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Endocrinology. 2008 Jun;149(6):3215-23. doi: 10.1210/en.2007-1339. Epub 2008 Mar 6.

Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.

Author information

1
Institut Pasteur de Lille, Département d'Athérosclérose, and Institut National de la Santé et de la Recherche Médicale Unité 545, Lille F59019, France.

Abstract

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

PMID:
18325987
DOI:
10.1210/en.2007-1339
[Indexed for MEDLINE]

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