期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：1
页码：131-136
DOI：10.1073/pnas.0135855100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 {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 LPA1, LPA2, or LPA3 receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPAx 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.
