PPAR Research

PPAR Research / 2006 / Article

Research Article | Open Access

Volume 2006 |Article ID 69612 | 9 pages | https://doi.org/10.1155/PPAR/2006/69612

Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-α (PPARα)

Received28 Dec 2005
Revised30 Mar 2006
Accepted25 Apr 2006
Published27 Jun 2006


The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-α (PPARα) was examined. PPAR-binding protein (PBP), PPARγ coactivator-1α (PGC-1α), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPARα activity in the presence of Wy-14,643. The effects on PPARα activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1α, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1α. The interaction of PPARα with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPARα occurs predominantly via the carboxyl-terminus and mutating 456LHPLL to 456LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPARα is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely.


  1. C Dreyer, G Krey, H Keller, F Givel, G Helftenbein, and W Wahli, “Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992. View at: Google Scholar
  2. R A Roberts, N H James, N J Woodyatt, N Macdonald, and J D Tugwood, “Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPARα),” Carcinogenesis, vol. 19, no. 1, pp. 43–48, 1998. View at: Google Scholar
  3. N H James, J H Gill, R Brindle et al., “Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis,” Toxicology Letters, vol. 102-103, pp. 91–96, 1998. View at: Google Scholar
  4. M J Olson, “DNA strand breaks induced by hydrogen peroxide in isolated rat hepatocytes,” Journal of Toxicology and Environmental Health, vol. 23, no. 3, pp. 407–423, 1988. View at: Google Scholar
  5. J K Reddy and M S Rao, “Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis,” Mutation Research, vol. 214, no. 1, pp. 63–68, 1989. View at: Google Scholar
  6. Y Yu, P H Correll, and J P Vanden Heuvel, “Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPARγ-dependent mechanism,” Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, vol. 1581, no. 3, pp. 89–99, 2002. View at: Google Scholar
  7. V H Coulthard, S Matsuda, and D M Heery, “An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220,” Journal of Biological Chemistry, vol. 278, no. 13, pp. 10942–10951, 2003. View at: Google Scholar
  8. D M Heery, S Hoare, S Hussain, M G Parker, and H Sheppard, “Core LXXLL motif sequences in CREB-binding protein, SRC1, and RIP140 define affinity and selectivity for steroid and retinoid receptors,” Journal of Biological Chemistry, vol. 276, no. 9, pp. 6695–6702, 2001. View at: Google Scholar
  9. R B Lanz, N J McKenna, S A Onate et al., “A steroid receptor coactivator, SRA, functions as an RNA and is present in an SRC-1 complex,” Cell, vol. 97, no. 1, pp. 17–27, 1999. View at: Google Scholar
  10. J Bragança, T Swingler, F IR Marques et al., “Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2,” Journal of Biological Chemistry, vol. 277, no. 10, pp. 8559–8565, 2002. View at: Google Scholar
  11. R T Nolte, G B Wisely, S Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-γ,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at: Google Scholar
  12. J Uppenberg, C Svensson, M Jaki, G Bertilsson, L Jendeberg, and A Berkenstam, “Crystal structure of the ligand binding domain of the human nuclear receptor PPARγ,” Journal of Biological Chemistry, vol. 273, no. 47, pp. 31108–31112, 1998. View at: Google Scholar
  13. J K Reddy, “Carcinogenicity of peroxisome proliferators: evaluation and mechanisms,” Biochemical Society Transactions, vol. 18, no. 1, pp. 92–94, 1990. View at: Google Scholar
  14. C E Connor, J D Norris, G Broadwater et al., “Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor,” Cancer Research, vol. 61, no. 7, pp. 2917–2922, 2001. View at: Google Scholar
  15. P Dowell, V J Peterson, T M Zabriskie, and M Leid, “Ligand-induced peroxisome proliferator-activated receptor α conformational change,” Journal of Biological Chemistry, vol. 272, no. 3, pp. 2013–2020, 1997. View at: Google Scholar
  16. W K Sumanasekera, E S Tien, J W Davis, II, R Turpey, G H Perdew, and J P Vanden Heuvel, “Heat shock protein-90 (Hsp90) acts as a repressor of peroxisome proliferator-activated receptor-α (PPARα) and PPARβ activity,” Biochemistry, vol. 42, no. 36, pp. 10726–10735, 2003. View at: Google Scholar
  17. J D Tugwood, P R Holden, N H James, R A Prince, and R A Roberts, “A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: implications for species differences in responses to peroxisome proliferators,” Archives of Toxicology, vol. 72, no. 3, pp. 169–177, 1998. View at: Google Scholar
  18. C-Y Chang, J D Norris, H Grøn et al., “Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors α and β,” Molecular and Cellular Biology, vol. 19, no. 12, pp. 8226–8239, 1999. View at: Google Scholar
  19. E S Tien, J W Davis, and J P Vanden Heuvel, “Identification of the CREB-binding protein/p300-interacting protein CITED2 as a peroxisome proliferator-activated receptor α coregulator,” Journal of Biological Chemistry, vol. 279, no. 23, pp. 24053–24063, 2004. View at: Google Scholar
  20. Y Kodera, K-I Takeyama, A Murayama, M Suzawa, Y Masuhiro, and S Kato, “Ligand type-specific interactions of peroxisome proliferator-activated receptor γ with transcriptional coactivators,” Journal of Biological Chemistry, vol. 275, no. 43, pp. 33201–33204, 2000. View at: Google Scholar
  21. J Xu, Y Qiu, F J DeMayo, S Y Tsai, M-J Tsai, and B W O'Malley, “Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene,” Science, vol. 279, no. 5358, pp. 1922–1925, 1998. View at: Google Scholar
  22. J D Graham, D L Bain, J K Richer, T A Jackson, L Tung, and K B Horwitz, “Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer,” Steroids, vol. 65, no. 10-11, pp. 579–584, 2000. View at: Google Scholar
  23. M Xu, K J Modarress, J EW Meeker, and S S Jr Simons, “Steroid-induced conformational changes of rat glucocorticoid receptor cause altered trypsin cleavage of the putative helix 6 in the ligand binding domain,” Molecular and Cellular Endocrinology, vol. 155, no. 1-2, pp. 85–100, 1999. View at: Google Scholar
  24. R K Sharma, B G Lake, R Makowski et al., “Differential induction of peroxisomal and microsomal fatty-acid-oxidising enzymes by peroxisome proliferators in rat liver and kidney. Characterisation of a renal cytochrome P-450 and implications for peroxisome proliferation,” European Journal of Biochemistry, vol. 184, no. 1, pp. 69–78, 1989. View at: Google Scholar
  25. S Haubenwallner, A D Essenburg, B C Barnett et al., “Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action,” Journal of Lipid Research, vol. 36, no. 12, pp. 2541–2551, 1995. View at: Google Scholar
  26. T Takahashi, T Hirano, K Okada, and M Adachi, “Clinical and Experimental: apolipoprotein CIII deficiency prevents the development of hypertriglyceridemia in streptozotocin-induced diabetic mice,” Metabolism, vol. 52, no. 10, pp. 1354–1359, 2003. View at: Google Scholar
  27. C Karagianni, S Stabouli, K Roumeliotou et al., “Severe hypertriglyceridaemia in diabetic ketoacidosis: clinical and genetic study,” Diabetic Medicine, vol. 21, no. 4, pp. 380–382, 2004. View at: Google Scholar
  28. H Miyamoto, M Rahman, H Takatera et al., “A dominant-negative mutant of androgen receptor coregulator ARA54 inhibits androgen receptor-mediated prostate cancer growth,” Journal of Biological Chemistry, vol. 277, no. 7, pp. 4609–4617, 2002. View at: Google Scholar
  29. Y Wang and R J Miksicek, “Identification of a dominant negative form of the human estrogen receptor,” Molecular Endocrinology, vol. 5, no. 11, pp. 1707–1715, 1991. View at: Google Scholar
  30. J J Palvimo, P J Kallio, T Ikonen, M Mehto, and O A Janne, “Dominant negative regulation of trans-activation by the rat androgen receptor: roles of the N-terminal domain and heterodimer formation,” Molecular Endocrinology, vol. 7, no. 11, pp. 1399–1407, 1993. View at: Google Scholar
  31. W Seol, H-S Choi, and D D Moore, “An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors,” Science, vol. 272, no. 5266, pp. 1336–1339, 1996. View at: Google Scholar

Copyright © 2006 Eric S. Tien et al. 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.

0 Views | 0 Downloads | 0 Citations
 PDF  Download Citation  Citation
 Order printed copiesOrder
 Sign up for content alertsSign up