Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR[gamma] agonist

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Publisher: National Academy of Sciences
Document Type: Abstract
Length: 212 words

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Abstract :

Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated [LPA.sub.x] receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) as an intracellular receptor for LPA. The transcription factor PPAR[gamma], 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 PPAR[gamma]. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPAR[gamma]-controlled gene CD36, and induced monocyte lipid accumulation from oxidized low-density lipoprotein via the CD36 scavenger receptor. The synthetic LPA analogs were effective PPAR[gamma], agonists, but were poor ones for [LPA.sub.1], [LPA.sub.2], or [LPA.sub.3] receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and [LPA.sub.x] receptors, show that LPA directly activates PPAR[gamma]. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPAR[gamma] function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPAR[gamma] ligand, placing PPAR[gamma] in a signaling pathway, and PPAR[gamma] is the first intracellular receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPAR[gamma], in nucleated cells.

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Gale Document Number: GALE|A97060867