Endogenous ligand for an orphan receptor.

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolic Research

Background:

• Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor targeted by fibrate drugs for lipid management.
• The endogenous ligand for PPARalpha remained unidentified until this study.
• PPARalpha plays a crucial role in regulating fatty acid metabolism.

Purpose of the Study:

• To identify the physiologically relevant endogenous ligand of PPARalpha.
• To investigate the role of fatty acid synthase in producing this ligand.
• To confirm the identified ligand's ability to activate PPARalpha signaling in vivo.

Main Methods:

• Mass spectrometry was employed to identify the endogenous ligand.
• The study utilized in vivo experiments involving portal vein infusion.
• Gene expression analysis was performed for key fatty acid metabolism genes.

Main Results:

• 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16/18-GPC), a phospholipid, was identified as the endogenous PPARalpha ligand.
• The synthesis of 16/18-GPC is dependent on the nutritionally responsive enzyme, fatty acid synthase.
• Infusion of 16/18-GPC induced PPARalpha-dependent expression of acyl CoA oxidase and carnitine palmitoyl transferase.

Conclusions:

• 16/18-GPC is a key endogenous ligand for PPARalpha.
• Fatty acid synthase plays a critical role in regulating PPARalpha activity through 16/18-GPC production.
• This finding provides new insights into the regulation of lipid metabolism by endogenous signaling molecules.