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

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- (PPAR) 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-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 activation in liver. Direct involvement of hepatic PPAR was demonstrated using a liver-restricted expression of PPAR in mice. IL-1- or IL-6-mediated acute-phase response was inhibited by fenofibrate treatment in liver-specific PPAR-expressing mice but not in PPAR-deficient mice. In addition, we demonstrated that PPAR exerts a general control of the acute-phase response by using an inflammation/infection model of lipopolysaccharide. In such a context, liver-specific PPAR-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 behaves as a modulator of systemic inflammation and of the associated vascular response.