title: Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist.
abstract: Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated LPA(x) receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated receptor gamma (PPARgamma) as an intracellular receptor for LPA. The transcription factor PPARgamma 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 PPARgamma. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPARgamma-controlled gene CD36, and induced monocyte lipid accumulation from oxidized low-density lipoprotein via the CD36 scavenger receptor. The synthetic LPA analogs were effective PPARgamma agonists, but were poor ones for LPA(1), LPA(2), or LPA(3) receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPA(x) receptors, show that LPA directly activates PPARgamma. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPARgamma function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPARgamma ligand, placing PPARgamma in a signaling pathway, and PPARgamma is the first intracellular receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPARgamma in nucleated cells.
authors.affiliation: Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City 84112-5330, USA. tom.mcintyre@hmbg.utah.edu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: Aaron V
authors.initials: AV
authors.lastname: Pontsler
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Silva
authors.forename: Andy
authors.initials: A
authors.lastname: St  Hilaire
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Jerald C
authors.initials: JC
authors.lastname: Hinshaw
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hama
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D017930:Genes, Reporter; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists*; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D011994:Recombinant Proteins; D014157:Transcription Factors; D001616:beta-Galactosidase