Copyright © 2008 Ambra Pozzi and Jorge H. Capdevila. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

1. S. Kersten, B. Desvergne, and W. Wahli, “Roles of PPARS in health and disease,” Nature, vol. 405, no. 6785, pp. 421–424, 2000. View at Publisher · View at Google Scholar · View at PubMed
2. S. A. Kliewer, K. Umesono, D. J. Noonan, R. A. Heyman, and R. M. Evans, “Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors,” Nature, vol. 358, no. 6389, pp. 771–774, 1992. View at Publisher · View at Google Scholar · View at PubMed
3. A. Aranda and A. Pascual, “Nuclear hormone receptors and gene expression,” Physiological Reviews, vol. 81, no. 3, pp. 1269–1304, 2001.
4. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at Publisher · View at Google Scholar
5. R. K. Semple, V. K. K. Chatterjee, and S. O'Rahilly, “PPAR$\gamma$ and human metabolic disease,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 581–589, 2006. View at Publisher · View at Google Scholar · View at PubMed
6. P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPAR$\gamma$2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994. View at Publisher · View at Google Scholar
7. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-$\gamma$ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar · View at PubMed
8. N. Kubota, Y. Terauchi, H. Miki, et al., “PPAR$\gamma$ mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance,” Molecular Cell, vol. 4, no. 4, pp. 597–609, 1999. View at Publisher · View at Google Scholar
9. S. Schwartz, P. Raskin, V. Fonseca, and J. F. Graveline, “Effect of troglitazone in insulin-treated patients with type II diabetes mellitus,” The New England Journal of Medicine, vol. 338, no. 13, pp. 861–866, 1998. View at Publisher · View at Google Scholar
10. S. A. Kliewer, B. M. Forman, B. Blumberg, et al., “Differential expression and activation of a family of murine peroxisome proliferator-activated receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 15, pp. 7355–7359, 1994. View at Publisher · View at Google Scholar
11. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-$\alpha$, -$\beta$, and -$\gamma$ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at Publisher · View at Google Scholar
12. G. Rizzo and S. Fiorucci, “PPARs and other nuclear receptors in inflammation,” Current Opinion in Pharmacology, vol. 6, no. 4, pp. 421–427, 2006. View at Publisher · View at Google Scholar · View at PubMed
13. R. M. Touyz and E. L. Schiffrin, “Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications,” Vascular Pharmacology, vol. 45, no. 1, pp. 19–28, 2006. View at Publisher · View at Google Scholar · View at PubMed
14. S. Z. Duan, M. G. Usher, and R. M. Mortensen, “Peroxisome proliferator-activated receptor-$\gamma$-mediated effects in the vasculature,” Circulation Research, vol. 102, no. 3, pp. 283–294, 2008. View at Publisher · View at Google Scholar · View at PubMed
15. S. Theocharis, A. Margeli, P. Vielh, and G. Kouraklis, “Peroxisome proliferator-activated receptor-$\gamma$ ligands as cell-cycle modulators,” Cancer Treatment Reviews, vol. 30, no. 6, pp. 545–554, 2004. View at Publisher · View at Google Scholar · View at PubMed
16. R. A. Roberts, S. Chevalier, S. C. Hasmall, N. H. James, S. C. Cosulich, and N. Macdonald, “PPAR$\alpha$ and the regulation of cell division and apoptosis,” Toxicology, vol. 181-182, pp. 167–170, 2002. View at Publisher · View at Google Scholar
17. C. Giaginis, A. Tsantili-Kakoulidou, and S. Theocharis, “Peroxisome proliferator-activated receptor-$\gamma$ ligands: potential pharmacological agents for targeting the angiogenesis signaling cascade in cancer,” PPAR Research, vol. 2008, Article ID 431763, 12 pages, 2008. View at Publisher · View at Google Scholar · View at PubMed
18. Y. Yasui, M. Kim, and T. Tanaka, “PPAR ligands for cancer chemoprevention,” PPAR Research, vol. 2008, Article ID 548919, 10 pages, 2008. View at Publisher · View at Google Scholar · View at PubMed
19. L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004. View at Publisher · View at Google Scholar · View at PubMed
20. J.-S. Annicotte, I. Iankova, S. Miard, et al., “Peroxisome proliferator-activated receptor $\gamma$ regulates E-cadherin expression and inhibits growth and invasion of prostate cancer,” Molecular and Cellular Biology, vol. 26, no. 20, pp. 7561–7574, 2006. View at Publisher · View at Google Scholar · View at PubMed
21. M. Li, T. W. Lee, A. P. C. Yim, T. S. K. Mok, and G. G. Chen, “Apoptosis induced by troglitazone is both peroxisome proliterator-activated receptor-$\gamma$- and ERK-dependent in human non-small lung cancer cells,” Journal of Cellular Physiology, vol. 209, no. 2, pp. 428–438, 2006. View at Publisher · View at Google Scholar · View at PubMed
22. X. Xin, S. Yang, J. Kowalski, and M. E. Gerritsen, “Peroxisome proliferator-activated receptor $\gamma$ ligands are potent inhibitors of angiogenesis in vitro and in vivo,” Journal of Biological Chemistry, vol. 274, no. 13, pp. 9116–9121, 1999. View at Publisher · View at Google Scholar
23. M. Meissner, M. Stein, C. Urbich, et al., “PPAR$\alpha$ activators inhibit vascular endothelial growth factor receptor-2 expression by repressing Sp1-dependent DNA binding and transactivation,” Circulation Research, vol. 94, no. 3, pp. 324–332, 2004. View at Publisher · View at Google Scholar · View at PubMed
24. S. Goetze, F. Eilers, A. Bungenstock, et al., “PPAR activators inhibit endothelial cell migration by targeting Akt,” Biochemical and Biophysical Research Communications, vol. 293, no. 5, pp. 1431–1437, 2002. View at Publisher · View at Google Scholar · View at PubMed
25. J. Varet, L. Vincent, P. Mirshahi, et al., “Fenofibrate inhibits angiogenesis in vitro and in vivo,” Cellular and Molecular Life Sciences, vol. 60, no. 4, pp. 810–819, 2003. View at Publisher · View at Google Scholar
26. C. Blanquart, O. Barbier, J. C. Fruchart, B. Staels, and C. Glineur, “Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 85, no. 2–5, pp. 267–273, 2003. View at Publisher · View at Google Scholar
27. N. Niho, M. Takahashi, T. Kitamura, et al., “Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands,” Cancer Research, vol. 63, no. 18, pp. 6090–6095, 2003.
28. C. A. McAlpine, Y. Barak, I. Matise, and R. T. Cormier, “Intestinal-specific PPAR$\gamma$ deficiency enhances tumorigenesis in ${\text{Apc}}^{\text{Min/+}}$ mice,” International Journal of Cancer, vol. 119, no. 10, pp. 2339–2346, 2006. View at Publisher · View at Google Scholar · View at PubMed
29. A.-M. Lefebvre, I. Chen, P. Desreumaux, et al., “Activation of the peroxisome proliferator-activated receptor $\gamma$ promotes the development of colon tumors in C57BL/6J-${\text{Apc}}^{Min}/+$ mice,” Nature Medicine, vol. 4, no. 9, pp. 1053–1057, 1998. View at Publisher · View at Google Scholar · View at PubMed
30. Y. Guan, C. Hao, D. R. Cha, et al., “Thiazolidinediones expand body fluid volume through PPAR$\gamma$ stimulation of ENaC-mediated renal salt absorption,” Nature Medicine, vol. 11, no. 8, pp. 861–866, 2005. View at Publisher · View at Google Scholar · View at PubMed
31. D. Wang, H. Wang, Y. Guo, et al., “Crosstalk between peroxisome proliferator-activated receptor $\delta$ and VEGF stimulates cancer progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 50, pp. 19069–19074, 2006. View at Publisher · View at Google Scholar · View at PubMed
32. H. E. Marin, M. A. Peraza, A. N. Billin, et al., “Ligand activation of peroxisome proliferator-activated receptor $\beta$ inhibits colon carcinogenesis,” Cancer Research, vol. 66, no. 8, pp. 4394–4401, 2006. View at Publisher · View at Google Scholar · View at PubMed
33. F. J. Gonzalez and Y. M. Shah, “PPAR$\alpha$: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators,” Toxicology, vol. 246, no. 1, pp. 2–8, 2008. View at Publisher · View at Google Scholar · View at PubMed
34. J. M. Peters, C. Cheung, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor-$\alpha$ and liver cancer: where do we stand?,” Journal of Molecular Medicine, vol. 83, no. 10, pp. 774–785, 2005. View at Publisher · View at Google Scholar · View at PubMed
35. J. C. Corton, P. J. Lapinskas, and F. J. Gonzalez, “Central role of PPAR$\alpha$ in the mechanism of action of hepatocarcinogenic peroxisome proliferators,” Mutation Research, vol. 448, no. 2, pp. 139–151, 2000. View at Publisher · View at Google Scholar
36. A. D. Blann, F. M. Belgore, J. Constans, C. Conri, and G. Y. H. Lip, “Plasma vascular endothelial growth factor and its receptor Flt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate,” The American Journal of Cardiology, vol. 87, no. 10, pp. 1160–1163, 2001. View at Publisher · View at Google Scholar
37. F. Biscetti, E. Gaetani, A. Flex, et al., “Selective activation of peroxisome proliferator-activated receptor (PPAR)$\alpha$ and PPAR$\gamma$ induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism,” Diabetes, vol. 57, no. 5, pp. 1394–1404, 2008. View at Publisher · View at Google Scholar · View at PubMed
38. A. Pozzi, M. R. Ibanez, A. E. Gatica, et al., “Peroxisomal proliferator-activated receptor-$\alpha$-dependent inhibition of endothelial cell proliferation and tumorigenesis,” Journal of Biological Chemistry, vol. 282, no. 24, pp. 17685–17695, 2007. View at Publisher · View at Google Scholar · View at PubMed
39. A. Pozzi, I. Macias-Perez, T. Abair, et al., “Characterization of 5,6- and 8,9-epoxyeicosatrienoic acids (5,6- and 8,9-EET) as potent in vivo angiogenic lipids,” Journal of Biological Chemistry, vol. 280, no. 29, pp. 27138–27146, 2005. View at Publisher · View at Google Scholar · View at PubMed
40. U. R. Michaelis and I. Fleming, “From endothelium-derived hyperpolarizing factor (EDHF) to angiogenesis: epoxyeicosatrienoic acids (EETs) and cell signaling,” Pharmacology & Therapeutics, vol. 111, no. 3, pp. 584–595, 2006. View at Publisher · View at Google Scholar · View at PubMed
41. I. Fleming, “Epoxyeicosatrienoic acids, cell signaling and angiogenesis,” Prostaglandins & Other Lipid Mediators, vol. 82, no. 1–4, pp. 60–67, 2007. View at Publisher · View at Google Scholar · View at PubMed
42. J. H. Capdevila, J. R. Falck, and R. C. Harris, “Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase,” Journal of Lipid Research, vol. 41, no. 2, pp. 163–181, 2000.
43. J. H. Capdevila, J. R. Falck, E. Dishman, and A. Karara, “Cytochrome P-450 arachidonate oxygenase,” Methods in Enzymology, vol. 187, pp. 385–394, 1990. View at Publisher · View at Google Scholar
44. M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming, “Cytochrome P450 2C9-induced endothelial cell proliferation involves induction of mitogen-activated protein (MAP) kinase phosphatase-1, inhibition of the c-Jun N-terminal kinase, and up-regulation of cyclin D1,” Journal of Biological Chemistry, vol. 277, no. 18, pp. 15671–15676, 2002. View at Publisher · View at Google Scholar · View at PubMed
45. M. Potente, B. Fisslthaler, R. Busse, and I. Fleming, “11,12-epoxyeicosatrienoic acid-induced inhibition of FOXO factors promotes endothelial proliferation by down-regulating ${\text{p27}}^{\mathrm{Kip1}}$,” Journal of Biological Chemistry, vol. 278, no. 32, pp. 29619–29625, 2003. View at Publisher · View at Google Scholar · View at PubMed
46. U. R. Michaelis, J. R. Falck, R. Schmidt, R. Busse, and I. Fleming, “Cytochrome P4502C9-derived epoxyeicosatrienoic acids induce the expression of cyclooxygenase-2 in endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 2, pp. 321–326, 2005. View at Publisher · View at Google Scholar · View at PubMed
47. U. R. Michaelis, B. Fisslthaler, M. Medhora, D. Harder, I. Fleming, and R. Busse, “Cytochrome P450 2C9-derived epoxyeicosatrienoic acids induce angiogenesis via cross-talk with the epidermal growth factor receptor (EGFR),” The FASEB Journal, vol. 17, no. 6, pp. 770–772, 2003. View at Publisher · View at Google Scholar · View at PubMed
48. D. Panigrahy, A. Kaipainen, S. Huang, et al., “PPAR$\alpha$ agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 3, pp. 985–990, 2008. View at Publisher · View at Google Scholar · View at PubMed
49. Y. Yokoyama, B. Xin, T. Shigeto, et al., “Clofibric acid, a peroxisome proliferator-activated receptor $\alpha$ ligand, inhibits growth of human ovarian cancer,” Molecular Cancer Therapeutics, vol. 6, no. 4, pp. 1379–1386, 2007. View at Publisher · View at Google Scholar · View at PubMed
50. L. Jackson, W. Wahli, L. Michalik, et al., “Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer,” Gut, vol. 52, no. 9, pp. 1317–1322, 2003. View at Publisher · View at Google Scholar
51. N. Niho, M. Mutoh, M. Takahashi, K. Tsutsumi, T. Sugimura, and K. Wakabayashi, “Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2970–2974, 2005. View at Publisher · View at Google Scholar · View at PubMed
52. Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor $\alpha$ regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation,” Molecular and Cellular Biology, vol. 27, no. 12, pp. 4238–4247, 2007. View at Publisher · View at Google Scholar · View at PubMed
53. K. Morimura, C. Cheung, J. M. Ward, J. K. Reddy, and F. J. Gonzalez, “Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor $\alpha$ to Wy-14,643-induced liver tumorigenesis,” Carcinogenesis, vol. 27, no. 5, pp. 1074–1080, 2006. View at Publisher · View at Google Scholar · View at PubMed
54. Q. Yang, T. Nagano, Y. Shah, C. Cheung, S. Ito, and F. J. Gonzalez, “The PPAR$\alpha$-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR$\alpha$,” Toxicological Sciences, vol. 101, no. 1, pp. 132–139, 2008. View at Publisher · View at Google Scholar · View at PubMed
55. Y. Ito, O. Yamanoshita, N. Asaeda, et al., “Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor $\alpha$-independent pathway,” Journal of Occupational Health, vol. 49, no. 3, pp. 172–182, 2007. View at Publisher · View at Google Scholar
56. F. Gizard, C. Amant, O. Barbier, et al., “PPAR$\alpha$ inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor ${\text{p16}}^{\text{INK4a}}$,” The Journal of Clinical Investigation, vol. 115, no. 11, pp. 3228–3238, 2005. View at Publisher · View at Google Scholar · View at PubMed
57. A. Kaipainen, M. W. Kieran, S. Huang, et al., “PPAR$\alpha$ deficiency in inflammatory cells suppresses tumor growth,” PLoS ONE, vol. 2, no. 2, p. e260, 2007. View at Publisher · View at Google Scholar · View at PubMed
58. P. Howroyd, C. Swanson, C. Dunn, R. C. Cattley, and J. C. Corton, “Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$),” Toxicologic Pathology, vol. 32, no. 5, pp. 591–599, 2004. View at Publisher · View at Google Scholar
59. G. P. Collett, A. M. Betts, M. I. Johnson, et al., “Peroxisome proliferator-activated receptor $\alpha$ is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma,” Clinical Cancer Research, vol. 6, no. 8, pp. 3241–3248, 2000.
60. K. M. Suchanek, F. J. May, J. A. Robinson, et al., “Peroxisome proliferator-activated receptor $\alpha$ in the human breast cancer cell lines MCF-7 and MDA-MB-231,” Molecular Carcinogenesis, vol. 34, no. 4, pp. 165–171, 2002. View at Publisher · View at Google Scholar · View at PubMed
61. K. M. Suchanek, F. J. May, W. J. Lee, N. A. Holman, and S. J. Roberts-Thomson, “Peroxisome proliferator-activated receptor $\beta$ expression in human breast epithelial cell lines of tumorigenic and non-tumorigenic origin,” The International Journal of Biochemistry & Cell Biology, vol. 34, no. 9, pp. 1051–1058, 2002. View at Publisher · View at Google Scholar
62. T. Tanaka, H. Kohno, S.-I. Yoshitani, et al., “Ligands for peroxisome proliferator-activated receptors $\alpha$ and $\gamma$ inhibit chemically induced colitis and formation of aberrant crypt foci in rats,” Cancer Research, vol. 61, no. 6, pp. 2424–2428, 2001.
63. G. Muzio, M. Maggiora, M. Oraldi, A. Trombetta, and R. A. Canuto, “PPAR$\alpha$ and PP2A are involved in the proapoptotic effect of conjugated linoleic acid on human hepatoma cell line SK-HEP-1,” International Journal of Cancer, vol. 121, no. 11, pp. 2395–2401, 2007. View at Publisher · View at Google Scholar · View at PubMed
64. M. Maggiora, M. Bologna, M. P. Cerù, et al., “An overview of the effect of linoleic and conjugated-linoleic acids on the growth of several human tumor cell lines,” International Journal of Cancer, vol. 112, no. 6, pp. 909–919, 2004. View at Publisher · View at Google Scholar · View at PubMed
65. S. A. Saidi, C. M. Holland, D. S. Charnock-Jones, and S. K. Smith, “In vitro and in vivo effects of the PPAR-alpha agonists fenofibrate and retinoic acid in endometrial cancer,” Molecular Cancer, vol. 5, article 13, 2006. View at Publisher · View at Google Scholar · View at PubMed
66. P. Thuillier, G. J. Anchiraico, K. P. Nickel, et al., “Activators of peroxisome proliferator-activated receptor-$\alpha$ partially inhibit mouse skin tumor promotion,” Molecular Carcinogenesis, vol. 29, no. 3, pp. 134–142, 2000. View at Publisher · View at Google Scholar
67. M. Grabacka, P. M. Plonka, K. Urbanska, and K. Reiss, “Peroxisome proliferator-activated receptor $\alpha$ activation decreases metastatic potential of melanoma cells in vitro via down-regulation of Akt,” Clinical Cancer Research, vol. 12, no. 10, pp. 3028–3036, 2006. View at Publisher · View at Google Scholar · View at PubMed
68. M. Grabacka, W. Placha, P. M. Plonka, et al., “Inhibition of melanoma metastases by fenofibrate,” Archives of Dermatological Research, vol. 296, no. 2, pp. 54–58, 2004. View at Publisher · View at Google Scholar · View at PubMed
69. T. Hays, I. Rusyn, A. M. Burns, et al., “Role of peroxisome proliferator-activated receptor-$\alpha$ (PPAR$\alpha$) in bezafibrate-induced hepatocarcinogenesis and cholestasis,” Carcinogenesis, vol. 26, no. 1, pp. 219–227, 2005. View at Publisher · View at Google Scholar · View at PubMed
70. F. J. Gonzalez, “The peroxisome proliferator-activated receptor $\alpha$ (PPAR$\alpha$): role in hepatocarcinogenesis,” Molecular and Cellular Endocrinology, vol. 193, no. 1-2, pp. 71–79, 2002. View at Publisher · View at Google Scholar
71. K. Takashima, Y. Ito, F. J. Gonzalez, and T. Nakajima, “Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Ppar$\alpha$-null mice,” Journal of Occupational Health, vol. 50, no. 2, pp. 169–180, 2008. View at Publisher · View at Google Scholar
72. H. B. Rubins, S. J. Robins, D. Collins, et al., “Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol,” The New England Journal of Medicine, vol. 341, no. 6, pp. 410–418, 1999. View at Publisher · View at Google Scholar · View at PubMed
73. M. H. Frick, O. Elo, K. Haapa, et al., “Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease,” The New England Journal of Medicine, vol. 317, no. 20, pp. 1237–1245, 1987.