Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver

The nuclear receptor PPAR alpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPAR alpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPAR alpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPAR alpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPAR alpha agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPAR alpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPAR alpha ligand-binding domain and coactivator peptide motifs was comparable to PPAR alpha agonists, but interactions with PPAR delta were weak and none were detected with PPAR gamma. Portal vein infusion of 16:0/18:1-GPC induced PPAR alpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPAR alpha ligand.