The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) can be activated pharmacologically by fibrate drugs, lowering triglycerides and raising high-density lipoprotein. However, until recently, the endogenous ligand of PPARα had been unknown. A new study reports the identity of a physiologically relevant endogenous PPARα ligand as a phospholipid that is dependent upon a nutritionally responsive enzyme, fatty acid synthase. Mass spectrometry identified this phospholipid as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16/18-GPC) and as the endogenous ligand of PPARα. In vivo experiments involving portal vein infusion of 16/18-GPC induced PPARα-dependent expression of the fatty acid metabolism genes acyl CoA oxidase and carnitine palmitoyl transferase.