Global Suppression of IL-6-induced Acute Phase Response Gene Expression after Chronic in Vivo Treatment with the Peroxisome Proliferator-activated Receptor-α Activator Fenofibrate

Abstract

The peroxisome proliferator-activated receptor α (PPARα), which is highly expressed in liver, plays key roles in lipid metabolism and inflammation. Interleukin-6 (IL-6) is the principal inducer of acute phase response (APR) gene expression. In the present study, we demonstrate that chronic treatment with the PPARα agonist fenofibrate fully prevents the IL-6-induced APR gene expression in wild-type but not in PPARα-deficient mice. PPARα prevents the IL-6-induced expression of the positive APR genes fibrinogen-α, -β, γ, haptoglobulin, and serum amyloid A and the IL-6-induced suppression of the negative APR gene, major urinary protein. Furthermore, the effect of PPARα on the APR gene expression does not simply consist in a delayed systemic response to IL-6 but occurs directly at the transcriptional level. This global suppression of acute phase gene transcription may be explained by two PPARα-dependent in vivo effects: 1) PPARα activation results in the down-regulation of the IL-6 receptor components gp80 and gp130 in the liver, thereby reducing the phosphorylation and activation of the downstream transcription factors STAT3 and c-Jun that transduce the IL-6 signal; and 2) PPARα reduces the basal expression of the transcription factors CCAAT enhancer-binding protein-α, -β, -δ, which are responsible for immediate and maintained transcription of APR genes. A similar global effect of fenofibrate on acute phase protein expression is observed in hyperlipidemic patients chronically treated with fenofibrate, which displayed decreased plasma concentrations of the positive APR proteins fibrinogen, C-reactive protein, serum amyloid A, plasminogen, and α2-macroglobulin and increased plasma concentrations of the negative APR albumin, underlining the clinical significance of our findings.