Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) gamma Activators and Pan-PPAR Partial Agonists

Author(s):Show less -

Liberato, Marcelo Vizona ^[1] ; Nascimento, Alessandro S. ^[1] ; Ayers, Steven D. ^[2] ; Lin, Jean Z. ^[2] ; Cvoro, Aleksandra ^[2] ; Silveira, Rodrigo L. ^[3] ; Martinez, Leandro ^[3] ; Souza, Paulo C. T. ^[3] ; Saidemberg, Daniel ^[4] ; Deng, Tuo ^[2] ; Amato, Angela Angelica ^[5] ; Togashi, Marie ^[5] ; Hsueh, Willa A. ^[2] ; Phillips, Kevin ^[2] ; Palma, Mario Sergio ^[4] ; Neves, Francisco A. R. ^[5] ; Skaf, Munir S. ^[3] ; Webb, Paul ^[2] ; Polikarpov, Igor ^[1]

Affiliation

^[1] Univ Sao Paulo, Sao Carlos Phys Inst, Sao Paulo - Brazil

^[2] Methodist Hosp, Houston, TX 77030 - USA

^[3] Univ Estadual Campinas, Inst Chem, Sao Paulo - Brazil

^[4] Sao Paulo State Univ, Inst Biosci, Sao Paulo - Brazil

^[5] Univ Brasilia, Dept Pharmaceut Sci, Brasilia, DF - Brazil

• Document type: Journal article
• Source: PLoS One; v. 7, n. 5 MAY 23 2012.
• Web of Science Citations: 70

Abstract

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) gamma 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 PPAR gamma 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 PPAR gamma 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 PPAR gamma LBD, stronger partial agonists with full length PPAR gamma and exhibit full blockade of PPAR gamma phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPAR gamma 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/beta-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 PPAR gamma modulators with useful clinical profiles among natural products. (AU)

• FAPESP's process: 06/06831-8 - Molecular dynamics simulations of thyroid hormone receptors
• Grantee: Leandro Martinez
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants