ArticleJournal of the American Chemical Society2023
Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation.
Article in Journal of the American Chemical Society, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
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- RT206 Couples Partial PPARα/γ Agonism with Ligand-Dependent Allosteric Potentiation of FXR Signaling in Liver Cells.Biomolecules · 2026Article
- Tocotrienol metabolites redirect lipid mediator production in innate immune cells towards inflammation resolution.Acta pharmaceutica Sinica. B · 2026Article
- Peroxisome proliferator-activated receptor gamma (PPARγ) as a mechano-metabolic transducer: coordinating lipid homeostasis through mechanical cues.Molecular biomedicine · 2026Review
- Microbiota-derived 10-hydroxystearic acid activates PPARα to restore gut epithelial barrier integrity and enhance anti-retroviral therapy.Nature microbiology · 2026Article
- An Agonist/Antagonist Photo-Switchable Vitamin D Mimetic Enables Bidirectional Optical Control of VDR.Angewandte Chemie (International ed. in English) · 2026Article
- Development of a Brain-Penetrant Nurr1 Agonist Tool.ChemMedChem · 2026Article
- An aerosolized dual-action autotaxin inhibitor-PPARγ agonist for the treatment of pulmonary fibrosis.Cell reports. Medicine · 2026Article
- Structural Tuning of Vidofludimus for High-Efficacy NR4A Agonism.Journal of medicinal chemistry · 2026Article
- Systematic Optimization of Fragment TLX Ligands toward Agonism and Inverse Agonism.Journal of medicinal chemistry · 2026Article
- The metabolic dysfunction-associated steatohepatitis (MASH) drug resmetirom exhibits broad nuclear receptor activity with minimal functional impact.Scientific reports · 2026Article
- Article
- Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety.bioRxiv : the preprint server for biology · 2025Article
- Comparative Profiling and Chemogenomics Application of Chemical Tools for NR4A Nuclear Receptors.Journal of medicinal chemistry · 2025Article
- Multi-Target Glitazones for Modulating Peroxisome Proliferator-Activated Receptor-γ, Cyclooxygenase-2, and Carbonic Anhydrases for the Management of Metabolic Dysfunction.ACS pharmacology & translational science · 2025Article
- Chemical Composition and Anti-Lung Cancer Activities ofPharmaceuticals (Basel, Switzerland) · 2025Article
- Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.ACS pharmacology & translational science · 2025Article
- A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression.Journal of medicinal chemistry · 2025Article
- Article
- Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lipid-sensing transcription factor PPARγ is the target of antidiabetic thiazolidinediones (TZD). At two sites within its ligand binding domain, it also binds oxidized vitamin E metabolites and the vitamin E mimetic garcinoic acid. While the canonical interaction within the TZD binding site mediates classical PPARγ activation, the effects of the second binding on PPARγ activity remain elusive. Here, we identified an agonist mimicking dual binding of vitamin E metabolites and developed a selective ligand of the second site, unveiling potential noncanonical regulation of PPARγ activities. We found that this alternative binding event can simultaneously occur with orthosteric ligands and it exerted different effects on PPARγ-cofactor interactions compared to both orthosteric PPARγ agonists and antagonists, indicating the diverse roles of the two binding sites. Alternative site binding lacked the pro-adipogenic effect of TZD and mediated no classical PPAR signaling in differential gene expression analysis but markedly diminished FOXO signaling, suggesting potential therapeutic applications.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.