Structural basis for the activation of PPARγ by oxidized fatty acids

Toshimasa Itoh, Louise Fairall, Kush Amin, Yuka Inaba, Attila Szanto, Balint L. Balint, Laszlo Nagy, Keiko Yamamoto, John W.R. Schwabe

Research output: Contribution to journalArticlepeer-review

Abstract

The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has important roles in adipogenesis and immune response as well as roles in both lipid and carbohydrate metabolism. Although synthetic agonists for PPARγ are widely used as insulin sensitizers, the identity of the natural ligand(s) for PPARγ is still not clear. Suggested natural ligands include 15-deoxy-Δ12,14-prostaglandin J2 and oxidized fatty acids such as 9-HODE and 13-HODE. Crystal structures of PPARγ have revealed the mode of recognition for synthetic compounds. Here we report structures of PPARγ bound to oxidized fatty acids that are likely to be natural ligands for this receptor. These structures reveal that the receptor can (i) simultaneously bind two fatty acids and (ii) couple covalently with conjugated oxo fatty acids. Thermal stability and gene expression analyses suggest that such covalent ligands are particularly effective activators of PPARγ and thus may serve as potent and biologically relevant ligands.

Original languageEnglish (US)
Pages (from-to)924-931
Number of pages8
JournalNature Structural and Molecular Biology
Volume15
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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