Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/348833
Type: Artigo
Title: Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and Pan-PPAR partial agonists
Author: Liberato, Marcelo Vizoná
Nascimento, Alessandro S.
Ayers, Steven D.
Lin, Jean Z.
Cvoro, Aleksandra
Silveira, Rodrigo L.
Martínez, Leandro
Souza, Paulo C. T.
Saidemberg, Daniel
Tuo Deng
Amato, Angela Angelica
Togashi, Marie
Hsueh, Willa A.
Phillips, Kevin
Palma, Mário Sérgio
Neves, Francisco A. R.
Skaf, Munir S.
Webb, Paul
Polikarpov, Igor
Abstract: Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8–C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products
Subject: Ácidos graxos
Country: Estados Unidos
Editor: Public Library of Science
Rights: Aberto
Identifier DOI: 10.1371/journal.pone.0036297
Address: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036297
Date Issue: 2012
Appears in Collections:IQ - Artigos e Outros Documentos

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