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Endocrinology, doi:10.1210/en.2007-1339
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Endocrinology Vol. 149, No. 6 3215-3223
Copyright © 2008 by The Endocrine Society

Systemic and Distal Repercussions of Liver-Specific Peroxisome Proliferator-Activated Receptor-{alpha} Control of the Acute-Phase Response

Roxane M. Mansouri, Eric Baugé, Bart Staels and Philippe Gervois

Institut Pasteur de Lille (R.M,M., E.B., B.S., P.G.), Département d'Athérosclérose, and Institut National de la Santé et de la Recherche Médicale Unité 545, Lille F59019, France; and Faculté des Sciences Pharmaceutiques et Biologiques (R.M.M., B.S., P.G.), Université de Lille 2, Lille F-59006, France

Address all correspondence and requests for reprints to: Philippe Gervois, Laboratoire de biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, 3, rue du professeur Laguesse, BP83, Lille F-59006, France. E-mail: philippe.gervois{at}univ-lille2.fr.

The acute-phase response is characterized by the modulation of liver expression of many proteins involved in a diversity of biological functions. Among them, some are associated with the pathology of atherosclerosis. We previously found that peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) agonists attenuate the IL-6 induction of acute-phase response gene expression in vitro and in vivo. In the current work, we found a PPAR{alpha}-dependent regulation of hepatic acute-phase response stimulated by IL-1. We also found that IL-1-stimulated expression of secondary wave cytokines such as IL-6 is prevented upon PPAR{alpha} activation in liver. Direct involvement of hepatic PPAR{alpha} was demonstrated using a liver-restricted expression of PPAR{alpha} in mice. IL-1- or IL-6-mediated acute-phase response was inhibited by fenofibrate treatment in liver-specific PPAR{alpha}-expressing mice but not in PPAR{alpha}-deficient mice. In addition, we demonstrated that PPAR{alpha} exerts a general control of the acute-phase response by using an inflammation/infection model of lipopolysaccharide. In such a context, liver-specific PPAR{alpha}-expressing mice displayed lower circulating levels of TNF, IL-1, and IL-6 cytokines. We found a distal repercussion of this lowering at the vascular wall level as illustrated by a decreased expression of adhesion molecules in aorta. In conclusion, we demonstrated that through a specific liver action, PPAR{alpha} behaves as a modulator of systemic inflammation and of the associated vascular response.







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