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
article
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. Chemicals / CAS: alpha 2 macroglobulin, 95568-41-5; fenofibrate, 49562-28-9; fibrinogen, 9001-32-5; peroxisome proliferator activated receptor alpha, 147258-70-6; stress activated protein kinase, 155215-87-5; Antilipemic Agents; Apolipoproteins; Fibrinogen, 9001-32-5; Haptoglobins; Interleukin-6; Procetofen, 49562-28-9; Receptors, Cytoplasmic and Nuclear; Serum Amyloid A Protein; Transcription Factors
Topics
Biomedical ResearchBiological organsEnzyme kineticsLipidsMetabolismPatient treatmentPlasmasAcute phase response (APR)Gene expressionGenetic engineeringAlbuminAlpha 2 macroglobulinCCAAT enhancer binding proteinCCAAT enhancer binding protein alphaCCAAT enhancer binding protein betaCCAAT enhancer binding protein deltaFenofibrateFibrinogenInterleukin 6peroxisome proliferator activated receptor agonistperoxisome proliferator activated receptor alphaserum amyloid ASTAT3 proteinStress activated protein kinaseTranscription factorUnclassified drugAcute phase responseAnimal experimentAnimal tissueClinical articleControlled studyDown regulationEnzyme activationFibrinogen blood levelGene expression regulationHyperlipidemiaIn vivo studyKnockout mouseLiverLong term careMaleMouseNonhumanProtein expressionProtein functionProtein phosphorylationTranscription regulationWild typeAcute-Phase ReactionAnimalsAntilipemic AgentsApolipoproteinsDown-RegulationFibrinogenHaptoglobinsHumansInterleukin-6MiceProcetofenReceptors, Cytoplasmic and NuclearSerum Amyloid A ProteinSignal TransductionTranscription FactorsAnimaliaEukaryota
TNO Identifier
237715
ISSN
00219258
Source
Journal of Biological Chemistry, 279(16), pp. 16154-16160.
Pages
16154-16160