Identification of an intracellular receptor for lysophosphatidic acid (LPA):: LPA is a transcellular PPARγ agonist
Identification of an intracellular receptor for lysophosphatidic acid (LPA):: LPA is a transcellular PPARγ agonist
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DOI：
10.1073/pnas.0135855100
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发表时间：
2003-01-07
影响因子：
11.1
通讯作者：
Prestwich, GD
中科院分区：
文献类型：
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作者：
McIntyre, TM;Pontsler, AV;Prestwich, GD
溶血磷脂酸（LPA）是一种多能性脂质介质，通过质膜相关的LPA（x）受体起作用，其作用包括许多，但不是全部。我们确定过氧化物酶体增殖物激活受体γ（PPARgamma）作为LPA的细胞内受体。转录因子PPARgamma被几种脂质配体激活，但来自生理信号通路的激动剂是未知的。我们发现，LPA，而不是其前体磷脂酸，取代药物罗格列酮从PPARgamma的配体结合口袋。LPA和新的LPA类似物，我们刺激的PPAR-responsive元件报告和内源性PPARgamma控制的基因CD 36的表达，并诱导单核细胞脂质积累从氧化低密度脂蛋白通过CD 36清道夫受体。合成的LPA类似物是有效的PPARgamma激动剂，但对于LPA（1）、LPA（2）或LPA（3）受体转染的细胞是差的。在缺乏核激素和LPAx受体的酵母中的转染研究表明，LPA直接激活PPARgamma。血清的主要生长因子是由凝血酶活化的血小板产生的LPA，并且来自活化的血小板的培养基刺激转染的RAW 264.7巨噬细胞中的PPARgamma功能。这种功能受到抑制的异位LPA-酰基转移酶的表达。LPA是一种生理性PPARgamma配体，将PPARgamma置于信号传导途径中，PPARgamma是第一种针对LPA鉴定的细胞内受体。此外，由刺激的血浆血小板产生的LPA激活有核细胞中的PPARgamma。
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 LPAx 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.