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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

Author: Gervois, P. · Kleemann, R. · Pilon, A. · Percevault, F. · Koenig, W. · Staels, B. · Kooistra, T.
Type:article
Date:2004
Institution: TNO Preventie en Gezondheid
Source:Journal of Biological Chemistry, 16, 279, 16154-16160
Identifier: 237715
doi: doi:10.1074/jbc.M400346200
Keywords: Biology · Biomedical Research · Biological organs · Enzyme kinetics · Lipids · Metabolism · Patient treatment · Plasmas · Acute phase response (APR) · Gene expression · Genetic engineering · Albumin · Alpha 2 macroglobulin · CCAAT enhancer binding protein · CCAAT enhancer binding protein alpha · CCAAT enhancer binding protein beta · CCAAT enhancer binding protein delta · Fenofibrate · Fibrinogen · Interleukin 6 · peroxisome proliferator activated receptor agonist · peroxisome proliferator activated receptor alpha · serum amyloid A · STAT3 protein · Stress activated protein kinase · Transcription factor · Unclassified drug · Acute phase response · Animal experiment · Animal tissue · Clinical article · Controlled study · Down regulation · Enzyme activation · Fibrinogen blood level · Gene expression regulation · Hyperlipidemia · In vivo study · Knockout mouse · Liver · Long term care · Male · Mouse · Nonhuman · Protein expression · Protein function · Protein phosphorylation · Transcription regulation · Wild type · Acute-Phase Reaction · Animals · Antilipemic Agents · Apolipoproteins · Down-Regulation · Fibrinogen · Haptoglobins · Humans · Interleukin-6 · Mice · Procetofen · Receptors, Cytoplasmic and Nuclear · Serum Amyloid A Protein · Signal Transduction · Transcription Factors · Animalia · Eukaryota

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. 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