GO:0035359 negative regulation of peroxisome proliferator activated receptor signaling pathway: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035359 describes any process that stops, prevents, or reduces the frequency, rate or extent of peroxisome proliferator activated receptor (PPAR) signaling.
• PPAR signaling is a ligand-activated nuclear receptor pathway that controls lipid metabolism, inflammation, and cell fate.
• Negative regulation of PPAR signaling occurs through transcriptional repression, post-translational modification, and metabolic feedback.
• Dysregulation of this process is linked to metabolic, inflammatory, and neoplastic diseases.
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential to dissect causal regulators of PPAR signaling.
• Understanding GO:0035359 provides a framework for therapeutic targeting of PPAR-dependent pathologies.
Description
The Gene Ontology term GO:0035359, negative regulation of peroxisome proliferator activated receptor signaling pathway, defines any biological process that stops, prevents, or reduces the frequency, rate or extent of the peroxisome proliferator activated receptor (PPAR) signaling pathway. PPARs are ligand-activated nuclear receptors that form heterodimers with retinoid X receptors and control the transcription of genes involved in lipid homeostasis, glucose metabolism, inflammation, and cell proliferation. Because PPAR signaling is central to metabolic and immune regulation, its negative regulation is critical for preventing excessive or inappropriate pathway activity. Researchers study GO:0035359 to understand how cells attenuate PPAR-driven transcription in response to physiological cues, pharmacological agents, and pathological stress. This term encompasses diverse molecular events, including the action of transcriptional corepressors, post-translational modifications of PPAR proteins, and the availability of endogenous ligands. In disease contexts, impaired negative regulation of PPAR signaling has been associated with metabolic disorders, inflammatory conditions, and cancer. Consequently, experimental models that manipulate this regulatory process are essential for identifying causal genes and developing targeted interventions.
negative regulation of peroxisome proliferator activated receptor signaling pathway At A Glance
| GO ID | GO:0035359 |
|---|---|
| GO term | negative regulation of peroxisome proliferator activated receptor signaling pathway |
| Ontology | biological_process |
| Synonym | negative regulation of PPAR signaling pathway |
| Major function | Attenuation of PPAR-mediated transcriptional programs controlling lipid metabolism, inflammation, and cell growth |
| Related pathway | Peroxisome proliferator activated receptor (PPAR) signaling pathway |
| Key regulators | Transcriptional corepressors, kinases, and metabolic enzymes |
| Disease relevance | Metabolic syndrome, inflammation, cancer |
What Is GO:0035359?
GO:0035359 is a biological process term that describes any mechanism that reduces or eliminates the activity of the peroxisome proliferator activated receptor signaling pathway. This includes processes that inhibit PPAR ligand binding, promote PPAR degradation, recruit transcriptional corepressors, or otherwise decrease the expression of PPAR target genes.
Why Is negative regulation of peroxisome proliferator activated receptor signaling pathway Important in Cell Biology?
Negative regulation of PPAR signaling is essential for maintaining metabolic homeostasis and preventing chronic inflammation. Dysregulation of this process contributes to the pathogenesis of insulin resistance, atherosclerosis, inflammatory bowel disease, and various cancers. Understanding the molecular players that negatively regulate PPAR signaling can reveal new therapeutic targets and biomarkers for these conditions.
• Controls the duration and intensity of PPAR-driven lipid metabolism.
• Prevents excessive inflammatory responses mediated by PPAR overactivation.
• Modulates insulin sensitivity and glucose homeostasis.
• Influences cell proliferation and differentiation in adipose tissue.
• Affects tumor progression in colorectal cancer and other malignancies.
• Provides a mechanism for pharmacological intervention with PPAR agonists/antagonists.
• Links gut microbiota and host metabolism through PPAR regulation.
• Contributes to the pathogenesis of IgA nephropathy via PPARα downregulation.
• Regulates T cell expansion and mitochondrial function through PPAR-related pathways.
• Serves as a model for studying nuclear receptor signaling attenuation.
What Happens During negative regulation of peroxisome proliferator activated receptor signaling pathway?
Transcriptional repression of PPAR target genes
In simple terms: The cell turns down the activity of PPAR by blocking the transcription of its target genes.
Negative regulation of PPAR signaling often involves the recruitment of transcriptional corepressors to PPAR-responsive promoters. For example, the transcription factor ZBTB9 has been shown to regulate PPARγ signaling in adipocytes in a cell-state-dependent manner, acting as a negative regulator. This repression reduces the expression of PPAR target genes involved in lipid uptake and storage.
Post-translational modification and degradation of PPAR proteins
In simple terms: Chemical tags or degradation signals are added to PPAR proteins to reduce their levels or activity.
PPAR proteins can be modified by phosphorylation, ubiquitination, or SUMOylation, leading to decreased transcriptional activity or proteasomal degradation. For instance, RBM43 controls PGC1α translation, which indirectly affects PPAR signaling through a PGC1α-STING signaling axis. Such modifications provide a rapid mechanism to attenuate PPAR signaling.
Ligand availability and metabolic feedback
In simple terms: The cell reduces the production of natural molecules that activate PPAR.
PPARs are activated by endogenous lipid ligands such as fatty acids and eicosanoids. Negative regulation can occur when the availability of these ligands is reduced. Bifidobacterium inhibits colorectal tumorigenesis through fatty acid isomerization and gut microbiota modulation, which may alter PPAR ligand production. Similarly, PGE2 inhibits TIL expansion by disrupting IL-2 signaling and mitochondrial function, potentially affecting PPAR-related metabolic pathways.
Cross-talk with inflammatory signaling pathways
In simple terms: Inflammatory signals can interfere with PPAR activity to shut down its effects.
Inflammatory mediators such as LPS can induce negative regulators of PPAR signaling. Berberine protects against LPS-induced intestinal injury, partly by modulating PPAR signaling. PPARβ/δ has emerging roles in inflammation, and its negative regulation may be important for resolving inflammatory responses.
Pharmacological and xenobiotic-mediated inhibition
In simple terms: Certain drugs or environmental chemicals can block PPAR signaling.
Perfluorodecanoic acid (PFDA) exhibits dual action on PPARα in hepatotoxicity, including negative regulation of PPARα signaling under certain conditions. This highlights how xenobiotics can disrupt PPAR signaling and contribute to liver toxicity.
Key Genes Involved in GO:0035359 negative regulation of peroxisome proliferator activated receptor signaling pathway
The following genes and proteins are experimentally implicated in the negative regulation of PPAR signaling, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ZBTB9 | Transcriptional repressor of PPARγ signaling in adipocytes | Cell-state-dependent regulation of PPARγ |
| RBM43 | Controls PGC1α translation, affecting PPAR signaling axis | Links RNA-binding protein to metabolic signaling |
| FABP1 | Fatty acid binding protein; downregulated by PPARα | Mediates IgA nephropathy via ferroptosis |
| PPARα | Nuclear receptor; target of negative regulation | Hepatotoxicity and lipid metabolism |
| PPARγ | Nuclear receptor; target of negative regulation | Adipocyte biology and insulin sensitivity |
| PPARβ/δ | Nuclear receptor; involved in inflammation | Inflammatory resolution |
| PGC1α | Transcriptional coactivator; regulated by RBM43 | Mitochondrial function and STING signaling |
| STING | Innate immune signaling adaptor | PGC1α-STING axis |
| IL-2 | Cytokine; signaling disrupted by PGE2 | TIL expansion and mitochondrial function |
| PGE2 | Prostaglandin; inhibits TIL expansion | Tumor immunology |
| Bifidobacterium | Gut microbe; modulates fatty acid isomerization | Colorectal tumorigenesis |
| Berberine | Natural compound; protects against LPS injury | Intestinal inflammation |
| PFDA | Xenobiotic; dual action on PPARα | Hepatotoxicity |
| LPS | Inflammatory stimulus; induces negative regulators | Intestinal injury model |
| NF-κB | Inflammatory transcription factor; cross-talks with PPAR | Inflammation |
| AP-1 | Transcription factor; may repress PPAR targets | Inflammation |
| SIRT1 | Deacetylase; can negatively regulate PPARγ | Metabolic regulation |
How Is negative regulation of peroxisome proliferator activated receptor signaling pathway Regulated?
Negative regulation of PPAR signaling is itself tightly regulated. For example, the transcription factor ZBTB9 is expressed in a cell-state-dependent manner to repress PPARγ in adipocytes. RBM43 controls PGC1α translation, which in turn affects a PGC1α-STING signaling axis that can modulate PPAR activity. Inflammatory signals such as LPS can induce negative regulators of PPAR signaling, as seen in intestinal injury models. Additionally, gut microbiota can influence PPAR signaling through metabolites derived from fatty acid isomerization.
negative regulation of peroxisome proliferator activated receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FABP1 | IgA nephropathy | Human mesangial cells with PPARα knockdown |
| PPARγ | Metabolic syndrome | Adipocyte-specific ZBTB9 knockout |
| PPARα | Hepatotoxicity | PFDA-treated hepatocytes |
| PPARβ/δ | Inflammation | LPS-induced intestinal injury model |
| Bifidobacterium | Colorectal cancer | Gut microbiota modulation in mice |
Metabolic and renal disorders
Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells. This illustrates how negative regulation of PPAR signaling can drive kidney disease. Similarly, impaired PPARγ regulation in adipocytes is linked to insulin resistance and metabolic syndrome.
Inflammation and intestinal injury
Berberine protects against LPS-induced intestinal injury, partly through modulation of PPAR signaling. PPARβ/δ has emerging roles in inflammation, and its negative regulation may be important for resolving inflammatory responses. PGE2 inhibits TIL expansion by disrupting IL-2 signaling and mitochondrial function, potentially involving PPAR-related metabolic pathways.
Cancer
Bifidobacterium inhibits the progression of colorectal tumorigenesis in mice through fatty acid isomerization and gut microbiota modulation, which may involve PPAR signaling. Negative regulation of PPAR signaling can influence tumor cell proliferation and survival, making it a potential therapeutic target.
Hepatotoxicity
Perfluorodecanoic acid (PFDA) exhibits dual action on PPARα in hepatotoxicity, including negative regulation of PPARα signaling. This highlights the importance of understanding negative regulation in toxicological contexts.
From negative regulation of peroxisome proliferator activated receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ZBTB9 negatively regulate PPARγ in adipocytes? | ZBTB9 knockout adipocytes |
| Does RBM43 control PGC1α translation? | RBM43 knockout cells |
| Does PPARα downregulation mediate FABP1 expression? | PPARα knockdown mesangial cells |
| Does PGE2 inhibit TIL expansion via PPAR? | PGE2-treated T cells |
| Does Bifidobacterium modulate PPAR signaling? | Bifidobacterium-treated mice |
| Does PFDA negatively regulate PPARα? | PFDA-treated hepatocytes |
How to Study the negative regulation of peroxisome proliferator activated receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptome changes | Identify PPAR target genes |
| ChIP-seq | PPAR DNA binding sites | Map PPAR occupancy |
| Proteomics | Protein modifications | Detect PPAR ubiquitination |
| Seahorse assay | Mitochondrial respiration | Assess metabolic effects |
| Lipidomics | Lipid species | Measure PPAR ligand availability |
| CRISPR screen | Gene knockout effects | Discover negative regulators |
| Reporter assay | PPAR transcriptional activity | Quantify negative regulation |
Transcriptomic analysis
RNA-seq can identify PPAR target genes whose expression is altered upon negative regulation. For example, ZBTB9 knockout adipocytes show changes in PPARγ target gene expression.
Proteomic and post-translational modification studies
Mass spectrometry-based proteomics can detect phosphorylation, ubiquitination, and SUMOylation of PPAR proteins, revealing mechanisms of negative regulation.
Metabolic assays
Seahorse analysis and lipidomics can measure mitochondrial function and lipid profiles, which reflect PPAR signaling activity.
CRISPR screening
Genome-wide CRISPR knockout screens can identify negative regulators of PPAR signaling by selecting for cells with altered PPAR reporter activity.
How CRISPR Can Be Used to Study GO:0035359 negative regulation of peroxisome proliferator activated receptor signaling pathway
Knockout
CRISPR knockout of candidate negative regulators such as ZBTB9 can confirm their role in repressing PPAR signaling. For example, ZBTB9 knockout in adipocytes increases PPARγ target gene expression.
Point Mutation
Point mutations can be introduced into PPAR response elements or PPAR proteins to disrupt negative regulation. This helps map specific residues required for corepressor binding.
Knock-in
Knock-in of tagged PPAR or corepressor alleles allows for chromatin immunoprecipitation and imaging studies to track negative regulation in real time.
Overexpression
Overexpression of negative regulators such as ZBTB9 or RBM43 can suppress PPAR signaling, providing gain-of-function evidence.
How EDITGENE Supports negative regulation of peroxisome proliferator activated receptor signaling pathway Research
Researchers studying negative regulation of peroxisome proliferator activated receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in attenuating PPAR activity. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of peroxisome proliferator activated receptor signaling pathway research.
Frequently Asked Questions About negative regulation of peroxisome proliferator activated receptor signaling pathway
What is GO:0035359?
GO:0035359 is the Gene Ontology term for negative regulation of peroxisome proliferator activated receptor signaling pathway, describing any process that reduces PPAR signaling.
What genes are involved in negative regulation of PPAR signaling?
Genes such as ZBTB9, RBM43, and FABP1 have been implicated in negatively regulating PPAR signaling.
How does ZBTB9 regulate PPARγ?
ZBTB9 acts as a transcriptional repressor of PPARγ in a cell-state-dependent manner in adipocytes.
What diseases are linked to negative regulation of PPAR signaling?
IgA nephropathy, metabolic syndrome, inflammation, and colorectal cancer have been linked to dysregulated negative regulation of PPAR signaling.
What experimental models are used to study GO:0035359?
Knockout, point mutation, knock-in, and overexpression cell models, as well as CRISPR screens, are commonly used.
How does RBM43 affect PPAR signaling?
RBM43 controls PGC1α translation, which affects a PGC1α-STING signaling axis that can modulate PPAR activity.
Can gut microbiota influence PPAR signaling?
Yes, Bifidobacterium inhibits colorectal tumorigenesis through fatty acid isomerization and gut microbiota modulation, potentially affecting PPAR signaling.
What is the role of PPARα in IgA nephropathy?
Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.
How does PGE2 affect PPAR signaling?
PGE2 inhibits TIL expansion by disrupting IL-2 signaling and mitochondrial function, which may involve PPAR-related pathways.
What CRISPR services does EDITGENE offer for PPAR research?
EDITGENE offers knockout, point mutation, knock-in, overexpression, CRISPR library screening, and bioinformatics services for PPAR-related genes.
Conclusion
GO:0035359, negative regulation of peroxisome proliferator activated receptor signaling pathway, is a critical biological process that attenuates PPAR-driven transcriptional programs. Its dysregulation contributes to metabolic, inflammatory, and neoplastic diseases. Understanding the molecular mechanisms and key genes involved, such as ZBTB9 and RBM43, provides opportunities for therapeutic intervention. CRISPR-based models are indispensable for dissecting these regulatory networks and identifying causal regulators.
References
- 1. Izadparast F et al.. 2022. Protective effect of berberine against LPS-induced injury in the intestine: a review.. Cell Cycle 21(22):2365-2378 PMID: 35852392
- 2. Dumesic PA et al.. 2025. RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.. Cell Metab 37(3):742-757.e8 PMID: 39965564
- 3. Wu J et al.. 2022. Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.. Int J Biol Sci 18(14):5438-5458 PMID: 36147466
- 4. Morotti M et al.. 2024. PGE(2) inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.. Nature 629(8011):426-434 PMID: 38658764
- 5. Xu X et al.. 2024. Cell-state-dependent regulation of PPARγ signaling by the transcription factor ZBTB9 in adipocytes.. J Biol Chem 300(12):107985 PMID: 39542250
- 6. Bishop-Bailey D et al.. 2009. Emerging roles of peroxisome proliferator-activated receptor-beta/delta in inflammation.. Pharmacol Ther 124(2):141-50 PMID: 19615407
- 7. Luo M et al.. 2017. Dual action of peroxisome proliferator-activated receptor alpha in perfluorodecanoic acid-induced hepatotoxicity.. Arch Toxicol 91(2):897-907 PMID: 27344344
- 8. Chen Y et al.. 2025. Bifidobacterium inhibits the progression of colorectal tumorigenesis in mice through fatty acid isomerization and gut microbiota modulation.. Gut Microbes 17(1):2464945 PMID: 39924893
