. Chem. 1996, 39, 665-668.
161. 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-α (PPAR-α) and PPAR-γ: effect of PPAR-α activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 1998, 47, 1841-1847.
162. 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. Bioorg. Med. Chem. Lett. 1999, 9, 533-538.
163. Ide, T.; Murakami, K.; Tobe, K.; Mochizuki, T.; Ohashi, M.; Akanuma, Y.; Kadowaki, T.; Yazaki, Y. Effects of PPARα activation on liver lipid metabolism in Zucker fatty rats. Diabetes Front 1998, 9, 345-346.
164. Shibata, T.; Matsui, K.; Nagao, K.; Shinkai, H.; Yonemori, F.; Wakitani, K. Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative. Eur. J. Pharmacol. 1999, 364, 211-219.
165. Shinkai, H.; Onogi, S.; Tanaka, M.; Shibata, T.; Iwao, M.; Wakitani, K.; Uchida, I. Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents. J. Med. Chem. 1998, 41, 1927-1933.
166. Upton, R.; Widdowson, P. S.; Ishii, S.; Tanaka, H.; Williams, G. Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555. Br. J. Pharmacol. 1998, 125, 1708-1714.
167. Pickavance, L.; Widdowson, P. S.; King, P.; Ishii, S.; Tanaka, H.; Williams, G. The development of overt diabetes in young Zucker Diabetic Fatty (ZDF) rats and the effects of chronic MCC-555 treatment. Br. J. Pharmacol. 1998, 125, 767-770.
168. Reginato, M. J.; Bailey, S. T.; Krakow, S. L.; Minami, C.; Ishii, S.; Tanaka, H.; Lazar, M. A. A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor γ-activating properties. J. Biol. Chem. 1998, 273, 32679-32684.
169. Reddy, K. A.; Lohray, B. B.; Bhushan, V.; Reddy, A. S.; Rao Mamidi, N. V. S.; Reddy, P. P.; Saibaba, V.; Reddy, N. J.; Suryaprakash, A.; Misra, P.; Vikramadithyan, R. K.; Rajagopalan, R. Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives. J. Med. Chem. 1999, 42, 3265-3278.
170. Lohray, B. B.; Bhushan, V.; Reddy, A. S.; Rao, P. B.; Reddy, N. J.; Harikishore, P.; Haritha, N.; Vikramadityan, R. K.; Chakrabarti, R.; Rajagopalan, R.; Katneni, K. Novel euglycemic and hypolipidemic agents. 4. Pyridyl- and quinolinyl-containing thiazolidinediones. J. Med. Chem. 1999, 42, 2569-2581.
171. Sato, M.; Grese, T. A.; Dodge, J. A.; Bryant, H. U.; Turner, C. H. Emerging therapies for the prevention or treatment of postmenopausal osteoporosis. J. Med. Chem. 1999, 42, 1-24.
172. Sohda, T.; Mizuno, K.; Kawamatsu, Y. Studies on antidiabetic agents. VI. Asymmetric transformation of (±)-5-[4-(1-methylcyclohexylmethoxy)benzyl]-2,4- thiazolidinedione(ciglitazone) with optically active 1-phenylethylamines. Chem. Pharm. Bull. 1984, 32, 4460-4465.
173. Parks, D. J.; Tomkinson, N. C. O.; Villeneuve, M. S.; Blanchard, S. G.; Willson, T. M. Differential activity of rosiglitazone enantiomers at PPARγ. Bioorg. Med. Chem. Lett. 1998, 8, 3657-3658.
174. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith, D. G.; Smith, S. A. Non-thiazolidinedione antihyperglycemic agents. 1: α-Heteroatom substituted β-phenylpropanoic acids. Bioorg. Med. Chem. Lett. 1996, 6, 2121-2126.
175. Buckle, D. R.; Cantello, B. C. C.; Cawthorne, M. A.; Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley, R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Smith, D. G.; Smith, S. A. Non-thiazolidinedione antihyperglycemic agents. 2: α-Carbon substituted β-phenylpropanoic acids. Bioorg. Med. Chem. Lett. 1996, 6, 2127-2130.
176. Haigh, D.; Allen, G.; Birrell, H. C.; Buckle, D. R.; Cantello, B. C. C.; Eggleston, D. S.; Haltiwanger, R. C.; Holder, J. C.; Lister, C. A.; Pinto, I. L.; Rami, H. K.; Sime, J. T.; Smith, S. A.; Sweeney, J. D. Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of α-methoxy-β-phenylpropanoic acids. Bioorg. Med. Chem. 1999, 7, 821-830.
177. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W., Jr.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem. 1998, 41, 5020-5036.
178. Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-tyrosine PPARγ agonists, 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety. J. Med. Chem. 1998, 41, 5037-5054.
179. Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W., Jr.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W.-Q. N-2-Benzoylphenyl)-L-tyrosine PPARγ agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J. Med. Chem. 1998, 41, 5055-5069.
180. Brown, K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.; Harrington, W.; Novak, P. J.; Binz, J.; Hashim, M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.; Tong, T.; Menius, A.; Adkison, K. K., Noble, S. A.; Willson, T. M. A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes 1999, 48, 1415-1142.
181. Henke, B. R.; Adkison, K. K.; Blanchard, S. G.; Leesnitzer, L. M.; Robert A. Mook, J.; Kelli D. Plunket; Ray, J. A.; Roberson, C.; Unwalla, R.; Willson, T. M. Synthesis and biological activity of a novel series of indole-derived PPARγ agonists. Bioorg. Med. Chem. Lett. 1999, 9, 3329-3334.
182. Lehmann, J. M.; Lenhard, J. M.; Oliver, B. B.; Ringold, G. M.; Kliewer, S. A. Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other nonsteroidal antiinflammatory drugs. J. Biol. Chem. 1997, 272, 3406-3410.
183. Verrando, P.; Negrel, R.; Grimaldi, P.; Murphy, M.; Ailhaud, G. Differentiation of ob 17 preadipocytes to adipocytes. Triggering effects of clofenapate and indomethacin. Biochim. Biophys. Acta 1981, 663, 255-265.
184. Knight, D. M.; Chapman, A. B.; Navre, M.; Drinkwater, L.; Bruno, J. J.; Ringold, G. M. Requirements of triggering of adipocyte differentiation by glucocorticoids and indomethacin. Mol. Endocrinol. 1987, 1, 36-43.
185. Huang, J. T.; Welch, J. S.; Ricote, M.; Binder, C. J.; Willson, T. M.; Kelly, C.; Witztum, J. L.; Funk, C. D.; Conrad, D.; Glass, C. K. Interleukin-4-dependent production of PPAR-γ ligands in macrophages by 12/15-lipoxygenase. Nature 1999, 400, 378-382.
186. Nagy, L.; Tontonoz, P.; Alvarez, J. G. A.; Chen, H.; Evans, R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ. Cell 1998, 93, 229-240.
187. 2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 1995, 83, 813-819.
188. 2 and its metabolites promote neurite outgrowth induced by nerve growth factor in PC12 cells. Biochem. Biophys. Res. Commun. 1999, 258, 50-53.
189. 2. J. Lipid Mediators Cell Signalling 1995, 12, 443-448.
190. 2 and related compounds: an update. Prostaglandins Leukotrienes Essent. Fatty Acids 1992, 47, 1-12.
191. Narumiya, S.; Fukushima, M. Cyclopentenone prostaglandins: antiproliferative and antiviral actions and their molecular mechanism. Dev. Oncol. 1991, 67, 439-448.
192. Oberfield, J. L.; Collins, J. L.; Holmes, C. P.; Goreham, D. M.; Cooper, J. P.; Cobb, J. E.; Lenhard, J. M.; Hull-Ryde, E. A.; Mohr, C. P.; Blanchard, S. G.; Parks, D. J.; Moore, L. B.; Lehmann, J. M.; Plunket, K.; Miller, A. B.; Milburn, M. V.; Kliewer, S. A.; Willson, T. M. A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 6102-6106.
193. Weatherman, R. V.; Fletterick, R. J.; Scanlan, T. S. Nuclear-receptor ligands and ligand-binding domains. Annu. Rev. Biochem. 1999, 68, 559-581.
194. Spiegelman, B. M. PPAR-γ: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998, 47, 507-514.
195. Grossman, S. L.; Lessem, J. Mechanisms and clinical effects of thiazolidinediones. Expert Opin. Invest. Drugs 1997, 6, 1025-1040.
196. Chaiken, R. L.; Eckert-Norton, M.; Pasmantier, R.; Boden, G.; Ryan, I.; Gelfand, R. A.; Lebovitz, H. E. Metabolic effects of darglitazone, an insulin sensitizer, in NIDDM subjects. Diabetologia 1995, 38, 1307-1312.
197. Colca, J. R.; Morton, D. R. In New Antidiabetic Drugs; Bailey, C. J., Flatt, P. R., Eds.; Smith-Gordon: New York, 1990; pp 255-261.
198. Ikeda, H.; Taketomi, S.; Sugiyama, Y.; Shimura, Y.; Sohda, T.; Meguro, K.; Fujita, T. Effects of pioglitazone on glucose and lipid metabolism in normal and insulin resistant animals. Arzneim.-Forsch. 1990, 40, 156-162.
199. Horikoshi, H.; Yoshioka, T.; Kawasaki, T.; Nakamura, K.-I.; Matsunuma, N.; Yamaguchi, K.; Sasahara, K. Troglitazone (CS-045), a new antidiabetic drug. Annu. Rep. Sankyo Res. Lab. 1994, 46, 1-57.
200. Prigeon, R. L.; Kahn, S. E.; Porte, D., Jr. Effect of troglitazone on β cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 1998, 83, 819-823.
201. Fonseca, V. A.; Valiquett, T. R.; Huang, S. M.; Ghazzi, M. N.; Whitcomb, R. W. Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. J. Clin. Endocrinol. Metab. 1998, 83, 3169-3176.
202. Spencer, C. M.; Markham, A. Troglitazone. Drugs 1997, 54, 89-101.
203. Kumar, S.; Boulton, A. J. M.; Beck-Nielsen, H.; Berthezene, F.; Muggeo, M.; Persson, B.; Spinas, G. A.; Donoghue, S.; Lettis, S.; Stewart-Long, P. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 1996, 39, 701-709.
204. Ghazzi, M. N.; Perez, J. E.; Antonucci, T. K.; Driscoll, J. H.; Huang, S. M.; Faja, B. W.; Whitcomb, R. W. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997, 46, 433-439.
205. Wang, Q.; Dryden, S.; Frankish, H. M.; Bing, C.; Pickavance, L.; Hopkins, D.; Buckingham, R.; Williams, G. Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y. Br. J. Pharmacol. 1997, 122, 1405-1410.
206. Hallakou, S.; Doare, L.; Foufelle, F.; Kergoat, M.; Guerre-Millo, M.; Berthault, M.-F.; Dugail, I.; Morin, J.; Auwerx, J.; Ferre, P. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 1997, 46, 1393-1399.
207. Gimble, J. M.; Robinson, C. E.; Wu, X.; Kelly, K. A.; Rodriguez, B. R.; Kliewer, S. A.; Lehmann, J. M.; Morris, D. C. Peroxisome proliferator-activated receptor-γ activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol. Pharmacol. 1996, 50, 1087-1094.
208. Watkins, P. B.; Whitcomb, R. W. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med. 1998, 338, 916-917.
209. Jones, S. A.; Moore, L. B.; Shenk, J. L.; Wisely, G. B.; Hamilton, G. A.; McKee, D. D.; Tomkinson, N. C. O.; LeCluyse, E. L.; Lambert, M. H.; Willson, T. M.; Kliewer, S. A.; Moore, J. T. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 2000, 14, 27-39.
210. Kliewer, S. A.; Moore, J. T.; Wade, L.; Staudinger, J. L.; Watson, M. A.; Jones, S. A.; McKee, D. D.; Oliver, B. B.; Willson, T. M.; Zetterstrom, R. H.; Perlmann, T.; Lehmann, J. M. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998, 92, 73-82.
211. Lehmann, J. M.; McKee, D. D.; Watson, M. A.; Willson, T. M.; Moore, J. T.; Kliewer, S. A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 1998, 102, 1016-1023.
212. Bertilsson, G.; Heidrich, J.; Svensson, K.; Asman, M.; Jendeberg, L.; Sydow-Backman, M.; Ohlsson, R.; Postlind, H.; Blomquist, P.; Berkenstam, A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12208-12213.
213. Blumberg, B.; Sabbagh, W., Jr.; Juguilon, H.; Bolado, J., Jr.; Van Meter, C. M.; Ong, E. S.; Evans, R. M. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 1998, 12, 3195-3205.
214. Michalets, E. L. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998, 18, 84-112.
215. Ramachandran, V.; Kostrubsky, V. E.; Komoroski, B. J.; Zhang, S.; Dorko, K.; Esplen, J. E.; Strom, S. C.; Venkataramanan, R. Troglitazone increases cytochrome P-450 3A protein and activity in primary cultures of human hepatocytes. Drug Metab. Dispos. 1999, 27, 1194-1199.
216. Yamazaki, H.; Shibata, A.; Suzuki, M.; Nakajima, M.; Shimada, N.; Guengerich, F. P.; Yokoi, T. Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab. Dispos. 1999, 27, 1260-1266.
217. Pumford, N. R.; Halmes, N. C. Protein targets of xenobiotic reactive intermediates. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 91-117.
218. Mukherjee, R.; Davies, P. J. A.; Crombie, D. L.; Bischoff, E. D.; Cesario, R. M.; Jow, L.; Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R., Jr.; Heyman, R. A. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 1997, 386, 407-410.
219. Mukherjee, R.; Strasser, J.; Jow, L.; Hoener, P.; Paterniti, J. R., Jr; Heyman, R. A. RXR agonists activate PPARα-inducible genes, lower triglycerides, and raise HDL levels in vivo. Arterioscler. Thromb. Vase. Biol. 1998, 18, 272-276.
220. Miller, V. A.; Benedetti, F. M.; Rigas, J. R.; Verret, A. L.; Pfister, D. G.; Straus, D.; Kris, M. G.; Crisp, M.; Heyman, R.; Loewen, G. R.; Truglia, J. A.; Warrell, R. P., Jr. Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J. Clin. Oncol. 1997, 15, 790-795.
221. Sherman, S. I.; Gopal, J.; Haugen, B. R.; Chiu, A. C.; Whaley, K.; Nowlakha, P.; Duvic, M. Central hypothyroidism associated with retinoid X receptor-selective ligands. N. Engl. J. Med. 1999, 340, 1075-1079.
222. Rizvi, N. A.; Marshall, J. L.; Dahut, W.; Ness, E.; Truglia, J. A.; Loewen, G.; Gill, G. M.; Ulm, E. H.; Geiser, R.; Jaunakais, D.; Hawkins, M. J. A phase I study of LGD1069 in adults with advanced cancer. Clin. Cancer Res. 1999, 5, 1658-1664.
223. Burant, C. F.; Sreenan, S.; Hirano, K.-i.; Tai, T.-A. C.; Lohmiller, J.; Lukens, J.; Davidson, N. O.; Ross, S.; Graves, R. A. Troglitazone action is independent of adipose tissue. J. Clin. Invest. 1997, 100, 2900-2908.
224. Kruszynska, Y. T.; Mukherjee, R.; Jow, L.; Dana, S.; Paterniti, J. R., Jr.; Olefsky, J. M. Skeletal muscle peroxisome proliferator-activated receptor-γ expression in obesity and non-insulin-dependent diabetes mellitus. J. Clin. Invest. 1998, 101, 543-548.
225. Vidal-Puig, A. J.; Considine, R. V.; Jimenez-Linan, M.; Werman, A.; Pories, W. J.; Caro, J. F.; Flier, J. S. 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.
226. Park, K. S.; Ciaraldi, T. P.; Abrams-Carter, L.; Mudaliar, S.; Nikoulina, S. E.; Henry, R. R. PPAR-γ gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes 1997, 46, 1230-1234.
227. Wu, Z.; Xie, Y.; Morrison, R. F.; Bucher, N. L. R.; Farmer, S. R. PPARγ induces the insulin-dependent glucose transporter GLUT4 in the absence of C/EBPα during the conversion of 3T3 fibroblasts into adipocytes. J. Clin. Invest. 1998, 101, 22-32.
228. Young, P. W.; Cawthorne, M. A.; Coyle, P. J.; Holder, J. C.; Holman, G. D.; Kozka, I. J.; Kirkham, D. M.; Lister, C. A.; Smith, S. A. Repeat treatment of obese mice with BRL 49653, a new and potent insulin sensitizer, enhances insulin action in white adipocytes. Association with increased insulin binding and cell-surface GLUT4 as measured by photoaffinity labeling. Diabetes 1995, 44, 1087-1092.
229. Fleury, C.; Neverova, M.; Collins, S.; Raimbault, S.; Champigny, O.; Levi-Meyrueis, C.; Bouillaud, F.; Seldin, M. F.; Surwit, R. S.; Ricquier, D.; Warden, C. H. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 1997, 15, 269-272.
230. Randle, P. J. Regulatory interactions between lipids and carbohydrates: the Glucose Fatty Acid Cycle after 35 years. Diabetes/ Metab. Rev. 1998, 14, 263-283.
231. Martin, G.; Schoonjans, K.; Staels, B.; Auwerx, J. PPARγ activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes. Atherosclerosis 1998, 137, S75-S80.
232. Sreenan, S.; Keck, S.; Fuller, T.; Cockburn, B.; Burant, C. F. Effects of troglitazone on substrate storage and utilization in insulin-resistant rats. Am. J. Physiol 1999, 276, E1119-E1129.
233. Tontonoz, P.; Nagy, L.; Alvarez, J. G. A.; Thomazy, V. A.; Evans, R. M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998, 93, 241-252.
234. Aitman, T. J.; Glazier, A. M.; Wallace, C. A.; Cooper, L. D.; Norsworthy, P. J.; Wahid, F. N.; Al-Majali, K. M.; Trembling, P. M.; Mann, C. J.; Shoulders, C. C.; Graf, D.; Lezin, E. S.; Kurtz, T. W.; Kren, V.; Pravenec, M.; Ibrahimi, A.; Abumrad, N. A.; Stanton, L. W.; Scott, J. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nat. Genet. 1999, 21, 76-83.
235. Hallakou, S.; Foufelle, F.; Doare, L.; Kergoat, M.; Ferre, P. Pioglitazone-induced increase of insulin sensitivity in the muscles of the obese Zucker fa/fa rat cannot be explained by local adipocyte differentiation. Diabetologia 1998, 41, 963-968.
236. Okuno, A.; Tamemoto, H.; Tobe, K.; Ueki, K.; Mori, Y.; Iwamoto, K.; Umesono, K.; Akanuma, Y.; Fujiwara, T.; Horikoshi, H.; Yazaki, Y.; Kadowaki, T. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J. Clin. Invest. 1998, 101, 1354-1361.
237. Hotamisligil, G. S.; Peraldi, P.; Spiegelman, B. M. The molecular link between obesity and diabetes. Curr. Opin. Endocrinol. Diabetes 1996, 3, 16-23.
238. Peraldi, P.; Xu, M.; Spiegelman, B. M. Thiazolidinediones block tumor necrosis factor-α-induced inhibition of insulin signaling. J. Clin. Invest. 1997, 100, 1863-1869.
239. Miles, P. D. G.; Romeo, O. M.; Higo, K.; Cohen, A.; Rafaat, K.; Olefsky, J. M. TNF-α-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes 1997, 46, 1678-1683.
240. Rebrin, K.; Steil, G. M.; Mittelman, S. D.; Bergman, R. N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Invest. 1996, 98, 741-749.
241. Rebrin, K.; Steil, G. M.; Getty, L.; Bergman, R. N. Free fatty acid as a link to the regulation of hepatic glucose output by peripheral insulin. Diabetes 1995, 44, 1038-1045.
242. Digby, J. E.; Montague, C. T.; Sewter, C. P.; Sanders, L.; Wilkison, W. O.; O'Rahilly, S.; Prins, J. B. Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. Diabetes 1998, 47, 138-141.
243. Ristow, M.; Muller-Wieland, D.; Pfeiffer, A.; Krone, W.; Kahn, C. R. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N. Engl. J. Med. 1998, 339, 953-959.
244. Meirhaeghe, A.; Fajas, L.; Helbecque, N.; Cottel, D.; Lebel, P.; Dallongeville, J.; Deeb, S.; Auwerx, J.; Amouyell, P. A genetic polymorphism of the peroxisome proliferator-activated receptor γ gene influences plasma leptin levels in obese humans. Hum. Mol. Genet. 1998, 7, 435-440.
245. 12Ala PPARγ2 missense mutation. Biochem. Biophys. Res. Commun. 1997, 241, 270-274.
246. 12-Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat. Genet. 1998, 20, 284-287.
247. Valve, R.; Sivenius, K.; Miettinen, R.; Pihlajamaki, J.; Rissanen, A.; Deeb, S. S.; Auwerx, J.; Uusitupa, M.; Laakso, M. Two polymorphisms in the peroxisome proliferator-activated receptor-γ gene are associated with severe overweight among obese women. J. Clin. Endocrinol Metab. 1999, 84, 3708-3712.
248. 12Ala variant of the human peroxisome proliferator-activated receptor γ2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem. Biophys. Res. Commun. 1998, 251, 195-198.
249. 12Ala variant in the peroxisome proliferator-activated receptor-γ2 gene with obesity in two Caucasian populations. Diabetes 1998, 47, 1806-1808.
250. 12Ala variant of the peroxisome proliferation-activated receptor-γ2 (PPAR-γ2). Divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia 1999, 42, 892-895.
251. Koch, M.; Rett, K.; Maerker, E.; Volk, A.; Haist, K.; Deninger, M.; Renn, W.; Haring, H. U. The PPARγ2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects. Diabetologia 1999, 42, 758-762.
252. 12Ala missense mutation of the peroxisome proliferator activated receptor γ and diabetes mellitus. Biochem. Biophys. Res. Commun. 1999, 254, 450-453.
253. Hamann, A.; Munzberg, H.; Buttron, P.; Busing, B.; Hinney, A.; Mayer, H.; Siegfried, W.; Hebebrand, J.; Greten, H. Missense variants in the human peroxisome proliferator-activated receptor-γ2 gene in lean and obese subjects. Eur. J. Endocrinol. 1999, 141, 90-92.
254. Barak, Y.; Nelson, M. C.; Ong, E. S.; Jones, Y. Z.; Ruiz-Lozano, P.; Chien, K. R.; Koder, A.; Evans, R. M. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 1999, 4, 585-595.
255. Kubota, N.; Terauchi, Y.; Miki, H.; Tamemoto, H.; Yamauchi, T.; Komeda, K.; Satoh, S.; Nakano, R.; Ishii, C.; Sugiyama, T.; Eto, K.; Tsubamoto, Y.; Okuno, A.; Murakami, K.; Sekihara, H.; Hasegawa, G.; Naito, M.; Toyoshima, Y.; Tanaka, S.; Shiota, K.; Kitamura, T.; Fujita, T.; Ezaki, O.; Aizawa, S.; Nagai, R.; Tobe, K.; Kimura, S.; Kadowaki, T. PPARγ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol. Cell 1999, 4, 597-609.
256. Rosen, E. D.; Sarraf, P.; Troy, A. E.; Bradwin, G.; Moore, K.; Milstone, D. S.; Spiegelman, B. M.; Mortensen, R. M. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 1999, 4, 611-617.
257. Chen, D.; Garg, A. Monogenic disorders of obesity and body fat distribution. J. Lipid Res. 1999, 40, 1735-1746.
258. Girard, J. Is leptin the link between obesity and insulin resistance? Diabetes Metab. 1997, 23, 16-24.
259. Lowell, B. B. PPARγ: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999, 99, 239-242.
260. Rezulin prescribing information at http://www.parke-davis.com/ REZULIN.pdf.
261. Avandia prescribing information at http://www.avandia.com/ index.asp.
262. Actos prescribing information at http://www.actos.com/pi.htm.
263. McKeigue, P.; Berne, C.; Lithell, H. Insulin and hypertension. Handb. Hypertens. 1997, 17, 911-934.
264. Dubey, R. K.; Zhang, H. Y.; Reddy, S. R.; Boegehold, M. A.; Kotchen, T. A. Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats. Am. J. Physiol. 1993, 265, R726-R732.
265. Walker, A. B.; Chattington, P. D.; Buckingham, R. E.; Williams, G. The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 1999, 48, 1448-1453.
266. Yoshioka, S.; Nishino, H.; Shiraki, T.; Ikeda, K.; Koibe, H.; Okuno, A.; Wada, M.; Fujiwara, T.; Horikoshi, H. Antihypertensive effects of CS-045 treatment in obese Zucker rats. Metab. Clin. Exp. 1993, 42, 75-80.
267. Pershadsingh, H. A.; Szollosi, J.; Benson, S.; Hyun, W. C.; Feuerstein, B. G.; Kurtz, T. W. Effects of ciglitazone on blood pressure and intracellular calcium metabolism. Hypertension 1993, 21, 1020-1023.
268. Saku, K.; Zhang, B.; Ohta, T.; Arakawa, K. Troglitazone lowers blood pressure and enhances insulin sensitivity in Watanabe heritable hyperlipidemic rabbits. Am. J. Hypertens. 1997, 10, 1027-1033.
269. Kemnitz, J. W.; Elson, D. F.; Roecker, E. B.; Baum, S. T.; Bergman, R. N.; Meglasson, M. D. Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure in obese, insulin resistant rhesus monkeys. Diabetes 1994, 43, 204-211.
270. Zhang, H. Y.; Reddy, S. R.; Kotchen, T. A. Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity. Hypertension 1994, 24, 106-110.
271. Kotchen, T. A. Attenuation of hypertension by insulin-sensitizing agents. Hypertension 1996, 28, 219-223.
272. Morikang, E.; Benson, S. C.; Kurtz, T. W.; Pershadsingh, H. A. Effects of thiazolidinediones on growth and differentiation of human aorta and coronary myocytes. Am. J. Hypertens. 1997, 10, 440-446.
273. Law, R. E.; Meehan, W. P.; Xi, X.-P.; Graf, K.; Wuthrich, D. A.; Coats, W.; Faxon, D.; Hsueh, W. A. Troglitazone inhibits vascular smooth muscle cell growth and intimai hyperplasia. J. Clin. Invest. 1996, 98, 1897-1905.
274. Yoshimoto, T.; Naruse, M.; Shizume, H.; Naruse, K.; Tanabe, A.; Tanaka, M.; Tago, K.; Irie, K.; Muraki, T.; Demura, H.; Zardi, L. Vasculo-protective effects of insulin sensitizing agent pioglitazone in neointimal thickening and hypertensive vascular hypertrophy. Atherosclerosis 1999, 145, 333-340.
275. Graf, K.; Xi, X.-P.; Hsueh, W. A.; Law, R. E. Troglitazone inhibits angiotensin II-induced DNA synthesis and migration in vascular smooth muscle cells. FEBS Lett. 1997, 400, 119-121.
276. Force, T.; Bonventre, J. V. Growth factors and mitogen-activated protein kinases. Hypertension 1998, 31, 152-161.
277. Kotchen, T. A.; Zhang, H. Y.; Reddy, S.; Hoffmann, R. G. Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am. J. Physiol. 1996, 270, R660-R666.
278. Itoh, H.; Doi, K.; Tanaka, T.; Fukunaga, Y.; Hosoda, K.; Inoue, G.; Nishimura, H.; Yoshimasa, Y.; Yamori, Y.; Nakao, K. Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor γ. Clin. Exp. Pharmacol. Physiol. 1999, 26, 558-560.
279. Satoh, H.; Tsukamoto, K.; Hashimoto, Y.; Hashimoto, N.; Togo, M.; Hara, M.; Maekawa, H.; Isoo, N.; Kimura, S.; Watanabe, T. Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARγ on vascular endothelial function. Biochem. Biophys. Res. Commun. 1999, 254, 757-763.
280. Kato, K.; Satoh, H.; Endo, Y.; Yamada, D.; Midorikawa, S.; Sato, W.; Mizuno, K.; Fujita, T.; Tsukamoto, K.; Watanabe, T. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPARγ in endothelial function. Biochem. Biophys. Res. Commun. 1999, 258, 431-435.
281. Fonseca, V. A.; Reynolds, T.; Hemphill, D.; Randolph, C.; Wall, J.; Valiquet, T. R.; Graveline, J.; Fink, L. M. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J. Diabetes Complications 1998, 12, 181-186.
282. Zhang, F.; Sowers, J. R.; Ram, J. L.; Standley, P. R.; Peuler, J. D.
283. Knock, G. A.; Mishra, S. K.; Aaronson, P. I. Differential effects of insulin-sensitizers troglitazone and rosiglitazone on ion currents in rat vascular myocytes. Eur. J. Pharmacol. 1999, 368, 103-109.
284. Souza, S. C.; Yamamoto, M. T.; Franciosa, M. D.; Lien, P.; Greenberg, A. S. BRL 49653 blocks the lipolytic actions of tumor necrosis factor-α: A potential new insulin-sensitizing mechanism for thiazolidinediones. Diabetes 1998, 47, 691-695.
285. Chinetti, G.; Griglio, S.; Antonucci, M.; Torra, I. P.; Delerive, P.; Majd, Z.; Fruchart, J.-C.; Chapman, J.; Najib, J.; Staels, B. Activation of proliferator-activated receptors α and γ induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 1998, 273, 25573-25580.
286. Marx, N.; Sukhova, G.; Murphy, C.; Libby, P.; Plutzky, J. Macrophages in human atheroma contain PPARγ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPARγ) expression and reduction of MMP-9 activity through PPARγ activation in mononuclear phagocytes in vitro. Am. J. Pathol. 1998, 153, 17-23.
287. Ricote, M.; Li, A. C.; Willson, T. M.; Kelly, C. J.; Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 1998, 391, 79-82.
288. Jiang, C.; Ting, A. T.; Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 1998, 391, 82-86.
289. Su, C. G.; Wen, X.; Bailey, S. T.; Jiang, W.; Rangwala, S. M.; Keilbaugh, S. A.; Flanigan, A.; Murthy, S.; Lazar, M. A.; Wu, G. D. A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J. Clin. Invest. 1999, 104, 383-389.
290. Steinberg, D. Low-density lipoprotein oxidation and its pathobiological significance. J. Biol. Chem. 1997, 272, 20963-20966.
291. Spiegelman, B. M. PPARγ in monocytes: less pain, any gain? Cell 1998, 93, 153-155.
292. Ehrmann, D. A.; Schneider, D. J.; Sobel, B. E.; Cavaghan, M. K.; Imperial, J.; Rosenfield, R. L.; Polonsky, K. S. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 1997, 82, 2108-2116.
293. Minamikawa, J.; Tanaka, S.; Yamauchi, M.; Inoue, D.; Koshiyama, H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J. Clin. Endocrinol. Metab. 1998, 83, 1818-1820.
294. Altiok, S.; Xu, M.; Spiegelman, M. PPARγ induces cell cycle withdrawal: inhibition of E2F/DP DNA-binding activity via down-regulation of PP2A. Genes Dev. 1997, 11, 1987-1998.
295. Tontonoz, P.; Singer, S.; Forman, B. M.; Sarraf, P.; Fletcher, J. A.; Fletcher, C. D. M.; Brun, R. P.; Mueller, E.; Altiok, S.; Oppenheim, H.; Evans, R. M.; Spiegelman, B. M. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 237-241.
296. Demetri, G. D.; Fletcher, C. D. M.; Mueller, E.; Sarraf, P.; Naujoks, R.; Campbell, N.; Spiegelman, B. M.; Singer, S. Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 3951-3956.
297. Mueller, E.; Sarraf, P.; Tontonoz, P.; Evans, R. M.; Martin, K. J.; Zhang, M.; Fletcher, C.; Singer, S.; Spiegelman, B. M. Terminal differentiation of human breast cancer through PPARγ. Mol. Cell 1998, 1, 465-470.
298. Elstner, E.; Muller, C.; Koshizuka, K.; Williamson, E. A.; Park, D.; Asou, H.; Shintaku, P.; Said, J. W.; Heber, D.; Koeffler, H. P. Ligands for peroxisome proliferator-activated receptor γ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8806-8811.
299. Suh, N.; Wang, Y.; Williams, C. R.; Risingaong, R.; Gilmer, T.; Willson, T. M.; Sporn, M. B. A new ligand for the peroxisome proliferator activated receptor-γ (PPAR-γ), GW7845, inhibits rat mammary carcinogenesis. Cancer Res. 1999, 59, 5671-5673.
300. Gimble, J. M.; Pighetti, G. M.; Lerner, M. R.; Wu, X.; Lightfoot, S. A.; Brackett, D. J.; Darcy, K.; Hollingsworth, A. B. Expression of peroxisome proliferator activated receptor mRNA in normal and tumorigenic rodent mammary glands. Biochem. Biophys. Res. Commun. 1998, 253, 813-817.
301. Sarraf, P.; Mueller, E.; Jones, D.; King, F. J.; DeAngelo, D. J.; Partridge, J. B.; Holden, S. A.; Chen, L. B.; Singer, S.; Fletcher, C.; Spiegelman, B. M. Differentiation and reversal of malignant changes in colon cancer through PPARγ. Nat. Med. 1998, 4, 1046-1052.
302. Brockman, J. A.; Gupta, R. A.; DuBois, R. N. Activation of PPARγ leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology 1998, 115, 1049-1055.
303. Sarraf, P.; Mueller, E.; Smith, W. M.; Wright, H. M.; Kum, J. B.; Aaltonen, L. A.; De la Chapelle, A.; Spiegelman, B. M.; Eng, C. Loss-of-function mutations in PPARγ associated with human colon cancer. Mol. Cell 1999, 3, 799-804.
304. Min/+ mice. Nat. Med. 1998, 4, 1053-1057.
305. Saez, E.; Tontonoz, P.; Nelson, M. C.; Alvarez, J. G. A.; U, T. M.; Baird, S. M.; Thomazy, V. A.; Evans, R. M. Activators of the nuclear receptor PPARγ enhance colon polyp formation. Nat. Med. 1998, 4, 1058-1061.
306. Schmidt, A.; Endo, N.; Rutledge, S. J.; Vogel, R.; Shinar, D.; Rodan, G. A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol. Endocrinol. 1992, 6, 1634-1641.
307. Chen, F.; Law, S. W.; O'Malley, B. W. Identification of two mPPAR related receptors and evidence for the existence of five subfamily members. Biochem. Biophys. Res. Commun. 1993, 196, 671-677.
308. Amri, E.-Z.; Bonino, F.; Ailhaud, G.; Abumrad, N. A.; Grimaldi, P. A. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J. Biol. Chem. 1995, 270, 2367-2371.
309. Johnson, T. E.; Holloway, M. K.; Vogel, R.; Rutledge, S. J.; Perkins, J. J.; Rodan, G. A.; Schmidt, A. Structural requirements and cell-type specificity for ligand activation of peroxisome proliferator-activated receptors. J. Steroid Biochem. Mol. Biol. 1997, 63, 1-8.
310. Brooks, C. D. W.; Summers, J. B. Modulators of leukotriene biosynthesis and receptor activation. J. Med. Chem. 1996, 39, 2629-2654.
311. Schmidt, A.; Vogel, R. L.; Witherup, K. M.; Rutledge, S. J.; Pitzenberger, S. M.; Adam, M.; Rodan, G. A. Identification of fatty acid methyl ester as naturally occurring transcriptional regulators of the members of the peroxisome proliferator-activated receptor family. Lipids 1996, 31, 1115-1124.
312. Bastie, C.; Holst, D.; Gaillard, D.; Jehl-Pietri, C.; Grimaldi, P. A. Expression of peroxisome proliferator-activated receptor PPARδ promotes induction of PPARγ and adipocyte differentiation in 3T3C2 fibroblasts. J. Biol. Chem. 1999, 274, 21920-21925.
313. Brun, R. P.; Tontonoz, P.; Forman, B. M.; Ellis, R.; Chen, J.; Evans, R. M.; Spiegelman, B. M. Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 1996, 10, 974-984.
314. Lim, H.; Gupta, R. A.; Ma, W.-G.; Paria, B. C.; Moller, D. E.; Morrow, J. D.; DuBois, R. N.; Trzaskos, J. M.; Dey, S. K. Cyclooxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ. Genes Dev. 1999, 13, 1561-1574.
315. He, T.-C.; Chan, T. A.; Vogelstein, B.; Kinzler, K. W. PPARδ is an APC-regulated target of nonsteroidal antiinflammatory drugs. Cell 1999, 99, 335-345.
316. Auwerx, J. Regulation of gene expression by fatty acids and fibric acid derivatives: An integrative role for peroxisome proliferator activated receptors. Harm. Res. 1992, 38, 269-277.
317. Desvergne, B.; Ijpenberg, A.; Devchand, P. R.; Wahli, W. The peroxisome proliferator-activated receptors at the crossroad of diet and hormonal signaling. J. Steroid Biochem. Mol. Biol. 1998, 65, 65-74.
318. Cobb, J.; Dukes, I. Recent advances in the development of agents for the treatment of type 2 diabetes. Annu. Rep. Med. Chem. 1998, 33, 213-222.
319. Sliskovic, D. R.; Krause, B. R.; Bocan, T. M. A. Atherosclerosis: emerging pharmacological approaches. Annu. Rep. Med. Chem. 1999, 34, 101-110.
320. Glaxo Wellcome development pipeline at http://www.glaxowellcome.com/pipeline.htm.
321. Grundy, S. M. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am. J. Cardiol. 1999, 83, 25F-29F.
322. Ziboh, V. A. The significance of polyunsaturated fatty acids in cutaneous biology. Lipids 1996, 31, S249-S253.
323. Belch, J. J. F.; Muir, A. n-6 and n-3 essential fatty acids in rheumatoid arthritis and other rheumatic conditions. Proc. Nutr. Soc. 1998, 57, 563-569.
324. Kolonel, L. N.; Nomura, A. M. Y.; Cooney, R. V. Dietary fat and prostate cancer: current status. J. Natl. Cancer Inst. 1999, 91, 414-428.
325. Woutersen, R. A.; Appel, M. J.; Van Garderen-Hoetmer, A.; Wijnands, M. V. W. Dietary fat and carcinogenesis. Mutat. Res. 1999, 443, 111-127.
326. DeRisi, J. L.; Iyer, V. R.; Brown, P. O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 1997, 278, 680-686.