Systemic and distal repercussions of liver-specific peroxisome proliferator-activated receptor-α 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 (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.