Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

  1. Bart Staels and
  2. Jean-Charles Fruchart
  1. Department of Atherosclerosis, INSERM (Institut National de la Santé et de la Recherche Médicale) Unit 545, Institut Pasteur and Université de Lille, Lille, France
  1. Address correspondence and reprint requests to Prof. Bart Staels, Unité INSERM 545-Institut Pasteur, 1, rue du Professeur Calmette, 59019 Lille Cedex, France. E-mail: bart.staels{at}pasteur-lille.fr

Abstract

Peroxisome proliferator–activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARα and -γ are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARα. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPARγ, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARγ agonists are therefore used to treat type 2 diabetes. PPARα and -γ agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARα/γ agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPARδ, and its potential as a therapeutic target are currently under investigation.

Footnotes

  • J.-C.F. and B.S. have received educational sponsorships from AstraZeneca.

    apo, apolipoprotein; CHD, coronary heart disease; CRP, C-reactive protein; CVD, cardiovascular disease; FFA, free fatty acid; FPG, fasting plasma glucose; IL, interleukin; MI, myocardial infarction; PAI-1, plasminogen activator inhibitor type-1; PPAR, peroxisome proliferator–activated receptor; RXR, retinoid-X receptor; SENDCAP, St. Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention; TNF-α, tumor necrosis factor-α; TRIPOD, Troglitazone in the Prevention of Diabetes; VA-HIT, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 5, 2005.
    • Received January 27, 2005.
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