Please use this identifier to cite or link to this item: https://biore.bio.bg.ac.rs/handle/123456789/6430
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dc.contributor.authorPuhl, Ana C.en_US
dc.contributor.authorBernardes, Amandaen_US
dc.contributor.authorSilveira, Rodrigo L.en_US
dc.contributor.authorYuan, Jingen_US
dc.contributor.authorCampos, Jéssica L. O.en_US
dc.contributor.authorSaidemberg, Daniel M.en_US
dc.contributor.authorPalma, Mario S.en_US
dc.contributor.authorČvoro, Aleksandraen_US
dc.contributor.authorAyers, Stephen D.en_US
dc.contributor.authorWebb, Paul.en_US
dc.contributor.authorReinach, Peter S.en_US
dc.contributor.authorSkaf, Munir S.en_US
dc.contributor.authorPolikarpov, Igoren_US
dc.date.accessioned2023-11-07T12:58:51Z-
dc.date.available2023-11-07T12:58:51Z-
dc.date.issued2012-06-
dc.identifier.urihttps://biore.bio.bg.ac.rs/handle/123456789/6430-
dc.description.abstractThe 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.en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeuticsen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.titleMode of peroxisome proliferator-activated receptor γ activation by luteolinen_US
dc.typeArticleen_US
dc.identifier.doi10.1124/mol.111.076216.-
dc.description.rankM21en_US
dc.description.impact4.883en_US
dc.description.startpage788en_US
dc.description.endpage799en_US
dc.relation.issn0026-895Xen_US
dc.description.volume81en_US
dc.description.issue6en_US
item.languageiso639-1en-
item.cerifentitytypePublications-
item.openairetypeArticle-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
crisitem.author.deptChair of Cell and Tissue Biology-
crisitem.author.orcid0009-0007-5643-1634-
Appears in Collections:Journal Article
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