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肝脏中过氧化物酶体增殖物激活受体α（PPARα）的生理相关内源性配体的鉴定。

Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.

作者信息

Chakravarthy Manu V, Lodhi Irfan J, Yin Li, Malapaka Raghu R V, Xu H Eric, Turk John, Semenkovich Clay F

机构信息

Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

出版信息

Cell. 2009 Aug 7;138(3):476-88. doi: 10.1016/j.cell.2009.05.036. Epub 2009 Jul 30.

DOI:10.1016/j.cell.2009.05.036
PMID:19646743
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2725194/
Abstract

The nuclear receptor PPARalpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARalpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARalpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARalpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPARalpha agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPARalpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPARalpha ligand-binding domain and coactivator peptide motifs was comparable to PPARalpha agonists, but interactions with PPARdelta were weak and none were detected with PPARgamma. Portal vein infusion of 16:0/18:1-GPC induced PPARalpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPARalpha ligand.

摘要

核受体PPARα可被用于治疗人类脂质代谢紊乱的药物激活。其内源性配体尚不清楚。脂肪酸合酶（FAS）失活会损害PPARα依赖的基因表达，这表明FAS参与了PPARα配体的生成。在此，我们证明了从小鼠肝脏分离出的与PPARα结合的磷脂的存在依赖于FAS。在诱导FAS活性的条件下，结合增加，并被全身性注射PPARα激动剂所取代。质谱鉴定该物质为1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱（16:0/18:1-GPC）。敲低磷脂酰胆碱合成所需的Cept1可抑制PPARα依赖的基因表达。16:0/18:1-GPC与PPARα配体结合域和共激活肽基序的相互作用与PPARα激动剂相当，但与PPARδ的相互作用较弱，与PPARγ未检测到相互作用。门静脉输注16:0/18:1-GPC可诱导PPARα依赖的基因表达并减少肝脏脂肪变性。这些数据表明16:0/18:1-GPC是一种生理相关的内源性PPARα配体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/2fda1c4c43ad/nihms121333f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/6050a4934ff7/nihms121333f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/5231c597ad55/nihms121333f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/650c1370ef5d/nihms121333f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/8d2b3a434a3e/nihms121333f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/261e67d17a58/nihms121333f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/da42665dad6f/nihms121333f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/2fda1c4c43ad/nihms121333f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/6050a4934ff7/nihms121333f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/5231c597ad55/nihms121333f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/650c1370ef5d/nihms121333f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/8d2b3a434a3e/nihms121333f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/261e67d17a58/nihms121333f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/da42665dad6f/nihms121333f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85c6/2725194/2fda1c4c43ad/nihms121333f7.jpg

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