Skip navigation
Please use this identifier to cite or link to this item:
Files in This Item:
File Description SizeFormat 
ARTIGO_MediumChainFatty.pdf603,24 kBAdobe PDFView/Open
Title: Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists
Authors: Liberato, Marcelo Vizoná
Nascimento, Alessandro Silva
Ayers, Steven D.
Lin, Jean Z.
Cvoro, Aleksandra
Silveira, Rodrigo Leandro
Martínez, Leandro
Souza, Paulo Cesar Telles de
Saidemberg, Daniel Menezes
Deng, Tuo
Amato, Angélica Amorim
Togashi, Marie
Hsueh, Willa Ann
Phillips, Kevin
Palma, Mário Sérgio
Neves, Francisco de Assis Rocha
Skaf, Munir Salomao
Webb, Paul
Polikarpov, Igor
Assunto:: Ácidos graxos
Issue Date: May-2012
Publisher: PLOS
Citation: LIBERATO, Marcelo Vizoná et al. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists. Plos One, v. 7, n. 5, maio 2012. Disponível em: <>. Acesso em: 29 maio 2013.
Abstract: 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.
Licença:: Plos One - Este é um artigo de acesso aberto distribuído sob os termos da Licença Creative Commons Attribution, que permite uso irrestrito, distribuição e reprodução em qualquer meio, desde que o autor original e a fonte sejam creditados. Fonte: Acesso em: 29 maio 2013.
Appears in Collections:FAR - Artigos publicados em periódicos

Show full item record Recommend this item " class="statisticsLink btn btn-primary" href="/handle/10482/13220/statistics">

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.