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

doi:10.1038/nsmb.1474

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 journal › Article › peer-review

308 Scopus citations

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-Δ^12,14-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 language	English (US)
Pages (from-to)	924-931
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	15
Issue number	9
DOIs	https://doi.org/10.1038/nsmb.1474
State	Published - Sep 2008
Externally published	Yes

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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title = "Structural basis for the activation of PPARγ by oxidized fatty acids",

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.",

author = "Toshimasa Itoh and Louise Fairall and Kush Amin and Yuka Inaba and Attila Szanto and Balint, {Balint L.} and Laszlo Nagy and Keiko Yamamoto and Schwabe, {John W.R.}",

note = "Funding Information: MS was carried out by A.R. Bottrill and S. Ibrahim of the Protein and Nucleic Acid Chemistry Laboratories (PNACL) Proteomics Facility at the University of Leicester. The Schwabe laboratory is supported by the Wellcome Trust. The Nagy laboratory is supported by the Howard Hughes Medical Institute, the Wellcome Trust and the Hungarian Scientific Research Fund. We acknowledge the European Synchrotron Radiation Facility (ESRF) for provision of synchrotron radiation facilities and thank the staff on beamline ID14.3.",

year = "2008",

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language = "English (US)",

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AU - Itoh, Toshimasa

AU - Fairall, Louise

AU - Amin, Kush

AU - Inaba, Yuka

AU - Szanto, Attila

AU - Balint, Balint L.

AU - Nagy, Laszlo

AU - Yamamoto, Keiko

AU - Schwabe, John W.R.

N1 - Funding Information: MS was carried out by A.R. Bottrill and S. Ibrahim of the Protein and Nucleic Acid Chemistry Laboratories (PNACL) Proteomics Facility at the University of Leicester. The Schwabe laboratory is supported by the Wellcome Trust. The Nagy laboratory is supported by the Howard Hughes Medical Institute, the Wellcome Trust and the Hungarian Scientific Research Fund. We acknowledge the European Synchrotron Radiation Facility (ESRF) for provision of synchrotron radiation facilities and thank the staff on beamline ID14.3.

PY - 2008/9

Y1 - 2008/9

N2 - 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.

AB - 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.

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Structural basis for the activation of PPARγ by oxidized fatty acids

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