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PPAR Research / 2008 / Article
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Peroxisome Proliferator-Activated Receptor δ, A Target with a Broad Therapeutic Potential for Drug Discovery

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Volume 2008 |Article ID 736362 | https://doi.org/10.1155/2008/736362

Francine M. Gregoire, "Peroxisome Proliferator-Activated Receptor : A Target with a Broad Therapeutic Potential for Drug Discovery", PPAR Research, vol. 2008, Article ID 736362, 2 pages, 2008. https://doi.org/10.1155/2008/736362

Peroxisome Proliferator-Activated Receptor : A Target with a Broad Therapeutic Potential for Drug Discovery

Received30 Dec 2008
Accepted30 Dec 2008
Published07 Apr 2009

The biology of Peroxisome proliferator-activated receptor (PPAR) alpha (α) and gamma (γ) has been intensely scrutinized for the last 20 years and the clinical use of both PPAR-α (fibrates) and PPAR-γ (thiazolididiones) agonists has led to the understanding of their key role in the treatment of hypertriglyceridemia and type 2 diabetes mellitus [1, 2]. In contrast, the understanding of PPAR delta (δ) biology still lags behind. The identification of small molecule agonists for PPAR-δ has shed some light on the function of this ubiquitously expressed receptor in preclinical models and early clinical studies [3]. They have revealed the multiple benefits of PPAR-δ activation on lipid disorders, diabetes, and inflammation [3, 4]. However, synthetic PPAR-δ agonists have yet to be marketed for clinical use in humans, partly due to the burden associated with their clinical development [3].

In this special issue of PPAR Research, the broad potential of PPAR-δ agonists for the treatment of metabolic disease is highlighted by 3 key articles. They include a review from de Lange et al. on the regulation of the oxidative capacity of muscle by PPAR-δ, an article by Perreault et al. which tackles opportunities and issues with the development of PPAR-δ agonist for the treatment of obesity, and finally a review from Wang that addresses the effect of PPAR-δ activation on vascular pathophysiological processes. A key question regarding the result of PPAR-δ activation, either via natural or via synthetic ligands, is its effect on cell proliferation and the risk of inducing cancer. This has been an area of intense debate as both pro- and antitumorigenic effects have been reported. This topic is concisely reviewed in this issue by Muller et al. Last but not least, two interesting and not well-characterized portions of PPAR-δ biology are presented. First, as PPAR-δ is expressed at high level in the brain, Hall et al. investigate the potential neuroprotective role of PPAR-δ activation in this organ. Second, although the role of PPAR-δ in embryo implantation was recognized early on with studies in knockout mice [5], the reproductive functions of PPAR-δ are still unclear. This topic and the projected potential applications of PPAR-δ ligands in assisted reproductive technology are addressed in Huang’s review.

Taken together, it is obvious that there is an urgent need for additional basic research to better characterize PPAR-δ function. The current availability of synthetic ligands should help to further dissect PPAR-δ-mediated responses in the brain as well as in other functions not addressed in this issue, including gut and skin homesotasis. Although challenges for the development of PPAR-δ agonists remains, they clearly hold great therapeutic promise, as highlighted by recent clinical findings indicating that MBX-8025, one of the most advanced PPAR-δ agonists currently in phase II clinical trial for dyslipidemia, displays hypolipidemic features not observed with the currently available dyslipidemia therapies [6, 7].

Francine M. Gregoire


  1. R. S. Loomba and R. Arora, “Fibrates: where are we now?,” Therapeutic Advances in Cardiovascular Disease, vol. 3, no. 1, pp. 91–96, 2009. View at: Publisher Site | Google Scholar
  2. F. Chiarelli and D. Di Marzio, “Peroxisome proliferator-activated receptor-γ agonists and diabetes: current evidence and future perspectives,” Vascular Health and Risk Management, vol. 4, no. 2, pp. 297–304, 2008. View at: Google Scholar
  3. A. N. Billin, “PPAR-β/δ agonists for type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home,” Expert Opinion on Investigational Drugs, vol. 17, no. 10, pp. 1465–1471, 2008. View at: Publisher Site | Google Scholar
  4. K. S. Kilgore and A. N. Billin, “PPARβ/δ ligands as modulators of the inflammatory response,” Current Opinion in Investigational Drugs, vol. 9, no. 5, pp. 463–469, 2008. View at: Google Scholar
  5. H. Lim, R. A. Gupta, W.-G. Ma et al., “Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARδ,” Genes & Development, vol. 13, no. 12, pp. 1561–1574, 1999. View at: Google Scholar
  6. A. Tesse, R. Andriantsitohaina, and T. Ragot, “PPARδ activity in cardiovascular diseases: a potential pharmacological target,” PPAR Research, vol. 2009, Article ID 745821, 9 pages, 2009. View at: Publisher Site | Google Scholar
  7. P. A. Rittenhouse, “Dyslipidemia rescue,” BioCentury, The Bernstein Report on BioBusiness, pp. A12–A13, 2008. View at: Google Scholar

Copyright © 2008 Francine M. Gregoire. 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.

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