دورية أكاديمية
Mode of peroxisome proliferator-activated receptor γ activation by luteolin.
| العنوان: | Mode of peroxisome proliferator-activated receptor γ activation by luteolin. |
|---|---|
| المؤلفون: | Puhl AC; Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil., Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM, Palma MS, Cvoro A, Ayers SD, Webb P, Reinach PS, Skaf MS, Polikarpov I |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2012 Jun; Vol. 81 (6), pp. 788-99. Date of Electronic Publication: 2012 Mar 05. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | Luteolin/*pharmacology , PPAR gamma/*agonists, 3T3-L1 Cells ; Animals ; Base Sequence ; DNA Primers ; Gene Expression Regulation/drug effects ; Humans ; Luteolin/chemistry ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Myristic Acid/chemistry ; PPAR gamma/chemistry ; PPAR gamma/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Rosiglitazone ; Thiazolidinediones/antagonists & inhibitors ; Thiazolidinediones/pharmacology |
| مستخلص: | The peroxisome proliferator-activated receptor γ (PPARγ) is a target for treatment of type II diabetes and other conditions. PPARγ full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPARγ but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPARγ agonist or an antagonist. We show that luteolin exhibits weak partial agonist/antagonist activity in transfections, inhibits several PPARγ target genes in 3T3-L1 cells (LPL, ORL1, and CEBPα) and PPARγ-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPARγ ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPARγ LBD conformer and occupies a space near the β-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPARγ, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the Ω-loop among H2', H3, and the β-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPARγ-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPARγ modulators. |
| سلسلة جزيئية: | PDB 3SZ1 |
| المشرفين على المادة: | 0 (DNA Primers) 0 (PPAR gamma) 0 (Thiazolidinediones) 05V02F2KDG (Rosiglitazone) 0I3V7S25AW (Myristic Acid) KUX1ZNC9J2 (Luteolin) |
| تواريخ الأحداث: | Date Created: 20120307 Date Completed: 20120716 Latest Revision: 20181201 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1124/mol.111.076216 |
| PMID: | 22391103 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!