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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
Open accessAbstract
The peroxisome proliferator-activated receptor alpha (PPARalpha), 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 PPARalpha agonist fenofibrate fully prevents the IL-6-induced APR gene expression in wild-type but not in PPARalpha-deficient mice. PPARalpha prevents the IL-6-induced expression of the positive APR genes fibrinogen-alpha, -beta, -gamma, haptoglobulin, and serum amyloid A and the IL-6-induced suppression of the negative APR gene, major urinary protein. Furthermore, the effect of PPARalpha 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 PPARalpha-dependent in vivo effects: 1) PPARalpha 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) PPARalpha reduces the basal expression of the transcription factors CCAAT enhancer-binding protein-alpha, -beta, -delta, 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 alpha2-macroglobulin and increased plasma concentrations of the negative APR albumin, underlining the clinical significance of our findings.
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“Pro-inflammatory responses negatively regulate PPARα in rodent models of atherosclerosis and early NAFLD that could be affecting astronauts as well75,76,79,80.”
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Metadata
- Authors
- Gervois, P., Kleemann, R., Pilon, A., Percevault, F., Koenig, W., Staels, B., & Kooistra, T.
- Affiliations
- Netherlands Organisation for Applied Scientific Research (NL)
- Inserm (FR)
- Corresponding author
- Gervois, Philippe
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 279
- Issue
- 16
- Pages
- 16154-16160
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2067332921
- Cited by
- 212
- References
- 37
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 9 · 2022: 7 · 2021: 7 · 2020: 13 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 9 · 2014: 7 · 2013: 11 · 2012: 15
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Fondation Leducq
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- fenofibrate, PPARα, interleukin-6, acute phase response, acute phase proteins, fibrinogen, haptoglobin, serum amyloid A, major urinary proteins, IL-6 receptor, STAT3, c-Jun, C/EBP transcription factors, liver, hyperlipidemia, C-reactive protein, alpha2-macroglobulin, plasminogen, albumin
- MeSH terms
- Acute-Phase Reaction, Serum Amyloid A Protein, Animals, Hypolipidemic Agents, Apolipoproteins, Fibrinogen, Haptoglobins, Humans, Fenofibrate, Transcription Factors, Signal Transduction, Down-Regulation, Interleukin-6, Receptors, Cytoplasmic and Nuclear, Mice
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