GO:0035360 positive regulation of peroxisome proliferator activated receptor signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035360 describes any process that increases the frequency, rate, or extent of peroxisome proliferator activated receptor (PPAR) signaling, a central lipid-sensing transcriptional axis.
• PPAR signaling is positively regulated by diverse inputs including metabolic sensors (AMPK/SIRT1/PGC-1α), inflammatory cues (STAT1/STAT6), and cell-state-dependent transcription factors such as ZBTB9.
• Dysregulation of positive PPAR regulation contributes to metabolic dysfunction-associated steatohepatitis (MASH), obesity-driven hepatocyte reprogramming, IgA nephropathy, and colon tumorigenesis.
• Key effector genes in this process include PPARA, PPARG, PGC-1α (PPARGC1A), FABP1, ZDHHC6, ZBTB9, and GPNMB-RYK signaling components.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of positive PPAR regulation in metabolic and inflammatory disease contexts.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to accelerate functional validation of PPAR signaling regulators.
Description
The Gene Ontology term GO:0035360, positive regulation of peroxisome proliferator activated receptor signaling pathway, captures any biological process that activates or increases the frequency, rate, or extent of signaling through peroxisome proliferator activated receptors (PPARs). PPARs are ligand-activated nuclear receptors that coordinate lipid metabolism, energy homeostasis, and inflammation, and their positive regulation is essential for adaptive responses to nutritional and metabolic stress. This term is therefore central to understanding how cells amplify PPAR-dependent transcriptional programs under physiological and pathological conditions.
positive regulation of peroxisome proliferator activated receptor signaling pathway At A Glance
| GO ID | GO:0035360 |
|---|---|
| GO term | positive regulation of peroxisome proliferator activated receptor signaling pathway |
| Ontology | biological_process |
| Synonym | positive regulation of PPAR signaling pathway |
| Major function | Enhances PPAR-mediated transcriptional regulation of lipid metabolism, energy homeostasis, and inflammation |
| Related receptors | PPARA, PPARG, PPARD |
| Key coactivators | PGC-1α (PPARGC1A), SIRT1 |
| Disease relevance | MASH, obesity, IgA nephropathy, colon cancer |
| Research methods | CRISPR KO/point mutation/KI/overexpression, RNA-seq, proteomics, lipidomics |
What Is GO:0035360?
GO:0035360 is a biological process defined as any process that activates or increases the frequency, rate, or extent of the peroxisome proliferator activated receptor signaling pathway. In practical terms, it encompasses molecular events that enhance PPAR ligand availability, receptor expression, coactivator recruitment, or downstream transcriptional output, thereby amplifying PPAR-driven gene expression programs.
Why Is positive regulation of peroxisome proliferator activated receptor signaling pathway Important in Cell Biology?
Positive regulation of PPAR signaling is a critical node in metabolic and inflammatory control because it determines the magnitude and duration of PPAR-dependent transcriptional responses. Dysregulation of this process is linked to major human diseases including metabolic dysfunction-associated steatohepatitis, obesity-associated hepatocyte reprogramming, IgA nephropathy, and colon tumorigenesis. Understanding how this positive regulation is achieved at the molecular level provides a rational basis for therapeutic strategies targeting PPAR pathways.
• Controls lipid and glucose homeostasis through PPARα and PPARγ target genes.
• Modulates inflammatory responses via STAT1/STAT6/PPARγ signaling in microglia.
• Drives hepatocyte metabolic reprogramming in obesity through PTPRK-dependent mechanisms.
• Promotes colon tumorigenesis via ZDHHC6-mediated PPARγ-driven lipid biosynthesis.
• Regulates ferroptosis in IgA nephropathy through PPARα-FABP1 axis.
• Influences T cell expansion and mitochondrial function via PGE2-IL-2 signaling.
• Cell-state-dependent regulation by ZBTB9 in adipocytes highlights context-specific control.
• Provides therapeutic targets for MASH, obesity, kidney disease, and cancer.
• Enables CRISPR-based functional genomics to identify novel positive regulators.
• Supports development of PPAR-modulating drugs with improved specificity.
What Happens During positive regulation of peroxisome proliferator activated receptor signaling pathway?
Ligand availability and receptor activation
In simple terms: This step is about making sure PPAR receptors have enough activating molecules to turn on their target genes.
Positive regulation begins with increased availability of endogenous PPAR ligands, such as fatty acids and eicosanoids, which bind and activate PPARα, PPARγ, or PPARδ. In hepatocytes, PTPRK regulates glycolysis and de novo lipogenesis, thereby influencing the lipid environment that supplies PPAR ligands. In colon cancer, ZDHHC6-mediated palmitoylation promotes PPARγ-driven lipid biosynthesis, enhancing receptor activation.
Transcriptional coactivator recruitment
In simple terms: Once PPARs are activated, they need helper proteins to boost the reading of target genes.
Activated PPARs recruit coactivators such as PGC-1α (PPARGC1A) and SIRT1 to enhance transcription of genes involved in energy homeostasis. The AMPK/SIRT1/PGC-1α axis represents a key positive regulatory module that amplifies PPAR signaling under metabolic stress. Cell-state-dependent factors like ZBTB9 can also modulate PPARγ signaling in adipocytes, influencing coactivator dynamics.
Inflammatory and cytokine modulation
In simple terms: Inflammatory signals can either boost or dampen PPAR activity depending on the context.
Ultrasound reduces inflammation by modulating M1/M2 microglial polarization through STAT1/STAT6/PPARγ signaling pathways, demonstrating that cytokine-driven STAT signaling can positively regulate PPARγ. Conversely, PGE2 inhibits TIL expansion by disrupting IL-2 signaling and mitochondrial function, indirectly affecting PPAR-dependent metabolic programs. These examples highlight context-dependent positive regulation of PPAR signaling by immune mediators.
Receptor crosstalk and feedback
In simple terms: PPAR signaling is fine-tuned by other receptors and feedback loops to avoid overactivation.
GPNMB acts as a ligand for RYK to drive MASH, and this signaling intersects with PPAR pathways in metabolic dysfunction. Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis, illustrating how loss of positive regulation can be pathogenic. These crosstalk mechanisms ensure that positive regulation of PPAR signaling is balanced with other metabolic and inflammatory inputs.
Key Genes Involved in GO:0035360 positive regulation of peroxisome proliferator activated receptor signaling pathway
The following genes and proteins are experimentally implicated in positive regulation of PPAR signaling, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PPARA | Nuclear receptor mediating lipid metabolism and ferroptosis regulation | Downregulation contributes to IgA nephropathy via FABP1 |
| PPARG | Nuclear receptor controlling lipid biosynthesis and inflammation | Target of ZDHHC6 in colon tumorigenesis; modulated by STAT1/STAT6 |
| PPARGC1A (PGC-1α) | Transcriptional coactivator enhancing PPAR target gene expression | Central to AMPK/SIRT1/PGC-1α energy homeostasis axis |
| SIRT1 | Deacetylase that positively regulates PGC-1α and PPAR signaling | Part of AMPK/SIRT1/PGC-1α module |
| AMPK | Energy sensor kinase that activates SIRT1/PGC-1α | Upstream positive regulator of PPAR signaling |
| FABP1 | Fatty acid binding protein mediating lipid transport | Downstream of PPARα in IgA nephropathy |
| ZDHHC6 | Palmitoyltransferase promoting PPARγ-driven lipid biosynthesis | Promotes colon tumorigenesis |
| ZBTB9 | Transcription factor regulating PPARγ signaling in adipocytes | Cell-state-dependent regulation |
| GPNMB | Ligand for RYK driving MASH | Intersects with PPAR pathways in metabolic dysfunction |
| RYK | Receptor for GPNMB | Mediates MASH pathogenesis |
| STAT1 | Transcription factor modulating M1 polarization | Part of STAT1/STAT6/PPARγ signaling |
| STAT6 | Transcription factor modulating M2 polarization | Part of STAT1/STAT6/PPARγ signaling |
| PTPRK | Phosphatase regulating glycolysis and lipogenesis | Promotes hepatocyte metabolic reprogramming in obesity |
| IL-2 | Cytokine supporting T cell expansion | Disrupted by PGE2, affecting mitochondrial function |
| PGE2 | Prostaglandin inhibiting TIL expansion | Disrupts IL-2 signaling and mitochondrial function |
How Is positive regulation of peroxisome proliferator activated receptor signaling pathway Regulated?
Positive regulation of PPAR signaling is controlled by multiple upstream inputs. The AMPK/SIRT1/PGC-1α axis acts as a master energy-sensing module that enhances PPAR transcriptional activity under metabolic stress. Inflammatory cytokines such as STAT1 and STAT6 modulate PPARγ signaling in microglia, linking immune status to PPAR activity. Cell-state-dependent transcription factors like ZBTB9 regulate PPARγ signaling in adipocytes, indicating context-specific control. Additionally, PTPRK influences glycolysis and de novo lipogenesis, thereby affecting the lipid ligand environment for PPARs. These regulatory layers ensure that PPAR signaling is appropriately amplified in response to physiological demands.
positive regulation of peroxisome proliferator activated receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GPNMB/RYK | MASH | Knockout mouse or hepatocyte-specific KO |
| PTPRK | Obesity-associated hepatocyte reprogramming | Liver-specific overexpression or KO |
| PPARA/FABP1 | IgA nephropathy | Mesangial cell KO or point mutation |
| ZDHHC6/PPARG | Colon tumorigenesis | Colon cancer cell line KO or overexpression |
| ZBTB9 | Adipocyte PPARγ signaling | Adipocyte-specific KO or knock-in |
Metabolic dysfunction-associated steatohepatitis (MASH)
GPNMB acts as a ligand for RYK to drive MASH, and this pathway intersects with PPAR signaling in metabolic dysfunction. Positive regulation of PPAR signaling may be protective or pathogenic depending on context, making it a key area for therapeutic intervention in MASH.
Obesity and hepatocyte metabolic reprogramming
PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity, influencing PPAR ligand availability and downstream signaling. This highlights how positive regulation of PPAR signaling is rewired in obesity-associated liver disease.
IgA nephropathy
Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells. Loss of positive PPAR regulation is therefore pathogenic in this kidney disease.
Colon tumorigenesis
Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via lipidome metabolic reprogramming. Positive regulation of PPARγ signaling can thus support tumor growth, indicating context-dependent oncogenic roles.
From positive regulation of peroxisome proliferator activated receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of a candidate gene reduce PPAR signaling? | CRISPR knockout in relevant cell line |
| Does a specific mutation alter PPAR coactivator binding? | Point mutation knock-in |
| Does tagging a PPAR regulator affect its localization? | Tagged knock-in (e.g., GFP) |
| Does overexpression of a regulator enhance PPAR target genes? | Overexpression cell model |
| Which genes are essential for positive PPAR regulation? | Genome-wide CRISPR library screening |
| How does a disease-associated variant affect PPAR signaling? | Knock-in of patient variant |
How to Study the positive regulation of peroxisome proliferator activated receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptome changes | Identify PPAR target genes upon regulator KO |
| Proteomics | Protein expression and modifications | Assess PPAR coactivator levels |
| Lipidomics | Lipid species and abundance | Measure PPAR ligand availability |
| PPAR reporter assay | PPAR transcriptional activity | Quantify positive regulation |
| ChIP-seq | PPAR binding sites | Map PPAR cistrome |
| CRISPR KO screen | Gene essentiality for PPAR signaling | Discover novel regulators |
| CRISPR activation screen | Gain-of-function effects | Identify enhancers of PPAR signaling |
Transcriptomic profiling
RNA-seq can measure changes in PPAR target gene expression upon genetic perturbation of candidate regulators, providing a global view of positive regulation.
Proteomic and lipidomic analysis
Proteomics and lipidomics reveal changes in PPAR protein levels and lipid ligand availability, as demonstrated in ZDHHC6-mediated lipid reprogramming and PTPRK-driven lipogenesis.
Functional assays for PPAR activity
PPAR reporter assays and ChIP-seq for PPAR binding sites can directly quantify positive regulation of PPAR signaling in response to genetic or pharmacological perturbations.
CRISPR screening
Genome-wide CRISPR knockout or activation screens identify novel positive regulators of PPAR signaling, as exemplified by studies on metabolic reprogramming.
How CRISPR Can Be Used to Study GO:0035360 positive regulation of peroxisome proliferator activated receptor signaling pathway
Knockout
CRISPR knockout of candidate genes such as PTPRK or ZDHHC6 can determine whether they are required for positive regulation of PPAR signaling in metabolic or cancer cell models.
Point Mutation
Point mutations can be introduced into PPAR coactivator interaction domains or phosphorylation sites to test their role in positive regulation, as illustrated by cell-state-dependent ZBTB9 regulation.
Knock-in
Knock-in of tagged versions of PPAR regulators (e.g., GFP-PGC-1α) allows live-cell imaging and interaction studies to dissect positive regulation mechanisms.
Overexpression
Overexpression of positive regulators such as PGC-1α or ZDHHC6 can enhance PPAR signaling and drive downstream phenotypes like lipid biosynthesis or tumorigenesis.
How EDITGENE Supports positive regulation of peroxisome proliferator activated receptor signaling pathway Research
Researchers studying positive regulation of peroxisome proliferator activated receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in enhancing PPAR activity. EDITGENE provides comprehensive CRISPR cell model and screening services to accelerate this functional validation.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of peroxisome proliferator activated receptor signaling pathway research.
Frequently Asked Questions About positive regulation of peroxisome proliferator activated receptor signaling pathway
What is GO:0035360?
GO:0035360 is the Gene Ontology term for positive regulation of peroxisome proliferator activated receptor signaling pathway, describing any process that increases PPAR signaling.
What genes are involved in positive regulation of PPAR signaling?
Key genes include PPARA, PPARG, PPARGC1A, SIRT1, AMPK, ZDHHC6, ZBTB9, PTPRK, and GPNMB/RYK.
How is PPAR signaling positively regulated?
It is positively regulated by ligand availability, coactivator recruitment (e.g., PGC-1α), and upstream kinases such as AMPK, as well as by inflammatory and metabolic cues.
What diseases are associated with dysregulated PPAR positive regulation?
Diseases include MASH, obesity-associated hepatocyte reprogramming, IgA nephropathy, and colon tumorigenesis.
What experimental models are used to study GO:0035360?
CRISPR knockout, point mutation, knock-in, overexpression cell models, and CRISPR library screens are commonly used.
How does ZDHHC6 regulate PPARγ signaling?
ZDHHC6 palmitoylates targets to promote PPARγ-driven lipid biosynthesis and colon tumorigenesis.
What is the role of PGC-1α in PPAR signaling?
PGC-1α is a transcriptional coactivator that enhances PPAR target gene expression as part of the AMPK/SIRT1/PGC-1α axis.
Can CRISPR screens identify new PPAR regulators?
Yes, genome-wide CRISPR knockout or activation screens have identified novel regulators of PPAR signaling in metabolic and cancer contexts.
How does PPARα downregulation affect kidney disease?
PPARα downregulation mediates FABP1 expression and stimulates ferroptosis in IgA nephropathy.
What services does EDITGENE offer for PPAR research?
EDITGENE provides CRISPR KO, point mutation, knock-in, overexpression cell models, library screening, and bioinformatics for PPAR signaling studies.
Conclusion
GO:0035360, positive regulation of peroxisome proliferator activated receptor signaling pathway, is a critical biological process that amplifies PPAR-dependent transcriptional programs in metabolism, inflammation, and disease. Understanding its molecular players and regulatory mechanisms offers therapeutic opportunities for MASH, obesity, kidney disease, and cancer. EDITGENE's CRISPR services empower researchers to functionally validate these regulators with precision and scale.
References
- 1. Xi Y et al.. 2026. RYK is a GPNMB receptor that drives MASH.. Nature 652(8110):703-711 PMID: 41708863
- 2. Hsu CH et al.. 2023. Ultrasound reduces inflammation by modulating M1/M2 polarization of microglia through STAT1/STAT6/PPARγ signaling pathways.. CNS Neurosci Ther 29(12):4113-4123 PMID: 37401041
- 3. Chen J et al.. 2025. AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.. CNS Neurosci Ther 31(11):e70657 PMID: 41268687
- 4. Gilglioni EH et al.. 2024. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.. Nat Commun 15(1):9522 PMID: 39496584
- 5. 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
- 6. Shan J et al.. 2024. Palmitoyltransferase ZDHHC6 promotes colon tumorigenesis by targeting PPARγ-driven lipid biosynthesis via regulating lipidome metabolic reprogramming.. J Exp Clin Cancer Res 43(1):227 PMID: 39148124
- 7. 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
- 8. 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
