{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:22:39Z","timestamp":1791332559489,"version":"4.3.1"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,1,7]]},"abstract":"<jats:p>\n                    Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated LPA\n                    <jats:sub>x<\/jats:sub>\n                    receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) as an intracellular receptor for LPA. The transcription factor PPAR\u03b3 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\u03b3. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPAR\u03b3-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\u03b3 agonists, but were poor ones for LPA\n                    <jats:sub>1<\/jats:sub>\n                    , LPA\n                    <jats:sub>2<\/jats:sub>\n                    , or LPA\n                    <jats:sub>3<\/jats:sub>\n                    receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPA\n                    <jats:sub>x<\/jats:sub>\n                    receptors, show that LPA directly activates PPAR\u03b3. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPAR\u03b3 function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPAR\u03b3 ligand, placing PPAR\u03b3 in a signaling pathway, and PPAR\u03b3 is the first intracellular receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPAR\u03b3 in nucleated cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0135855100","type":"journal-article","created":{"date-parts":[[2003,1,7]],"date-time":"2003-01-07T12:22:42Z","timestamp":1041942162000},"page":"131-136","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":476,"title":["Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPAR\u03b3 agonist"],"prefix":"10.1073","volume":"100","author":[{"given":"Thomas M.","family":"McIntyre","sequence":"first","affiliation":[{"name":"Program in Human Molecular Biology and Genetics, and Departments of Medicine and Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112-5330; Center for Cell Signaling, 420 Wakara Way, University of Utah, Salt Lake City, UT 84108; and Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron V.","family":"Pontsler","sequence":"additional","affiliation":[{"name":"Program in Human Molecular Biology and Genetics, and Departments of Medicine and Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112-5330; Center for Cell Signaling, 420 Wakara Way, University of Utah, Salt Lake City, UT 84108; and Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana R.","family":"Silva","sequence":"additional","affiliation":[{"name":"Program in Human Molecular Biology and Genetics, and Departments of Medicine and Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112-5330; Center for Cell Signaling, 420 Wakara Way, University of Utah, Salt Lake City, UT 84108; and Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"St. Hilaire","sequence":"additional","affiliation":[{"name":"Program in Human Molecular Biology and Genetics, and Departments of Medicine and Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112-5330; Center for Cell Signaling, 420 Wakara Way, University of Utah, Salt Lake City, UT 84108; 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