Structural basis for the activation of PPARgamma by oxidized fatty acids

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor crucial for adipogenesis, immune response, and metabolic regulation.
• Synthetic PPARgamma agonists are used as insulin sensitizers, but natural ligands remain largely unidentified.
• Potential natural ligands include oxidized fatty acids like 9-HODE and 13-HODE, and 15-deoxy-delta12,14-prostaglandin J2.

Purpose of the Study:

• To elucidate the structural basis of PPARgamma recognition by its natural ligands.
• To investigate the binding modes and activation mechanisms of oxidized fatty acids with PPARgamma.

Main Methods:

• X-ray crystallography to determine the structures of PPARgamma bound to oxidized fatty acids.
• Thermal stability assays to assess receptor-ligand interactions.
• Gene expression analysis to evaluate the functional consequences of ligand binding.

Main Results:

• Crystal structures revealed PPARgamma can bind two fatty acid molecules simultaneously.
• The receptor was observed to form covalent bonds with conjugated oxo fatty acids.
• Covalent binding of these ligands leads to particularly effective activation of PPARgamma.

Conclusions:

• Oxidized fatty acids, capable of simultaneous and covalent binding, are potent and biologically relevant natural ligands for PPARgamma.
• These findings provide new insights into the regulation of PPARgamma activity by endogenous compounds.
• The unique binding modes suggest novel therapeutic strategies targeting PPARgamma-mediated pathways.