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Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 145–156 (2007)Cite this article

Abstract

Intensive preclinical investigations have delineated a role for peroxisome proliferator-activated receptors (PPARs) in energy metabolism and inflammation. PPARs are activated by natural lipophilic ligands such as fatty acids and their derivatives. Normalization of lipid and glucose metabolism is achieved via pharmacological modulation of PPAR activity. PPARs may also alter atherosclerosis progression through direct effects on the vascular wall. PPARs regulate genes involved in the recruitment of leukocytes to endothelial cells, in vascular inflammation, in macrophage lipid homeostasis, and in thrombosis. PPARs therefore modulate metabolic and inflammatory perturbations that predispose to cardiovascular diseases and type 2 diabetes. The hypolipidemic fibrates and the antidiabetic thiazolidinediones are drugs that act via PPARα and PPARγ, respectively, and are used in clinical practice. PPARβ/δ ligands are currently in clinical evaluation. The pleiotropic actions of PPARs and the fact that chemically diverse PPAR agonists may induce distinct pharmacological responses have led to the emergence of new concepts for drug design. A more precise understanding of the molecular pathways implicated in the response to chemically distinct PPAR agonists should provide new opportunities for targeted therapeutic applications in the management of the metabolic syndrome, type 2 diabetes, and cardiovascular diseases.

Key Points

  • Peroxisome proliferator-activated receptors (PPARs) are major regulators of energy homeostasis and inflammation control

  • PPARs are modulators of cardiovascular disease risk

  • PPARs are pharmacological targets for treatment of the metabolic syndrome, diabetes, and atherosclerosis

  • Greater knowledge of the functions of PPARs in health and disease has led to new concepts of drug design

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Figure 1: Mechanisms of PPAR signaling.
Figure 2: PPARα in lipid and lipoprotein metabolism.
Figure 3: PPARγ improves insulin sensitivity by controlling the metabolic and the endocrine functions of adipose tissue.
Figure 4: Selective modulation of PPAR activity.
Figure 5: Scheme summarizing the pleiotropic actions of the three PPAR isotypes and the benefits on atherogenesis.

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  1. P Gervois is Professor of Biochemistry and Molecular Biology, J-C Fruchart is Professor of Biochemistry, and B Staels is Professor of Cell Biology at the Université de Lille 2. All authors are also Research Directors at INSERM U 545, Institut Pasteur de Lille, Université de Lille 2, Lille, France.

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  1. INSERM U 545, Institut Pasteur de Lille, 1 rue du Professeur Calmette, Lille, F-59019, France

    Philippe Gervois

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  1. Philippe Gervois
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Correspondence to Philippe Gervois.

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Gervois, P., Fruchart, JC. & Staels, B. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Rev Endocrinol 3, 145–156 (2007). https://doi.org/10.1038/ncpendmet0397

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