IDENTIFICATION OF THE PHYSIOLOGICALLY RELEVANT ENDOGENOUS LIGAND FOR PPAR?

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PPAR¿ is a nuclear receptor activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPAR¿-dependent gene expression is impaired in mice with tissue-specific inactivation of fatty acid synthase (FAS, which synthesizes palmitate, 16:0), suggesting that FAS is involved in generation of the PPAR¿ cellular ligand. Here we demonstrate the FAS-dependent presence of a specific phospholipid bound to wild type PPAR¿ isolated from the nuclear fraction of mouse liver. FAS-dependent binding of the same Molecular species was also demonstrated for DNA binding-defective (DBD) PPAR¿. Phospholipid binding to wild type as well as DBD PPAR¿ was increased under conditions that induce FAS activity and displaced within minutes by systemic injection of a PPAR¿ agonist.