Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist

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Abstract
Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated LPAx receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated receptor γ (PPARγ) as an intracellular receptor for LPA. The transcription factor PPARγ is activated by several lipid ligands, but agonists derived from physiologic signaling pathways are unknown. We show that LPA, but not its precursor phosphatidic acid, displaces the drug rosiglitazone from the ligand-binding pocket of PPARγ. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPARγ-controlled gene CD36, and induced monocyte lipid accumulation from oxidized low-density lipoprotein via the CD36 scavenger receptor. The synthetic LPA analogs were effective PPARγ agonists, but were poor ones for LPA1, LPA2, or LPA3 receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPAx receptors, show that LPA directly activates PPARγ. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPARγ function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPARγ ligand, placing PPARγ in a signaling pathway, and PPARγ is the first intracellular receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPARγ in nucleated cells.