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
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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, which could be affecting astronauts as well.
“Pro-inflammatory responses negatively regulate PPARα in rodent models of atherosclerosis and early NAFLD that could be affecting astronauts as well75,76,79,80.”
From Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions (2021) · cites this paper as [79]
The Abstract and Discussion (page numbers unavailable) describe the reverse relationship: activating PPARα suppresses IL-6-induced inflammatory gene expression in mice. Searches for inflammation down-regulating PPARα in atherosclerosis or early NAFLD found no passage addressing that claim; the copy also does not address astronauts. (LLM, conf=0.78)
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- 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
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Epidemiology › 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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