Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-alpha control of the acute-phase response.
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.
Mansouri
Roxane M
RM
Institut Pasteur de Lille, Département d'Athérosclérose, and Institut National de la Santé et de la Recherche Médicale Unité 545, Lille F59019, France.
Baugé
Eric
E
Staels
Bart
B
Gervois
Philippe
P
D000209:Acute-Phase Proteins / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology; D002467:Cell Nucleus / Q000502:physiology; D011345:Fenofibrate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000503:physiopathology; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics
D000209:Acute-Phase Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D047493:PPAR alpha; D012313:RNA; D011345:Fenofibrate